 [human epidermal growth factor receptor 2]–positive breast cancer relapse, that’s most frequently going to be detected by the medical oncologist who’s following that patient longitudinally from the time of diagnosis through their neoadjuvant or postneoadjuvant therapy. The medical oncologist is most likely going to pick up signs, symptoms, laboratory abnormalities, and imaging findings that suggest metastasis. At that point, it’s necessary to get a biopsy to confirm distant metastasis because you don’t want to mistake an inflammatory condition that might be benign, or even some other malignancy that has metastasized from a different organ.

Someone can have a history of breast cancer but then have a new metastatic colon cancer. So it’s necessary to get a biopsy of the first suspected metastasis to confirm that it’s breast cancer and then to repeat the biomarker work on the metastasis. This is because biomarkers can be inconsistent between the primary tumor and the metastatic tumor. These biomarkers are used to inform what treatment is best in metastatic 

+ breast cancer. It’s important to get the biopsy, to confirm that it’s not only breast cancer but that it remains 

+ and whether it expresses steroid receptors. All those are still important.

Finally, we rely on the radiologist also at that juncture, in addition to the pathologist, to catalog the extent of metastatic spread. We’re often using multiple imaging techniques like CT scans, bone scans, sometimes CT/PET [positron emission tomography], which is whole body. We rely on echocardiography in 

+ disease to make sure the baseline cardiac ejection fraction is suitable to entertain the possibility of HER2-targeted therapy. If patients have signs or symptoms of neurological dysfunction that could suggest central nervous system metastasis, then we’ll get an MRI imaging of the brain. Often, that involves consultation with the neuro-oncologist if there are breast cancer brain metastasis at that point. The neuro-oncology team consists of neurosurgeons, as well as radiotherapists, who might be doing, for example, stereotactic radiation or sometimes even whole-brain radiation for 

+ breast cancer brain metastasis. Of course, now we have therapeutic drugs that work in the brain as well, so the medical oncologist would supervise that type of treatment.

It’s often an integration of all those approaches for the modern treatment of HER2+ brain metastasis. The HER2+ metastatic landscape is very complex. There are a number of treatment options, and you need to know the biomarker perspective, as well as just the staging information—does it involve visceral disease, non-visceral CNS [central nervous system], and so forth—to come up with the best possible treatment plan for a metastatic patient.

 If a woman presents with metastatic disease, she may have de novo metastatic disease because with first-line therapy for 

+ metastatic breast cancer, more than 50% of those patients will fall into the category of de novometastatic disease, so she’ll have a primary breast cancer. She’ll often have regional nodal disease involved. Then you get your imaging studies—a PET/CT scan or CT scans, a bone scan—and she’s found to have what appears to be metastatic disease. You’ve gotten a biopsy of the primary breast cancer to ascertain what subtype it is, but then you have to biopsy a metastatic lesion to be sure that it’s metastatic disease. Second, you have to confirm it’s breast cancer; it could be a different primary cancer. Then you have to understand the subtype. HER2 testing still remains tricky.

About 20% of the time, when patients are enrolled on clinical trials for metastatic 

+ breast cancer, the HER2 results from a variety of community hospitals don’t match up with the central pathology review of the HER2. It’s generally in favor of overcalling: about 15%, 20% of the time it’s called 

+, but it’s not. It’s more of a borderline equivocal or

+. It’s very important to get the diagnosis right. Over the years I’ve figured out which ones I’m not 100% certain of. Even if it may say positive, I’m not 100% certain looking at it. I just err on the side of sending it though a central reference laboratory because if I treat the patient with the HER2-directed therapy and they’re not 

+, they’re not going to have an optimal outcome basically. So diagnosis is very critical.

Staging is very critical, whether a brain MRI is controversial, but I usually will get it at diagnosis. Basically, we have to see what’s going on with the patient at that time or her level of pain or other discomfort. We have to evaluate the problems she’s having that we may need to address. She may present with brain metastasis. She may have issues with an antecedent cardiac history. You have to involve a cardiologist and get an echocardiogram before you can start HER2-directed therapy. That’s another part of the multidisciplinary team.

Onco-cardiology is very important. We need to get all that squared away. Then the medical oncologist and the patient sit down and talk about the systemic treatment options because we want to get started with that. We may, however, get around to being able to do locoregional therapy for the patient. Many patients with 

+ disease who are de novo metastatic are going to do well for many years. We tend to be proactive about management of their primary breast cancer and regional lymph nodes. We’ll get the patients sooner than later to the breast surgeon and to the radiation oncologist, so they can see the patient from the beginning. This is so they can start to talk to her about potential surgical and radiation approaches.

Once the patient starts anti-HER2 directed therapy in the metastatic state, we obviously get echocardiograms every 3 months. Any type of diminution in cardiac functions, we get our cardiology colleagues involved. But oftentimes early on, patients do really well, and then we won’t have to do the imaging that often because we know patients are doing well and they have a serum tumor marker, for example, that’s going down. You don’t have to get that many scans. But sometimes you’re not sure how they’re responding, and you need to reengage your breast surgeons to ascertain what they think about the locoregional disease, and you have to rescan to see if somebody is benefiting. Sometimes you have to rebiopsy to understand what you’re dealing with, to get enough tissue for NGS [next-generation sequencing], etc. Those are the beginnings of the metastatic journey.

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An overview of optimal multidisciplinary care for a patient who presents with HER2+ metastatic breast cancer.

Multidisciplinary Care for a Patient With Metastatic HER2+ Breast Cancer

 A particular challenge is when patients are hospitalized. They oftentimes are at an outside institution, and you may not even know they’re hospitalized for a day or 2. Of course, you can get the medical records, but it may not be the same. You may not get a phone call for a couple of days, so you’re reliant on the family of the patient to let you know, so you can get a hold of the hospital that’s admitted the patient. That’s 1 challenge. When patients have scans and labs done closer to home because they live far away from the cancer center, comparing those with the previous scans can be a challenge. That’s more of a logistical thing—we have to get the most recent CT of the most recent scan to the other radiologist to have an addendum done. But that’s time consuming.

Another challenge is that a lot of times in the metastatic setting, there’s not enough tissue for the metastatic biopsy to test for standard biomarkers, PD-L1, next-generation sequencing, and so forth. There’s a variety of innovative diagnostic assays you can do to try to see what clinical trial opportunities are best for patients. But it’s also logistically complex because you’ll be sending tissue to multiple places. It’s very labor intensive for the clinic and all the personnel in the clinic to deal with that, as well as the pathology department. A lot of it is the amount of various aspects to things.

I didn’t mention wound care. Many of our patients have wound care issues. There are a lot of referrals and tracking those referrals to make sure patients get to the specialist in a timely fashion. Oftentimes, we have to get on the phone to make sure that appointment happens, and they’re not given the 2-month appointment. It’s complex because patients have a lot of needs, such as pain specialists. There aren’t a lot of people in psychiatry, palliative care, pain management, even pulmonary, particularly during the early COVID-19 days. Trying to get into very busy practices is challenging. Our patients have sleep apnea, and they have to get sleep studies. Their quality of life is suffering. Patients get migraine and headaches because we’re disrupting their normal hormonal patterns. We’ve got to get them to a migraine specialist. There are a lot of challenges getting patients to where they need to go in a timely fashion. It’s a lot of complexity. It’s a lot of work for the various people in our practice.

 The main challenge is getting all the data in a timely fashion so that it’s ready for presentation at a tumor board conference. This information comes from so many sources. Oftentimes, patients have been seen in multiple hospitals—maybe not even in your same state—and they could be traveling to your tumor conference to get an opinion, for example. Data acquisition is still a major challenge, and it’s important to try to get that in a timely fashion because patients want all this information as quickly as possible so they can get on with their therapy and treat the cancer as soon as possible. There’s a lot of anxiety to make sure that everything is done in a timely fashion as well as to get the best possible outcomes. That’s 1 major obstacle.

Another obstacle is an issue I mentioned previously: there are some situations where we don’t have good data to inform a particular patient’s treatment decision. In those cases, we rely on clinical judgment. There can be honest disagreement about what the best approach is even among experts. That’s another challenge in the tumor board multidisciplinary conference format, at my institution and every other institution where I’ve participated in tumor boards as a visiting faculty or at institutions where I practiced previously. There could be honest disagreement and debate. It can be very academic about what’s best for a particular patient, and there can be honest disagreement. In those cases, sometimes you need to present multiple options to patients and help them make an informed decision about what they think is best for them.

 I can’t emphasize enough how important the communication is to maintain among different specialists. That can take different forms—it can be done by telephone, by secure email, through the electronic health record. That’s the most important component. The second is the data accessibility. When those 2 pieces are in place, everything usually falls into place.

