Homing in on Targeted Treatment Strategies in Breast Cancer

Neelima Denduluri, MD

The fields of early-stage hormone receptor (HR)—positive and metastatic HER2-positive breast cancer have made great strides in recent years, said Neelima Denduluri, MD, and such progress could be attributed to the emergence of tailored treatment strategies and the use of HER2-directed agents, respectively.

“We’re making great headway in [the treatment of patients with] breast cancer. We need to tailor therapy in early [HR-positive, HER2-negative] breast cancer by using genomic assays because one size doesn't fit all. Some patients do well with endocrine therapy alone and some need chemotherapy in addition to endocrine therapy,” said Denduluri. “In metastatic HER2-positive breast cancer, we have a slew of new HER2-targeted agents, including but not limited to [fam-]trastuzumab deruxtecan (Enhertu), tucatinib, and margetuximab. These agents are really enhancing how we can treat patients.”

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Breast Cancer, Denduluri, associate chair of Breast Medical Oncology and medical oncologist at Virginia Cancer Specialists, of The US Oncology Network, shed light on the use of genomic assays in early-stage HR-positive/HER2-negative breast cancer, as well as the agents that are prolonging survival in patients with metastatic HER2-positive disease.

OncLive: How are you approaching treatment in patients with early-stage HR-positive, HER2-negative breast cancer?

Denduluri: Essentially the most common subtype of breast cancer in the early-stage setting is HR-positive, HER2-negative breast cancer. In order to treat that subtype of breast cancer adequately, we always offer surgery and sometimes radiation. We’re finding that systemically, this subtype of breast cancer can be divided into more molecular subtypes. We know that many patients can be treated safely with surgery and radiation; these patients may not need systemic therapy beyond endocrine therapy. Endocrine therapy targets estrogen and progesterone. However, other subtypes of breast cancer within estrogen receptor (ER)—positive, HER2-negative disease require additional therapeutic modalities, including chemotherapy.

Most patients with early-stage, node-negative, HR-positive, HER2-negative breast cancer do not need chemotherapy. However, we have genomic assays that show that if the tumor falls in the high-risk category, a significant benefit [can be achieved] with the addition of chemotherapy to endocrine therapy [in these patients]. We always want to mitigate the toxicities of chemotherapy. However, we know that the benefit of chemotherapy outweighs the risks in certain populations.

We now have genomic assays that we rely on; they are [part of our] standard of care and help us to decide in which group of patients we can safely give endocrine therapy alone to and who we need to escalate treatment in. With these genomic assays, we send the tumor sample to a lab to obtain the patient’s recurrence risk. Patients with a higher risk of recurrence need more than endocrine therapy alone. Patients whose tumors have a low biological risk will probably do OK with endocrine therapy alone.

Could you discuss the use of genomic assays in practice?

The most commonly used genomic assays in early breast cancer are the 21-gene recurrence score (Oncotype DX) or the 70-gene signature test (MammaPrint). The 21-gene recurrence score data have shown us from very large trials, such as TAILORx, that woman with low-risk node-negative, HR-positive HER2-negative disease may safely avoid chemotherapy. We’re also finding that [these data] aren’t necessarily limited to women. We can translate these data to men with breast cancer [as well]. Additionally, we know that patients with low-risk, node-positive disease have a good prognosis as well. We're increasingly able to identify patients in whom we can de-escalate therapy and not give chemotherapy to. [By doing this, we can also] potentially spare these patients the toxicity [associated with chemotherapy].

We also know that we really need to use clinical risk in conjunction with genomic risk. As some say, “doctors can't stop being doctors,” and we can't solely [ base our treatment decisions on] a number. While [we can base treatment decisions on risk in] the vast majority of patients, [we can’t do that for everyone]. For example, for patients who fall in the middle—particularly those under 50 years who may not have [gone through] menopause—we know that we need to escalate therapy, whether it’s with a second modality of endocrine therapy or chemotherapy. Those are all [the ways in which] these genomic assays [can] help us.

A second tool we use is the 70-gene signature, which was validated in the large MINDACT trial. From that trial, we learned that patients with low-risk signatures do quite well with endocrine therapy alone. Patients who are low-risk, according to their 70-gene signature, and high risk, according to their clinical risk, or vice versa may not derive a significant benefit from chemotherapy. However, patients who have a high clinical and genomic risk have a very high risk of recurrence; these patients need chemotherapy.

Additionally, these genomic assays [offer insight into] how we should be designing clinical trials. Patients who have high-risk genomics despite endocrine therapy and chemotherapy still have a substantial risk of recurrence. Should we enroll those patients in clinical trials in which we're applying additional modalities of therapy, such as CDK4/6 inhibitors?

Could you discuss some of the key studies that were presented at the 2019 San Antonio Breast Cancer Symposium?

We saw a lot of exciting data in the metastatic setting. Now we know that metastatic HER2-positive disease is a chronic disease. While we have not achieved a “home run,” we've certainly made great strides [in this space]. Up to 40% of patients are alive at 8 years, which was unheard of a decade ago. Now, we have novel targeted therapies available. For example, trastuzumab deruxtecan was just approved by the FDA; that drug confers significant benefit in patients with heavily pretreated metastatic HER2-positive disease, but we have to watch for toxicities like interstitial lung disease. The waterfall plots, the response rates, and progression-free survival (PFS) provide data we have not yet seen in metastatic HER2-positive breast cancer.

About 50% of patients [with HER2-positive disease] develop brain metastases in the metastatic setting, and that has truly been an unmet need. Agents like neratinib (Nerlynx) confer some benefit [in these patients]. However, it was very nice to see the HER2CLIMB data, which showed a significant overall survival (OS) benefit [with tucatinib] in those with [asymptomatic and progressive] brain metastases. Additionally, the toxicity of tucatinib seems to be very tolerable. While there is some rash [observed with this agent], it's not significant to the [point] of [some of the] other oral TKIs that we use in the clinic. Additionally, other toxicities, such as diarrhea, are also very tolerable.

Is there anything else that you would like to emphasize?

In [metastatic] ER-positive, HER2-negative breast cancer, we should not start chemotherapy up front, unless there is a true visceral crisis. Nearly all patients [with metastatic ER-positive, HER2-negative disease] should be offered a CDK4/6 inhibitor with endocrine therapy up front; the regimen has a better toxicity profile compared with traditional chemotherapy, and it also improves PFS and OS.

Additionally, surgical de-escalation is happening. We’re realizing that the extent of surgery, like systemic therapy, mirrors the biology of the disease. Additionally, radiation therapy is being tailored [to individual patients]. Accelerated partial breast irradiation and hypofractionated radiation therapy trials are examining new ways to deliver radiation therapy. Those trials are all exciting and really mirror the importance of tailoring local therapy [to individual patients], as we do with systemic therapy.