The challenges that most often occur in the setting where we see patients is that the patient will present with symptoms suggestive of a new finding within the chest. It could be because of a new diagnosis of a cancer or a new diagnosis of another condition, or it could potentially be because of a complication of a therapy that a patient is receiving. The patient may even present and come with a report of an abnormal imaging study that they had had performed at an outside center. The problem is that unless we have the actual images in front of us, we’re not able to give a complete assessment of the patient’s condition. We need to be able to see the images to integrate the imaging findings with the patient symptoms with the clinical history.

That’s the most common issue that we run into when we’re caring for patients. It will delay the assessment, the diagnosis, and the treatment. It’s mitigated by the patient having the information on hand as they present or having it sent before they come, and it’s remedied by simply providing that information after the visit. That’s the biggest challenge we run into, but it’s 1 we can deal with when it does occur.

 I’m sure there are some jurisdictions geographically where it’s difficult to amass the type of expertise that would be necessary for a multidisciplinary tumor board conference in breast cancer. While it’s routine and in an academic environment, in a busy community practice, it may be more challenging to bring all the experts together at the same time and at the same place. That can be a real challenge, especially in rural areas. But with the technology and the ability to do virtual tumor boards, that barrier is getting attention. Among experts in the area of breast cancer with varied expertise, this tumor board approach is becoming far more common. I’ve seen situations in which virtual access can bring everybody together. Previously, because of geography and rural areas, maybe that wasn’t possible, but now it is. It’s gaining a lot more traction, in areas where that were challenged by geography. So things are looking brighter in the future of breast cancer in this regard.

Key opinion leaders highlight the challenges inherent in using multidisciplinary care to manage breast cancer, particularly when a patient is seen at multiple institutions.

Challenges in the Multidisciplinary Management of Breast Cancer

 Having access to patient data is crucial to inform the ability to make the appropriate diagnosis and deliver the most appropriate treatment. So there’s incredibly high value to having access to clinical information, clinical imaging, clinical histories, that enhances the value of the services that can be provided by all specialists. That’s facilitated by access to electronic health records. That’s facilitated when the care is provided within a single health system that uses a uniform electronic health record. That makes it easy because all the information is accessible. Challenges occur when care may be delivered across different health systems, different providers who may use electronic health records that can be accessed across institutions, but often not. Those challenges have to be overcome because those data are essential. There are certainly ways to access data from other health systems and other electronic medical records [EMRs] so that all the information that’s necessary can be brought to bear in the clinical decision-making process. But it’s certainly facilitated when the care can be delivered in a setting where full data are available to all providers who are participating in the care of the patient.

 Multidisciplinary tumor boards are very useful in terms of being able to have multiple disciplines in the room reviewing a patient case and discussing management strategies. These days, there are a lot of ways we can communicate. Most of our emails are encrypted, so you can put multiple people on an email. Among our medical oncology team in the cancer center, we have specialized intranets that are secure and very easy to use. Within our EMR, we have the chart messages, of course. You can put multiple people on those chart messages. Most of our physicians are also on those. Many of our collaborators, however, aren’t part of our EMR. In the hospital too, they’re really critical. In the hospital EMR, which is different from our practice EMR, there’s the opportunity to have notes. Of course, we end up talking and texting a lot too. But within the EMR in the hospital, there can be communication among the various disciplines. But ultimately, it’s getting on the phone a lot. Some doctors I work with a lot, so we were on the phone quite a bit. Some patients have 2 cancers or have a very difficult problem, like leptomeningeal disease. There will be multiple physicians. I didn’t mention the neuro-oncologist, which is another area of expertise that’s critical for our patients with recurrent brain metastasis or leptomeningeal disease. Essentially, you’ll put together a comprehensive email and include all the disciplines who are helping that patient. Thankfully, with the technology today, it isn’t difficult when you take the time to do a comprehensive email or get on the phone.

 The best way is to be in the same conference at the same time and have a head-to-head debate. There are often great debates in tumor board conferences. There are lot of gray areas; randomized controlled trial data don’t apply to every patient. There are still lots of gray areas and lots of debates where there are data-free zones, even in 2021, if we don’t have the sophistication of randomized trial data to make an easy decision on the patient. We have to make judgment calls in many cases. This is where the debate and discussion come in. It can get heated, and everyone is passionate about their work and their knowledge base. They want to get their points across in the best way possible to get the best possible outcome. Sometimes, that brings in a lot of debate and discussion. Sometimes it comes down to the point where you may have to give a balanced discussion of a couple of pathways of treatment to the same patient at some juncture, so you can say, “According to the latest science, we’re equipoised between 2 possible treatments. We’ll present them both to you, and you can help make this decision.” Sometimes, patients weigh in on what sounds the most appealing to them. So the patient’s perspective is also critical in this decision-making process.

Focusing on the value of electronic systems and tumor boards, experts detail how best to communicate across disciplines in the management of breast cancer.

Multidisciplinary Care in BC: How Best to Communicate Patient Information

 The more expertise you can bring to the care of a woman or a man with breast cancer, the better their medical outcome as well as their holistic outcome. Patients appreciate that high-touch situation in the cancer center with multiple individuals looking out for them and talking to them. I forgot our exercise physiologists—we have exercise rooms and free exercise training information. The patient can go around in various places around the cancer center. I remember our patients, we have a center, which is for patient-support access to individual counseling, access to the support groups that may be useful, access to child life information, and so forth.

If the patient can go around the cancer center and go to all these places, if they can get a variety of support, it’s terrific for them. They can get things taken care of sooner rather than later. It can help them tolerate therapy. Patients can’t benefit from therapy unless they can tolerate the therapy and rehab from the therapy. Being able to get comorbidities taken care of, such as diabetes, nutrition, weight loss, and exercise, very substantially helps patients in terms of their quality of life but also for their longevity and remaining recurrence-free. I’m a big believer in that. But if you don’t have expert surgical care, radiation care, and pathology care, patients aren’t going to get the right diagnosis. They’re not going to get the right treatments. It’s critical to have a high level of expertise in many disciplines.

 It’s critical to have expertise from a variety of areas to get the best therapeutic outcome in the modern age. The various interventions for breast cancer are so nuanced based on randomized clinical trials. To keep up to date with all the unfolding information in real time is a challenge. It’s necessary to have specialization in different areas to keep track of all that literature so that you can make the best use of the most recent data sets in making a real time decision for a patient. It’s not infrequent that we’re using data from the latest ASCO [American Society of Clinical Oncology Annual Meeting], or from the latest San Antonio Breast Cancer Symposium, the latest Society of Surgical Oncology meeting, or the latest radiation therapy international conference. It’s typical that we’re using cutting-edge information. The pace of new treatments that have become available in breast cancer is at an all-time high right now. The only way you can keep pace and get the best outcomes with the latest cutting-edge information is to have an interdisciplinary team working on each individual case.

 When care is delivered in a multidisciplinary fashion, the patient receives the benefit of access to exquisite specialty expertise for any issue they may encounter and having all those specialists bring that expertise together for their care. It’s impossible for 1 physician to have exquisite expertise across all the domains that may be relevant for a patient, particularly a patient with complicated cancer history, and particularly a patient with potential complications of cancer therapy. The ability to integrate across multiple disciplines and provide that exquisite level of detailed expertise to a single patient as a result of the communication between physicians elevates the quality of the patient-centered care. It’s ideal if it can be done within a single physical site, where a patient can see multiple specialists in a single visit to an ambulatory setting. Certainly it can be accomplished using visits to more than 1 ambulatory site if necessary, and it can be accomplished using a combination of on-site visits and remote visits guided by televideo visits. There are multiple ways to deliver a multidisciplinary approach, but the benefits are noticed by patients and noticed by providers who care for patients in a multidisciplinary setting.

Shared insight on how nuanced multidisciplinary care can positively impact outcomes when treating a patient with breast cancer.

Difference in Breast Cancer Outcomes With Multidisciplinary Care

 Breast cancer is a very complex disease. As you know, there are multiple subtypes, and most of those subtypes have subtypes within them. Indeed, it’s been said that breast cancer is like snowflakes: there are probably no 2 cases that are identical in terms of actual mutational profiles of an individual’s tumors. So it’s a very complex situation. Consequently, it’s necessary to engage multiple disciplines in medical sciences to diagnose and treat breast cancer definitively. To do that, in my opinion, it’s required to have experts from a range of medical disciplines to make the correct diagnosis, establish prognosis, and direct the appropriate therapies. For example, a patient who’s having routine annual mammographic screening relies on the mammography unit and also the radiologist, who’s interpreting the mammographic images to make the right calls and doing callbacks in case additional views need to be taken. Sometimes, ultrasonography needs to be done to adequately stage breast cancers, and MRI can be necessary for this disease as well. That’s a whole discipline unto itself of breast imaging that has experts that focus only on that issue.

Next, you might need to do a biopsy, so that’s going to involve the pathologist. And the pathology is critical to establishing the correct diagnosis to do all the special stains, to get a look at all the biomarkers in breast cancer, the steroid receptor status, as well as the HER2 [human epidermal growth factor receptor 2] status. Consider the fact, for example, when you’re looking at a HER2 copy number using fluorescence in situ hybridization [FISH] techniques, the current ASCO [American Society of Clinical Oncology]–CAP [College of American Pathologists] guidelines recognize 6 patterns of FISH staining in breast cancer. It’s become so nuanced that you need a dedicated breast pathologist to make interpretations about the histopathologic subtype, and to make all the interpretations necessary for all the biomarkers that inform your therapeutic decisions. All of that is extremely critical.

The surgeons do the lion’s share of the work in terms of treating cancers. They surgically can remove the tumor on block with clear margins, and that’s probably the most impactful treatment used. But it’s a very complex situation because breast cancer presents in different stages. Some are even unresectable at the time of diagnosis if they present in a locally advanced or stage III disease. It’s a whole discipline of breast surgical oncology unto itself, and it requires extra training and special expertise to become a breast surgeon.

After the surgery, all that material goes back to the pathologist to get the correct staging. Additional images may be required if the lymph nodes are positive or if they have other high-risk features, and you need to do, let’s say, CT scan imaging, PET [positron emission tomography]/CT, or CT and bone scan imaging to look for distant metastatic sites. Then the medical oncologists weigh in on integrating all this information from surgery regarding stage and all the pathologic information, the biomarker information. The medical oncologist integrates all that data and comes up with a systemic therapy recommendation on the basis of the best-available science, and all the historical literature from randomized controlled trials that direct our modern approach to therapy of early stage breast cancer. The radiation therapist also weighs in, especially for patients who have lumpectomy as opposed to mastectomy.

Although they received postlumpectomy radiation, there are multiple techniques in breast radiation. It’s not a 1-size-fits-all discipline anymore at all. There can be localized ways of giving radiation therapy—intraoperative radiation, for example—and there could be different durations of radiation therapy. That’s a very nuanced and specialized area, also with a lot of ongoing research. In addition to all these individuals, it’s not infrequent that we find genetic predisposition to breast cancer. For example, a 

, or any number of other cancers predisposing genetic alterations that can be inherited. We’re often in consultation with geneticists to discuss those alterations, some of which may inform treatment for breast cancer—for 

 mutations, for example. Some of these mutations require screening for other types of cancer. You may be interested in screening for pancreatic cancer, for example, in a patient with a 

Then you’ve triaged the rest of their family, who might be carrying an alteration and might require a high-risk screening program or even prophylactic surgery. That’s another discipline that’s integrated into the mix. Finally, this is such a complex and difficult series of medical interventions that patients go through. It can be very stressful and emotional, so we often call on our colleagues who have expertise in psychosocial support as well to support our patients. At a typical tumor board, we’ll have representatives from all these disciplines in a group in the same session, and we review all the data firsthand and get the entire relevant patient history. Then I come up with a treatment plan that’s informed by all these disciplines in an interdisciplinary fashion. It’s a consensus treatment algorithm that the group decides would be highly tailored to that patient’s case.

You can have 2 patients in the waiting room with the same-size tumors and the same number of lymph nodes, and they may get completely different treatment recommendations. That’s how different breast cancers become compared with the old days where staging was the main criteria for deciding on treatment algorithms. Now it’s much more about biology of cancer and genetics of cancer, not just the anatomical stage that makes these difficult decisions. It’s really a group effort, and everyone has equal weight in these decisions. Ultimately, we’ll present that entire group’s recommendation to the patient for their consideration and help educate the patient about the contributions that each team member has made to their overall treatment plan.

 Pulmonology and critical care will have roles at different times for patients with different diagnoses. The cancer that we see very frequently is lung cancer, and we have a role in all different stages of the patient’s journey if they have lung cancer. We have a role in prevention of lung cancer, and that usually focuses on identifying risk factors for lung cancer. Most commonly that’s smoking and helping our patients stop smoking. Then our role also is important in terms of early detection. There are screening modalities that are effective for early identification of lung cancer—mainly, chest CT screening for high-risk individuals.

We play a significant role in helping our patients navigate the pathway to have a lung cancer screening and to then determine if there are abnormal findings and whether those abnormal findings relate to a cancer. If so, we’ll have a role in staging that cancer and in guiding the patients to the most appropriate treatment based on the specific diagnosis of lung cancer they may have and their staging. During the course of their disease and their disease treatment, there may be symptoms that develop related to their treatment or related to the tumor progression over time if that occurs. Then we’ll have a role, typically through interventional pulmonology subspecialists, for the diagnosis that may be related to those symptoms and treatments that may help patients have symptom relief.

That’s the story for lung cancer. For other cancers, such as breast cancer, our place in the journey will likely be different. For patients who have breast cancer and a prior history of lung disease, prior to beginning systemic therapy that may be associated with a risk of lung disease, the pulmonologist will often have an important role in characterizing the underlying lung disease, determining its severity, and working with the oncologist and with the patient to determine what might be the most appropriate systemic treatments for the patient given the potential risk of treatments for furthering lung disease or causing new lung disease.

For patients who receive treatments for breast cancer, there can be complications associated with the treatments, including interstitial lung disease. When patients have new symptoms or new abnormal findings on their chest imaging, a pulmonologist often will have a role in working with the oncologist and the patient to determine what might be the cause of the new symptoms or findings, determine if they may be related to the study drug, and work with the oncologist and the patient to determine the best approach toward treating those new symptoms and new findings. That will depend on the drug. It will depend on the setting and the abnormal findings.

Finally, also in the breast cancer sphere, patients have systemic disease, so there may be involvement of the lung, with metastases to the lung that can cause symptoms. We’ll have a role in helping to determine whether the findings on the chest imaging from the breast cancer can be treated with a variety of tools we have available—for example, tools to drain fluid that may accumulate in the lungs and tools to address metastases that may occur in the lungs. We have multiple roles at multiple times in patients’ journeys that occur in multiple different cancers. In all these scenarios, the key is the continuity of communication between the patient, the providers on the pulmonary specialty and the oncologist specialty, and any other specialties involved.

Comprehensive details on how multidisciplinary care is applied during a patient’s treatment journey, with a focus on pulmonology and critical care.

Managing Breast Cancer: Collaboration Throughout the Treatment Journey

 A true foundation of care for patients in the ambulatory setting involves patient-centered care, and that’s often multidisciplinary. That is the fundamental tenet that lies behind the structure of our respiratory institute, and it’s crucial for cancer care across different cancer types. For patients to have the most appropriate diagnosis, staging, and treatment for their cancers, it often requires cooperation between multiple physicians of multiple specialties—oncologists, pulmonologists, infectious disease specialists, internists, and surgeons. When all these specialties work together, the patients get the best patient-centered care that’s appropriate for their disease.

 The number of disciplines that help patients with breast cancer is a long list of people, from that initial diagnosis through treatment of early-stage disease and unfortunately sometimes into treatment of metastatic disease. There are a vast number of disciplines involved. From a broader view, we start with the radiologist, who is critically important. Oftentimes, we have to back up and say that primary care physician would be the 1 who reminds them and puts the order in for breast imaging. We do mammogram, the MRI, and an ultrasound. So we have the primary care physician involved as well as the radiologist.

The pathologist is also critically important. If cancer is diagnosed, then we have the nurse navigator who often helps, and then the breast surgeon. Oftentimes, there’s a breast nurse practitioner physician assistant as well, but there’s a lot of education for the patient. Then there’s the plastic reconstruction surgeon, who’s also involved. The radiation oncologist gets involved early on, as does the medical oncologist. The genetic experts are also critical. Sometimes, there’s an outside pathologist. You have to go to expert pathology groups outside your own institution if there are equivocal results. Then we have our expert oncology nurses and our oncology pharmacist, who are critically important too, helping us access medications, making sure doses and schedules are correct—drug-drug interactions, administration of therapy, and so forth. Sometimes, we have to get a reproductive endocrinologist involved because of fertility issues in young women, who need to do egg harvesting and embryo preservation.

We then will go on during treatment. That depends on what toxicity has come up, so we often have to mobilize several of our collaborators and colleagues—a dermatologist, a hepatology specialist, a pulmonologist. We also get our colleagues who are experts in scalp cooling. Our experts in reimbursement are critical as well for a lot of these therapies, including scalp cooling. Women usually in the curative saying will have surgery radiation therapy. We have our rehabilitation experts. We have our physical therapists, who are expert in preventing and managing lymphedema, rehabbing shoulders, and rehabbing people after therapy. We have nutritionists and dietitians. We have physicians who are expert in bariatric medicine—I think obesity medicine is the new name as a board certification. That’s very important as well.

We have to involve endocrinologist frequently because of diabetes. That’s quite common during treatment and after treatment. We have to involve a gynecologist because women sometimes have to have oophorectomy. It’s not uncommon for women to have oophorectomy. Unfortunately, some patients go on to develop metastatic disease. So we involve our interventional radiologist to get access to metastatic lesions and get enough tissue to be able to evaluate the standard biomarkers. But also, now we’re collaborating with experts in molecular medicine—a molecular pathologist, who’s doing a deep dive into the genome to find what mutations exists, such as 

If it’s triple-negative disease, we involve our geneticists if they haven’t already been involved to look for germline 

. We have an expert pathology review of the tissue. The medical oncologist is very involved at that time, but it depends on what has come up. If patients suffer from arthralgias and myalgias, we may involve a rheumatologist or an immunologist. We need a pulmonologist, our GI [gastrointestinal] doctors, our hepatologist, our infectious disease specialist, and our hematologist too. Sometimes patients will have a pancytopenia, and we need our hematologist involved. It really depends on which toxicity has come up as well.

We need our palliative care specialist because of the management of variety of adverse effects is sometimes more difficult than a medical oncologist can provide. We have our own nurse practitioners and physician assistants who do a lot of education. We have specialized nurse practitioners who discuss end-of-life choices that patients may have during education. In that regard, our oncology nurses are invaluable—our oncology infusion nurses, our pharmacist. This is because metastatic disease involves a lot of complex medications for drug-drug interactions. We eventually involve our hospice colleagues toward the end of life as well.

That’s a broad overview. There are a lot of practitioners who we call upon. What I didn’t mention was involving psychiatry and psychology, which is a lot of counseling and social work. This is very important with various aspects—economic, socioeconomic, family dynamics, and so forth—for patients going through breast cancer. Also, we have expert financial counselors to counsel the patients. But we also have experts at accessing treatments for patients. That’s a real expertise these days, regarding patient-access programs for therapies but also foundation around the country, that can help people with co-pay assistance. There’s a lot of expertise that’s necessary to optimize patient care.

Experts reflect on the importance of multidisciplinary care and outline the many disciplines involved in diagnosing and treating breast cancer.

Managing Breast Cancer: Who’s Involved in Multidisciplinary Care?

Adam, say a few words for us about what therapeutic approaches you’re most excited about from an investigational standpoint that might take us into the future.

There are lots of things that people are doing now. They’re doing the usual of combining immune checkpoint inhibitors with PARP inhibitors. Someone on this call did review that—it may have been Kevin—about the CGAS pathway that’s activated by PARP inhibitors in immune cells and antigen-presenting cells, that may be involved in tumor immunity. You’re boosting them by relieving the suppression with a checkpoint inhibitor. It was a really nice theory behind it. A number of different checkpoint inhibitors are being used. Sacituzumab is used in earlier lines of therapy with or without checkpoint inhibitors.

Even trastuzumab deruxtecan is being used in the triple negative space. That’s not even thinking about all the other immune approaches that are in very early trials in the phase 1, phase 2 setting, bispecific antibodies trying to join various points of the immune system. People are trying to figure this out. The overall theme is that triple-negative breast cancer is an inflammatory disease. It’s the inflammatory or immune response that you really have to modulate or that is being modulated and being suppressed somehow as you get to later lines. How do we activate that? We call it making cold tumors, hot or whatever that is. That’s the other thing.

Of course, we haven’t even talk about all the AKT inhibitors. It turns out 10% to 15%, or more or less depending on whom you listen to, of triple-negative breast cancers have a mutation to the AKTp 10 and 4 pathway. Then there’s the whole PI3 kinase pathway. There’s this whole area there that could be exploited and is—capivasertib and ipatasertib are being used. A lot of things out there are exciting. The whole thing with sacituzumab and everything just jazzed everybody up about this field. At least it jazzed me up. When Suzette Delaloge or that group in France redoes this real-world analysis 4 or 5 years from now, we’re going to see some survival benefit in triple-negative breast cancer because of it.

Beautiful. Thank you so much. I’m going to give everybody a chance to go around. Let’s go around the Zoom here—give just 1 final thought. Anything you’d like to highlight from our discussion from triple-negative breast cancer, early stage or metastatic, from ESMO [European Society for Medical Oncology]? Let me start with Kevin. Do you have any last words?

 Yeah, as we’ve discussed, sacituzumab govitecan was really a huge story out of ESMO. As we’ve discussed, there is this story in terms of checkpoint inhibition in the metastatic, operable setting. That story evolves and continues. The other thing, in terms of future directions to think about, is what’s going to be the role of circulating markers in the operable setting like cell-free DNA. As prognostic and predictive, we think about some of these super-interesting agents in the metastatic setting, which may translate to the operable setting. Will that help us define risk and response better?

Thank you. That will be a brave new world, I must say. Sara Tolaney, how about you?

 First, I’ll echo Kevin’s comment that a lot of our discussion stemmed around at the beginning: Who needs preoperative immunotherapy? While we all hand wave and think about risk, I think we need a biomarker. I do hope we can learn to be able to tailor therapy for our patients better than we are. We need to improve outcomes, lessen the toxicity, make sure we’re not giving patients drugs that aren’t helping them.

I do hope we’ll learn more. I know there is a lot being invested to be able to discover potential predictors. Hopefully we’ll be able to get there. In terms of exciting combinations, there are just so many exciting things, which is very promising. Taking the sacituzumab story, a lot of us are really interested to better understand if ADCs [antibody-drug conjugates] work better with immunotherapy. Could it be a way for us to get those tumors that aren’t traditionally responding to immunotherapy to respond? For example, could you take a PD-L1–negative tumor and get it to respond to immunotherapy if it’s used to maybe a better backbone? An ADC could get us there. There is a lot of work being done to potentially allow immunotherapy to work in these colder tumors. We’ll see more to come.

Thank you. Such great thoughts, you guys. It’s really super. Sara Hurvitz, how about you?

 At the risk of being redundant, I will echo what my colleagues have said: Biomarkers are the key because triple-negative breast cancer is classified by what it is not. It’s clearly very old school, and we need to define subsets. Biomarkers are going to be the key. Not only genomics but proteomics are going to be very helpful in defining targets we can go after.

The second thing I would like to say is that with the Delaloge data that we’ve all been referencing, the rates of de novometastatic breast cancer are very high for 

-positive and hormone receptor–positive breast cancer. It’s underscoring how we are getting really good and sophisticated at how to treat in the curative setting. We need to get there for triple negative, so that the majority of the triple negative we’re seeing in the metastatic setting is de novo and not recurrent. That will move the survival forward.

Thank you. None of us can retire until we get there. We have to see that one too. Adam, you have the last word, with something you’d like to note from the top of your mind.

I’ll echo everything you say. We have a lot of new directions. As I think about this disease, in particular triple-negative disease, 1 of the things I’m going to try to do—because we have some pretty strong, hard-core, basic immunologists at my institution—is try to get them interested in this as a model system. They are at some of our other institutions. For the hard-core basic immunologist, the answer may rest in the tumor. But because the immune response has so much to do with the host that maybe there are biomarkers in the host that will tell us which way to go. I’ve started to interact with them. They do these 15-dimensional flow-cell sorting of immune cell subsets of the peripheral blood and single-cell RNA sequencing of these subsets after they flow them.

Maybe there’s something in there. It’s incredibly complicated stuff. It’s way over me, but it seems as if that may be where some of these answers may lie. It will also be in the tumor, it will be in circulating DNA, but the markers are there. I agree with everybody. We need markers for who is going to benefit from this. Because when you benefit, you do really well, and I think that’s fine. I’ll leave it at that.

Super. Thank you, guys. It’s so exciting talking to you. I am really struck by the energy people have to continue to push up that hill. It’s really apparent that you guys are asking the next questions. It’s really gratifying. Thank you for a wonderful conversation. Thank you to everyone who participated. I hope you found this really useful. Nice update on ESMO, with a lot of new data. We hope to be back after San Antonio Breast Cancer Symposium with another discussion. Thank you very much for participating.

Future Directions for Treatment of TNBC

Let’s spend a little time on toxicities in terms of hints for us all about how we manage toxicities. What do we have to lookout for, and how do we manage them? Sara Tolaney, could you say a few words about that?

 Sacituzumab is given on days 1 and 8 of a 21-day cycle. What we’ve seen is that the most frequent toxicity is really neutropenia. About 60% of patients do end up getting grade 3 or 4 neutropenia. Because of this, we did see in the ASCENT trial that almost 50% of people ended up using growth factor support. I very commonly will add on growth factor support when giving it. If they come in and their neutrophil counts are a little low, then I realize that they can’t really tolerate treatment at this dose unless they get a growth factor. I definitely introduce that early with any signs of neutropenia.

The other adverse effect to keep in mind is diarrhea, although I will say it is mostly low-grade diarrhea. The rate of grade 3/4 diarrhea is very low, and it was about 10% in the ASCENT trial. Most of my patients have intermittent loose stool, so maybe every once in a while they may need to take loperamide. I counsel them on that when starting the sacituzumab, but it’s not that they need prophylactic loperamide or anything like that for the majority of our patients. I also let people know that they will lose their hair. All my patients generally do lose their hair. Obviously, at this point in time many patients are going to go into it without hair if it’s in the later-line setting. For those with hair, it’s important to let them know.

I also generally premedicate patients, so on the day of treatment I usually give a Zofran and a Decadron prior to treatment. I have use Zofran at home as needed if they want. Some people will use something like Aloxi instead of Zofran, but either way, generally that’s what’s used. I don’t really have much trouble though with nausea. Honestly, most of my patients actually do pretty well with it outside the neutropenia and intermittent loose stool and fatigue. Those are the major things that we deal with.

It was interesting to think about. One of the reasons sacituzumab had a big impact in survival—those curves are very impressive: They really pull apart immediately and quite strongly continuing to pull apart; it’s an amazing set of curves—is that it really is possible to continue the therapy. It is something that we don’t usually have to stop. You don’t get into treatment limiting toxicity. I want to get Adam’s take on this because you and your practice have are very good stewards of resources. As Sara just said, about half the patients in ASCENT who are on sacituzumab end up getting growth factors.

On the 1 hand, you say, if they’re not having diarrhea or other toxicities and they just can’t get their day 8 on time, maybe we should just do a dose or 2 of filgrastim to make sure that they can get their day 8. The survival advantage started with the 10 mg/kg, so maybe we want to get the initial cycles and keep it up there. On the other hand, I forget what percentage of patients did require dose reduction, but there are of course always are patients who require dose reduction, yet you still see this very nice survival advantage in spite of the fact that some patients got a dose reduction. I have been going down to 7.5 mg/kg in patients who can’t get their day 8 and I want them to. I don’t want them to be missing day 8, so I’ve been going down.

On the other hand, 50% did get growth factors in this. That’s where we saw the survival. I know we don’t really know the answer about whether we just dose reduce without growth factors, because a lot of our guidelines suggest that unless there is definite, known impact on dose intensity in the metastatic setting, the dose reduction should be considered. What’s your take on that, Adam?

You just mentioned it, Joyce. Twenty-two percent of the patients had a dose reduction in the sacituzumab govitecan arm, so we have no idea what their PFS [progression-free survival] and OS [overall survival] were. That needs to be presented. The problem is that the company was bought by Gilead Sciences, Inc, and who knows what their priorities are going to be, but that data will probably need to be presented somewhere. That’s the first thing. The second thing is that 50% did require growth factors. Normally in a non-OS setting, we would try to avoid them, but maybe we need to rethink that.

Traditionally, the approach for my colleagues here and me has always been single palliative chemotherapy. You reduce the dose, and you don’t use growth factors, but I think I’m changing that. I’ve found as we do more of this, we’re using more growth factors. Initially we didn’t in a clinical trial. I use a little more dose reduction, but I’m starting to use growth factors more with this.

I must say, this is a remarkably non-cross-resistant agent. I’ve had a number of patients who really were quite primary refractory from the get-go and very symptomatic who have had responses. It does make me want to think more about what you just said about this has a survival impact here. At least in the beginning, I have to really try to keep the dose intensity up for these patients. I’m going to really rethink that.

I want to also mention the bystander effect about sacituzumab. Even if some cells don’t have Trop-2, maybe the expression is a little heterogeneous, when the SN-38 is cleaved—it’s a cleavable linker; it’s such a high concentration of the SN-38 on the antibody—you get diffusion to the other cells, and it can kill the cells even though they don’t have Trop-2. This really nice bystander effect probably helps play a role in the effectiveness of this agent. It’s a remarkable drug, and we’re going to see a lot of it in other cancers and it will be moved up into the curative setting very quickly.

Phase 3 ASCENT Trial in mTNBC: Managing Adverse Events

Let’s turn to the very important new data that came out of ESMO [European Society for Medical Oncology Congress], because we have a new survival impact for our metastatic triple negatives. Adam, you were an investigator in a sense, can you tell us about that?

 Well, we were all on the paper. The bottom line is that it’s uncommon in our business to actually have in the third line a disease that really was refractory to a lot of stuff in survival benefit. And this is pretty cool. I’ll go quickly because there’s a lot we want to talk about. The bottom line is ASCENT was 529 patients. Sacituzumab is a monoclonal antibody to the Trop-2 antigen, and it has a cleavable linker to SN-38. That is an irinotecan derivative, which is a Trop-1 inhibitor. It was 529 patients who were randomized 1:1 to sacituzumab, day 1 and 8 of every 21-day cycle vs physician’s treatment of choice. I think it was eribulin, capecitabine, or gemcitabine, and then there were some other ones, but the bottom line is it was physician’s choice of therapy.

Just to give you the top-line data, the prior anticancer regimens was a median of 4. I think that did include adjuvant therapy. They were the typical ones we thought of, but it was 4. They had at least 2 lines in the metastatic setting, probably 2 to 3 lines. There were some patients who had up to 17 lines, which is surprising. But the bottom line is the progression-free survival went from 1.7, and that’s really important. That 1.7 number is now the baseline. It’s the standard of care that we can use now when we start evaluating other agents in the third-line setting in triple-negative disease.

Everybody is progressing. It’s 1.7 from the time you get the next scan. But it was increased to 5.6, and that’s gratifying because that pretty much was what we saw in the phase 2 trial, so it replicated that. But the most important part of this was the overall survival benefit, which went from 6.7 months to 12.1 months. It had a hazard ratio of 0.5 in a previously intractable disease. There were better response rates, and the overall response was 82% vs 11% with the physician’s standard of care, which is what we all expect.

I don’t know if we’re supposed to talk about the adverse events that are predominantly hematologic and diarrhea. I think we will talk about that in a bit. But the bottom line is that the hazard ratio…went in favor of sacituzumab. This is pretty good data. It is pretty solid, and it really represents a standard of care. There is a reason that Gilead Sciences, Inc bought Immunomedics for $21 billion.

 That’s a good point. There you go. That speaks volumes.

 Obviously this is going to be expanded to the ER [estrogen receptor]–positive setting. I think we are all probably investigators on a TROPICS trial. But the bottom line is this: How often do we see this? It’s pretty dramatic. I wonder what the holes are in this study.

 I don’t know. Sara, are there any holes? I guess we’ve got accelerated approval, is that right? What do you think will happen going forward, and how do you incorporate sacituzumab? We’ve had it under accelerated approval. What do you think overall about this?

 I think it’s really exciting. The accelerated approval and Adiyta Bardia’s data were really quite nice. We saw the 35% or so objective response rate in heavily pretreated triple-negative breast cancer. We were so wanting some sort of positive data with a therapy like this in heavily pretreated triple-negative disease that we all leaped to use it without randomized data. I didn’t dream these data were going to be this good, and I was really excited when we saw that it was not just PFS [progression-free survival] but OS [overall survival]. But I do want to call out how horribly patients do with single-agent chemotherapy in the control arm. What we see in practice underscores how bad the outcome is in the second-, third-, fourth-, and fifth-line setting for triple-negative disease.

It’s great for patients. I’m incorporating it now in the third line setting and have been since the approval. I am tempted to use it in the second-line setting in the patient, especially for someone whose tumor is not PD-L1 positive or who has had a fast relapse. I’m trying to move it up a little, but this is an area where we’re going to see it move up, and we’re going to see different combination strategies as well. It highlights how important clinical trials are in this setting and in patients who are heavily pretreated.

 Thank you so much. Kevin, can you tell us a little more about kind of what sacituzumab is? Why was it so dramatically not cross resistant in this heavily pretreated population?

 Sacituzumab govitecan targets Trop-2, which is expressed on epithelial cells. Going back to the point that Adam made, we’re seeing benefits with this drug. Not just in triple-negative breast cancer, hormone receptor positive, 

 negative—those data have been published—but in urothelial cancer, lung cancer, etc. It’s a protein that can be broadly expressed. It’s linked with a stable linker to SN-38, the topoisomerase inhibitor. To the question that you had posed, in terms of cross-resistance, 1 of the things is that the payload is a different class of antineoplastic agents compared with taxanes, anthracyclines, etc. This subsequently has different toxicity profiles as well.

That’s part of why we’re seeing this nice activity a little later on. Just to reiterate 1 of the points that was previously raised, we’ve been in circumstances in which we’ve seen great data in phase 2 studies that unfortunately don’t always translate into phase 3 trials. The phase 2 data were published, and we’re also seeing a great response rate. We see this exact same response rate of about a third in this phase 3 trial. So it was nice to see these data in a randomized setting.

Phase 3 ASCENT Trial in mTNBC

 Before we go on to the new survival data with sacituzumab govitecan that came out of ESMO [European Society for Medical Oncology Congress], which I do want to spend some time on, let’s stop here for a second and summarize.

Let’s go around, so each of us can summarize how you in general approach the first- and second-line treatment in the very heterogeneous group of patients who are triple-negative breast cancer. Because we certainly have de novo, we have pretreated, we have rapidly recurring, we’ve got PD-L1 positive, we’ve got germline, 

, and we take a little bit of a different approach. It’s a tricky question. Kevin, let me start with you. How do you sequence these in the first- and second-line setting?

 I check PD-L1 status. If somebody is in that 40% or so range of having a PD-L1 positive tumor, I’ll give them a checkpoint inhibitor alone with chemotherapy. Even, for instance—I know we just spent some time talking about 

 mutations and the potential for PARP inhibitors—if I had a patient who was a germline 

 mutation carrier and had a PD-L1–positive tumor. I would tend to, outside a clinical trial, use the checkpoint inhibitor first because we can see some durability of response.

Although we can see some really nice responses with PARP inhibitors, the durability is not quite the same. Especially for those patients with checkpoint inhibitors who have long-term responses. There is some question in ongoing studies about combining those 2 agents, so we’ll see some of those data in the future. But I do think that in the absence of having a 

 mutation, this is somewhat dependent upon what they’ve received before: their time, their comorbidities, etc. The ASCENT data that we’re about to talk about were really important.

We keep talking about this disease-free interval that’s less than 12 months. If I had a patient who had an early relapse and then went on to get a checkpoint inhibitor, for instance, I would think about using sacituzumab govitecan in the second line. In the ASCENT trial, in patients who received therapy in the operable setting and reoccurred early, that did count as a line. I know we’ll spend some time talking about those data, but that’s generally how I tend to approach that in the first and second lines.

 Thank you. How about Adam? How do you approach first and second line?

 Like everybody else. Single-agent chemotherapy and sequential therapy still remain the standard of care: taxane, palbociclib, capecitabine, carboplatin-gemcitabine, whatever you use. That remains the standard, to be honest with you. If you’re 1 of those 40% of patients who are SP142 positive, it’s going to be CPS [combined positive score] of 10, probably at some point with pembrolizumab as well. They’ll get the checkpoint inhibitor plus probably a taxane, and a taxane will depend on which checkpoint inhibitor you use.

Second-line therapy at this point will almost always be single-agent chemotherapy, except for those scenarios in which you relapse pretty quickly, as Kevin said. In my case, that will be probably be eribulin. In the third line, as we’re about to talk about, everybody is going to use sacituzumab—at least in my practice, as many who can get it. Because most of us were on the paper as investigators, we know what the data showed. But the thing, that really is going to be pretty dramatic. That’s how I’m going to do it. We’re going to mix in other things as time goes on. But for me, that’s going to be the treatment approach.

 I agree with what they both said. The only additional point I want to make is that in patients who have both a 

 mutation and PD-L1 expression in the tumor, I would sequence first with the atezolizumab nab-paclitaxel. Given data that consistently show that a patient has the best chance of responding with frontline therapy, their immune system is more intact. That makes sense even if their disease-free interval was relatively short. I would still consider using something like pembrolizumab and gemcitabine-carboplatin as opposed to doing frontline PARP inhibitor because I want to get that immunotherapy in earlier.

 Thank you. Thanks for that key point. Sara, anything you’d like to add? Any other points on this?

 No, everyone did it really well. It’s just very critical to make sure we do get PD-L1 testing in our triple-negative patients, so you know in that first-line setting. As Sarah had mentioned, it seems that immunotherapy doesn’t work well outside the first line. We have very limited data in combination with chemotherapy outside the first line. But from the largest data sets, it seems it’s best up front. So I agree, getting PD-L1 status up front is critical to help make that first branching point. I also tend to use PARP after immunotherapy, even in my germline 

 carriers, because I worry about exposing them to immunotherapy later and not seeing that benefit. But we know PARP still has PFS [progression-free survival] benefit even in the later-line settings.

 I’ll add 1 thing. I’m really intrigued by KEYNOTE-119. We couldn’t really talk about it that much, but what Javier Cortés presented at San Antonio Breast Cancer Symposium last year that the CPS 20 patients—those uncommon patients in KEYNOTE-119—actually responded to single-agent pembrolizumab. I’m not sure what to make of it.

 Yeah, the higher the PD-L1 staining in KEYNOTE-119, the better the benefit. The more patients benefited more durably. That’s clearly a very powerful strategy for patients, so always checking it right from the beginning of the first line metastatic is key. Let’s not forget to test all of our triple negatives for germline 

. Or you can get NGS [next-generation sequencing]. If you get a somatic mutation, then go ahead and do germline to see if it’s in the germline. We have those PARP inhibitors for patients as well.

Sequencing Therapies for mTNBC

Let’s spend a little bit of time with a summary of where we are for patients with germline 

 mutations in the metastatic setting. Sara, could you give us a summary of where we are on that?

: We’ve all been excited to see the data that have emerged with PARP inhibitors for our patients with germline 

mutations. We have 2 phase 3 trials, OlympiAD as well as EMBRACA. OlympiAD had compared olaparib to standard-of-care physician’s choice chemotherapy, whereas EMBRACA had compared talazoparib in very similar design to choice of chemotherapy. Both trials did not allow platinum in the control arm and also did not allow patients who had progressed on prior platinum. Both studies very nicely demonstrated a statistically significant improvement in progression-free survival [PFS], both of them around a delta of about 3 months between the 2 arms favoring the PARP inhibitor over chemotherapy.

There were also nice analyses showing better quality of life in the PARP inhibitor arm compared to chemotherapy. We were all hoping to see larger differences, potentially, in terms of PFS, and also we were hoping to see a survival benefit, but neither study has demonstrated a statistically significant improvement in overall survival. There was this hint in the first-line subgroup analysis of OlympiAD that there was a trend toward better survival with olaparib compared to chemotherapy. That’s a subgroup analysis, and the overall studies did not show a survival benefit. Now, obviously it’s challenging because people do cross over.

In EMBRACA, about half the people on the chemotherapy arm crossed over to getting PARP, and some people go on to get platinum. It does make survival challenging to demonstrate. There are studies that are ongoing trying to look at adding agents to PARP to see if we can do better. We’ll certainly learn more as time goes on. It also sounds like we’re getting some new intriguing data that PARP inhibitors may also work outside of just germline 

patients. Nadine Tung, MD, had presented some data at ASCO [the American Society of Clinical Oncology annual meeting] that has shown that in patients who have somatic 

 mutation, so the mutation in the tumor rather than a germline mutation, had about a 50% response rate. So very similar to the response rates that we see in the germline 

Obviously this is a small group of patients. Some have reported maybe around 2% or 3% of our patients have somatic 

. Then there were also really impressive data in germline 

 suggesting that olaparib had about an 80% response. This is a tiny trial that had 11 patients, and I think 9 out of 11 patients had a partial response and the other 2 had stable disease. That’s a pretty big home run to have that level of activity. They are expanding that trial to get larger numbers of patients in the somatic 

 subgroups. We’ll get better numbers, but I think definitely there’s a hint that PARP inhibitors can have activity in those 2 groups as well.

Thank you. That was very exciting. Yes, we’ve enlarged the group of patients, I think, that can benefit. I think that was practice changing. Let’s look for those somatic 

mutations on our NGS [next-generation sequencing]. If you find germline 

, let’s use the Nadine Tung data to get preauthorization for a PARP inhibitor. I thought that was really practice changing. Thanks a lot, Sara.

Standard of Care for BRCA+ mTNBC

 How about you, Sara? What do you do with all the data at hand right now in your practice? What’s your approach to testing for PD-L1?

: Right now, we are testing with SP142 on that Ventana platform. Really, because as Sara Hurvitz very nicely reviewed that analysis that Hope Rugo, MD, had done, suggesting that the SP142 antibody was really the best predictor of benefit to atezolizumab. Given that, we did feel like we even had to validate the platform at Dana-Farber Cancer Institute in order to do that, because for the other diseases, our pathologists have been using a different antibody. We had to just do this for breast cancer, but they made it happen because of the strong data there are to support using it as a predictor for atezolizumab benefit. As Kevin alluded to, we are waiting to see if pembrolizumab is going to be approved based on KEYNOTE-355.

Obviously, as we discussed, that does utilize a different antibody with 22C3. We have had some discussions with our pathologists about what the impact of that would be at our institution. Are we going to start testing with one antibody vs the other, or both? They told us they will not test for both, and that we really have to make up our minds and pick one. I do think we are going to have to make a decision here because it’s hard to do all of these tests, and there is some discordance, even in Hope’s very good presentation. If you looked at the CPS [combined positive score] 10 subgroup and SP142-1, there was still some discordance, even though the CPS 10 did seem to have the most overlap compared to CPS 1 or 22C3 with 1. There was still some discordance. You could have one assay be positive and the other one negative.

This is why this field is so confusing. We’ll probably end up continuing with the SP142 since that’s what our institution has now figured out how to do. Then the question is going to be what do you pick? Are you going to pick using taxane with pembrolizumab vs nab-paclitaxel with atezolizumab? Are you going to use carboplatin-gemcitabine? It’s probably going to depend on the patient. The nice thing about KEYNOTE-355 is it did include patients who had early relapse. We don’t have that yet, we’ll eventually get that from IMpassion132, but we don’t have those data yet.

We’re stuck with a taxane backbone with atezolizumab, and I think that’s not what we want to give to someone who relapsed soon after adjuvant taxane, and we don’t yet have data for that. I probably would use carboplatin-gemcitabine-pembrolizumab in an early relapsed patient. That being said, if you look at the subgroup analyses in KEYNOTE-355, they didn’t quite do as well as the taxane group. We all have to be cautious because obviously the carboplatin-gemcitabine arm is more weighted with early relapsed patients who are bad performers compared to the taxane arm. That study is not powered to compare the chemotherapy. We cannot use it to say one is a better backbone than the other. It does make us wonder, obviously, how good is carboplatin-gemcitabine-pembrolizumab in an early relapsed patient? How much benefit are we really seeing in that specific subgroup?

Because we do see them, unfortunately, not infrequently. In that group I probably will use pembrolizumab. I will also throw my hands up in the air about IMpassion131. One thing I will point out, and I was totally surprised, I really thought it was definitely going to be true that paclitaxel-atezolizumab would be the same as nab-paclitaxel-atezolizumab. It is interesting if you look at the study design, the number of patients in the control arm who are PD-L1 positive is very small. That control arm is performing much better in terms of survival than the IMpassion130 control arm. It does make you wonder why is that? Is there some difference in the patient populations?

I think Kevin was alluding to that. Technically it’s the same number of patients who had had prior taxane exposure, but we don’t know the nuances of that. How long ago was that prior taxane? Was it different in the 2 studies? The number of de novo patients is also smaller in IMpassion131. There are some very subtle differences. We don’t know the differences in PD-L1 testing on primary vs metastatic, and there are some very small differences that potentially could pan out here. I agree I didn’t really think steroids were going to make a difference because we saw in the early disease setting it probably doesn’t matter. This is a different setting, it’s a metastatic population where the immune microenvironment isn’t as good.

It sounds like most people do continue their steroids through the whole time they’re on chemotherapy for most patients in IMpassion131. They were getting it for quite a long time, not just for a couple of doses, so maybe it had a little impact. I honestly don’t know what the right answer is.

: Can I make one comment before you go on?

: The steroid issue was an interesting one because if you look at the adverse events of special interest, there were less in IMpassion130.

: I agree. Maybe it’s just mismatching. I think it’s still the most likely explanation.It’s likely that PD-1 low positivity, it’s a patient selection issue, maybe a random patient selection. But I’m still looking at that steroids and looking at the fewer adverse events of special interest.

 Yes, that’s an interesting point there. It sounds like’s in summary, we’ve got 2 trials now with now with nab-paclitaxel and atezolizumab—the IMpassion130 with a survival advantage, that’s firm, and then the IMpassion031 in the preoperative setting that has a very nice delta on pathologic complete response. Atezolizumab is really doing well with nab-paclitaxel, that ought to be the standard of care for our patients who we’re going to give a taxane to, correct me if I’m wrong. There are some patients where the taxane may not make sense for a variety of reasons. Then we do have the gemcitabine, carboplatin, and pembrolizumab. It’s not FDA approved yet, but it’s not an unreasonable choice for patients where taxane is not the best choice for them.

Then we do have the pembrolizumab approval as well for tumor mutational burden high. I don’t know if that’s actually approved, but the MSI [microsatellite instability] high is approved. We have data in metastatic breast cancer that’s tumor mutational burden high, where pembrolizumab can have a positive impact as a single agent. There are some durable responses in those patients, and then MSI high. We don’t find those very often when we do next-generation sequencing, but we will find them occasionally. We do have the opportunity to use pembrolizumab for those patients.

We will stay tuned as some of the data mature, like KEYNOTE-355 on survival, and as we see other trials that we’ll talk about a little bit later to try to improve upon the impact with the immune therapy in the metastatic setting. Thank you guys so much for that summary. I think that brings us right up to date about where we are.

Testing for PD-L1 Expression in mTNBC

I want to come back and get everybody’s take on this. But let’s bring in KEYNOTE-355 before we have a larger conversation. Sarah Hurvitz, could you mention KEYNOTE-355? We saw those data at ASCO [the American Society of Clinical Oncology annual meeting], and could you talk a little bit about testing, like is any assay okay for PD-L1?

: The 355 clinical trial was also in the first-line setting, as Adam indicated. It had a little different disease free interval that was allowed. Patients could go on if their disease free interval was at least six months on this trial from treatment in the adjuvant setting, as opposed to IMpassion130 where it was 12 months. And they allowed treatment of physician’s choice based chemotherapy, so either nab-paclitaxel, plain paclitaxel, or gemcitabine-carboplatin. And interestingly, but not surprisingly, about 55 % of patients chose to use gemcitabine-carboplatin, which omits the need to lose one’s hair. They didn’t report how many got straight paclitaxel versus nab-paclitaxel, when I looked through the slides.

Maybe somebody else knows what the percentage was, but at any rate, patients received either the placebo or pembrolizumab, and they determined essentially the triple negative status as well as PD-L1 status. They used this thing called the CPS [combined positive score], which is a combined score looking at the number of PD-L1 positive tumor cells, lymphocytes, and macrophages divided by the number of tumor cells. Then they based their outcomes on this. When they looked at the progression-free survival [PFS], it was a hierarchical statistical design. First they looked at the PFS for CPS of 10 or greater, and the hazard ratio was 0.65, and it met their statistical significance. The median PFS was 9.7 months for pembrolizumab vs 5.6 months.

This was a nice 4-month, almost, improved median PFS. Then they go to the second step, which is looking at the median PFS in patients with a CPS of at least 1. Now, although there’s about a 2-month improvement in PFS, the hazard ratio isn’t as good, it’s 0.74. And while the 

value was .0014, it didn’t meet the predefined level of significance. They weren’t allowed to statistically look at the next question, which is the overall intent-to-treat population. They looked at it numerically. There was about a 2-month improvement in median PFS, but they wouldn’t give a significance value because they hadn’t met that step before. We see that there is this benefit with pembrolizumab. We don’t know if it’s dependent on which chemotherapy you choose. That wasn’t didn’t appear to be a factor. Some patients did get paclitaxel, and the benefit seems to be in the patients who are CPS 10 or greater.

Then the question is how do we test our patients and decide what therapy to give them? We’ve got the SP142 assay for PD-L1 in the tumor immune cells if we’re going to choose atezolizumab. Do we use the CPS score with the 22C3? This is just mind blowing. If you’re a general medical oncologist, how does one keep up with this? Well, Hope Rugo, MD, actually did a nice analysis and presented at ESMO [the European Society for Medical Oncology Congress] in 2019, looking at the different assays. And actually the SP142 antibody for PD-L1 expression, if you’re positive for SP142, then the other assays are likely to be positive, but the opposite can’t be said true.

If you’re looking just at the IMpassion130 data, and the analysis she did was somewhere around 600 patients where tumors were looked at by these 3 different antibodies: SP142, 22C3, and the SP263. She showed that the PFS was most strongly associated with the SP142, so it was most associated with benefit from atezolizumab. We don’t know that for other immune checkpoint inhibitors. This field is rapidly evolving and rapidly becoming quite confusing, in my opinion. We are going to continue to need to do tissue analyses to better understand how we need to test to identify patients who will benefit.

Thank you. That’s fabulous, great state-of-the-art summary, honestly. I want to ask Kevin and Sara Tolaney, given all the data we’ve just heard beautifully summarized, where are we right now in practice? We’ve got survival with IMpassion130, final survival data. Albeit, the intent-to-treat population was not positive for survival in IMpassion130, but the PD-L1 subset was. Negative, atezolizumab and paclitaxel, positive progression-free survival, but not yet survival. We don’t have the data yet for KEYNOTE-355, so we have a gemcitabine-carboplatin opportunity there for patients. How do you use this in practice? I’m also curious how you guys test in your institutions. Do you have multiple antibodies, do you tend to use 1 antibody? Let me start with Kevin.

: A lot of really great questions in there. As Sara Hurvitz had mentioned, the antibodies are not all the same. There are different pre-analytic and analytic considerations between the antibodies. To me, the specific biomarker associates with that specific agent. For SP142, that’s the predictor that I utilize for determination of whether to use atezolizumab. As Adam said, I also think we’re all a bit surprised, disappointed, and baffled by the results of IMpassion131. At this very moment, the approval really just is for atezolizumab in patients with PD-L1 positive tumors, but later in the year we’ll see whether this expands to pembrolizumab based upon KEYNOTE-355.

One of the distinguishing features, as was already mentioned, was the 12 vs 6 months and gives the flexibility of a different chemotherapy regimen. At the end of the day, to go back to one of the things that Adam had said, I wish I had a great explanation of why there is this difference between the 2 IMpassion trials. There has been some hand-waving, could it be the difference of the 2:1 randomization, and a smaller study, and then steroids for Taxol? But ultimately, as Sara Hurvitz previously mentioned, in the neoadjuvant setting patients got Taxol and they received steroids. We saw that that was a positive study, so I think that there is still much to learn.

I wonder, in terms of the differences between those 2 studies, whether there is just, by chance, a difference in terms of the biology of the tumors in those patients who were enrolled. There seems to be this subset of patients who are really driving a lot of the benefit. Is it possible that there were more immunomodulatory tumors in IMpassion130 compared to IMpassion131? Is there a difference in terms of the ratio of the subset of patients who are really long-term benefiting with those patients with durable responses? I don’t think we quite know a great explanation for the data that we have right now.

It sounds like in your practice, the atezolizumab, nab-paclitaxel is the standard of care for the SP142. Is that what you guys use, Kevin?

: Yes, that’s exactly right. For those patients who don’t have a recurrence within 12 months of their operable therapy, it’s to use SP142 and to use nab-paclitaxel along with atezolizumab, with the consideration of neuropathy and things that would concern me about using a taxane.

Would do ever consider the gemcitabine-carboplatin and pembrolizumab for people who recur more quickly or something, or who decline alopecia-induced chemotherapy?

: If this becomes an approved regimen, for sure. That’s one of the benefits of that study, the lower period from time to reoccurrence, as well as giving drugs that have different mechanisms of action, and patients may not have developed chemotherapy resistance.

KEYNOTE-355 Trial in mTNBC

Let’s transition to metastatic breast cancer because in triple negative there were new data that came out at ESMO [the European Society for Medical Oncology Virtual Congress], some of them very important, potentially practice changing. Let’s turn to Kevin, and he could give us an overview of the general strategies we have in metastatic triple negative breast cancer. Could you discuss overall outcomes and prognosis because we will get into how do we all sequence things in our own practice, but just from a general standpoint, Kevin?

: Sure. I think that if there is 1 subtype of breast cancer for which we really need additional therapeutics, it’s this subtype of breast cancer. Thankfully, we have had recent approvals of new drugs. In the frontline setting, for those patients who have PD-L1 positive tumors right now, there is the approval of giving atezolizumab, the PD-L1 inhibitor, in combination with nab-paclitaxel. We’ll talk about other studies that were recently reported with checkpoint inhibition in the metastatic setting. Also, for patients who have germline 

mutations, we have PARP inhibitors that are approved for patients with HER2-negative disease.

Then we’ll also talk about the approval of sacituzumab govitecan, which is an antibody-drug conjugate, targeting Trop-2, that’s linked to SN-38. For a long time, all we really had for these patients were chemotherapies, and now with the advent of a new antibody-drug conjugate as well as PARP inhibitors and checkpoint inhibitors, that’s really changed and is improving the outcomes of some of our patients.

Thank you. There’s been some progress, but unfortunately, median overall survival is still in the 16-month range. In France, Suzette Delaloge, MD, MSc, showed at ESMO this lovely real-world evidence database from across academic centers in France going back to 2008 through 2016/2017, that the median overall survival in metastatic triple negative disease is about 14 months. It hadn’t changed. It is very sad, so we definitely need improvement in this group of patients.

Now, that did not take into account any of the new checkpoint inhibitor data that we’ve seen with atezolizumab, the new approval, of course. That is hopefully going to make an impact. But let’s talk about checkpoint inhibitor therapy in the metastatic setting. Adam, could you update us on what we’ve learned from IMpassion130, IMpassion131, and how do you today use the checkpoint inhibitors in your metastatic practice?

Suzette Delaloge’s real-world analysis is really cool, and it says that we made huge progress in HER2-positive disease. We’re getting there. Actually, those data were accumulated before CDK4, so we’re going to get there with ER positive, and it will look pretty good. I think the stuff we’re going to present and talk about in the next half hour is going to tell us where we’re going to go, at least in the first stage with this, and probably help it. The first one was IMpassion130 that everybody’s familiar with. It was 902 patients with first-line metastatic advanced triple negative breast cancer with a treatment-free interval greater than 12 months.

This is really important, and I think it is the biggest difference between this trial and KEYNOTE-355 that we’re going to talk about. The patients in this trial all got nab-paclitaxel with or without atezolizumab and were treated until progression. The bottom line is that in the overall data, in the initial cut of this data, in survival and in PFS [progression-free survival], there really didn’t seem to be significant differences. They only appeared to occur when you looked at the PD-L1 subtype. You had to have, again by the SP142 assay, you had to be 1%. Basically, this is now the final analysis of these data, looking at it, actually the overall survival, overall as well as in the PD-L1 positive population.

In this trial again, I think the median follow-up was fairly long. There was a small increase in overall survival, in the intent-to-treat population, it was about 21 months with the checkpoint inhibitor vs 18.7 months. It was not statistically significant. The hazard ratio was about 0.87. When you look at the PD-L1 population, the difference was quite substantial. It was 25.4 months, which is pretty much what it had been in the past with some of the other cuts of the data, vs 17.9, about 18 months overall survival in the PD-L1 negative population. That was a hazard ratio of 0.67, which was statistically significant.

It was interesting. It was really the only group across all of the 4 subgroups. You had to have atezolizumab, nanoparticle paclitaxel, and be PD-L1 positive, and basically you had the benefit. The other 3 sub arms of the trial didn’t really. When you look at the hazard ratio for overall survival, the big groups had no prior taxane treatment and people who were PD-L1 positive. This shows us thatthe long-term survival is maintained in the study. That was IMpassion130, and I’m really curious to hear what my colleagues would have thought going into ESMO or before we heard the press release. We had seen the KEYNOTE-355 data with paclitaxel that looked like it was going to work, and we figured it was just like a throwaway trial. They just did paclitaxel and it was going to work, and it would be the same, and we’ll go on and move on.

The surprise, and David Miles, MD, presented this, it was pretty surprising in IMpassion131. The IMpassion131 was also a fairly substantial trial that randomized people to paclitaxel with or without atezolizumab, very similar design. There was really nothing different in this study, and it was basically a dead negative. I looked over these data, I pored over it, as I’m sure we all did, trying to find a subgroup. It was a little smaller. It was a 2:1 randomization for atezolizumab to placebo, but nonetheless there was no difference. The hazard ratio was 0.82. You look at these curves, maybe after 6 months there may have been a tiny separation for atezolizumab, but really not much.

It’s crazy that the forest plot was dead negative. There was little bit of response rate benefit. The overall investigator-assessed response rate in the PD-L1 positive population was 64% vs 55%. But really in the overall survival analysis, it was flat negative and if anything, the hazard ratio trended to touch toward the other group. Although when you really look at the data, the hazard ratio crossed 1, but there was a numerical difference. It was 28 months vs 22 with the paclitaxel. Is it simply play of chance? I don’t know, but there is no separation of these curves whatsoever. That’s the big mystery, and I’m really curious to hear what my colleagues have to say. With atezolizumab at least, we have benefit for survival in the PD-1/PD-L1 population in the first line with nanoparticle paclitaxel. But with non-nano, with standard paclitaxel, we don’t.

Yes, no question. Amazing. I think we were all taken aback, including in the PD-L1 positive population, in the intent to treat as well as PD-L1 positive, no benefit from atezolizumab in combination with regular paclitaxel.

Standard of Care for Metastatic TNBC

Just to finish the early-stage setting, I’m just going to turn us to Sara Tolaney. We definitely have an unmet need. No question. Thankfully, there are a number of hypotheses being looked at. I want to get Sara’s take. What do you think are some of the more promising strategies and some of the clinical trials that are ongoing to get us to the next level of benefit?

 A lot of the trials in the early disease setting are trying to say, “How can we improve outcomes for our highest-risk patients?” For example, the patients who have residual disease. Can we do better, potentially, then capecitabine is doing based on CREATE-X? We have trials that are comparing capecitabine with platinum therapy. That’s being done through the ECOG trial. I think we’ll learn more if there is a difference in outcomes.

There is a study that’s starting called the SASCIA trial, which is going to compare sacituzumab with treatment of choice in patients with residual disease. That’s particularly exciting because I think that sacituzumab seems to work really well in a refractory population. Maybe in this residual disease population that will have significant benefit. Then there are also studies that are looking at immunotherapy in patients with residual disease. This is going to be challenging because those trials are really focused on patients who didn’t get preoperative immunotherapy. We’ll learn if there is a benefit in the adjuvant setting in that population. Obviously this whole paradigm could shift if immunotherapy really does become part of the standard preoperative setting, as well as the adjuvant setting.

Joyce O'Shaughnessy, MD, Baylor-Sammons Cancer Center

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