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Bridging the Gaps in Breast Cancer

Dr Kalinsky on Remaining Treatment Questions in Breast Cancer

Kevin Kalinsky, MD, MS, associate professor, the Department of Hematology and Medical Oncology, Emory University School of Medicine, director, the Glenn Family Breast Center, Breast Medical Oncology, Louisa and Rand Glenn Family Chair in Breast Cancer Research, Winship Cancer Institute of Emory University, discusses key takeaways from 

the 2023 Bridging the Gaps in Breast Cancer meeting

, highlighting questions that continue to persist in the treatment of breast cancer.

The Bridging the Gaps meeting sparked conversations covering a range of concepts, delving into the current landscape of estrogen-driven breast cancers and HER2-positive breast cancers, Kalinsky begins. Discussions touched upon considerations for patients choosing to opt in or out of specific therapies, as well as the progress in developing various novel agents, he states. Notably, the conversation explored the realm of antibody-drug conjugates (ADCs). Although the discussions yielded answers to some questions, it remains evident that as more advances are made across the breast cancer treatment paradigm, the more questions emerge, Kalinsky says.

An observation from the ongoing conversation surrounds the rapid pace of developments and the need to keep pace with the evolving understanding of this landscape, he expands. Despite gaining a clearer comprehension of certain phenomena, the approval of new drugs can introduce distinct resistance mechanisms that shape future therapeutic approaches. Much of the discussions revolved around grappling with these quandaries in patient care, Kalinsky emphasizes, adding that time was dedicated to exploring the development of novel drugs. Over the past few years, a discernible shift has occurred in the approach to treating patients within certain subtypes of breast cancer, such as estrogen-driven, HER2-low, or triple-negative disease, Kalinsky states. A central focus has been on defining the criteria for adjusting treatment paradigms, such as whether the bar for such adjustments relies on achieving an improvement in progression-free survival vs overall survival, he explains.

The intricacies of resistance mechanisms, especially concerning ADCs, have been a focal point of research, Kalinsky continues, adding that discussions touched upon whether resistance stems from the drug's target or its payload. Previous data in genitourinary cancers have suggested that combining ADCs may represent an effective strategy. Although numerous questions remain, the ongoing dialogue is an encouraging sign for patients, Kalinsky concludes.

Kevin Kalinsky, MD, MS, discusses key takeaways from the 2023 Bridging the Gaps in Breast Cancer meeting, highlighting questions that continue to persist in the treatment of breast cancer.


Dr Basho on Treatment Considerations With ADCs in Breast Cancer

Reva K Basho, MD, senior director, the Women's Cancer Program, the Ellison Institute, Providence Specialty Medical Group, discusses the use of antibody-drug conjugates (ADCs) across the spectrum of breast cancer subtypes 

at the 2023 Bridging the Gaps in Breast Cancer meeting

Basho says that oncologists are fortunate to be practicing in a time when numerous ADCs are entering the breast cancer armamentarium and improving patient outcomes. However, with the growing number of available agents, particularly those with similar payloads, it has become important to contemplate the sequencing of these treatments, she states. This becomes especially critical as these agents advance into earlier lines of therapy, encompassing curative and first-line metastatic disease, Basho explains. A key issue that has also arisen is how to navigate the treatment of patients transitioning from ADCs, she notes.

Delving into the underlying mechanisms of resistance is pivotal—whether it occurs at the antibody or payload level—and gaining a nuanced understanding is essential to effectively tailor the selection of agents for individual patients, Basho continues. The applicability of this inquiry extends across the diverse subtypes of breast cancer. Notably, ADCs are now being employed in the metastatic setting for patients with HER2-positive, triple-negative, hormone receptor–positive, and HER2-low disease, rendering this question relevant for a wide spectrum of patients with breast cancer, she emphasizes. Ideally, the implementation of ADCs as a method for chemotherapy delivery holds promise for accessing more potent payloads and adopting a targeted approach through antibody targeting, she says.

In considering the broader landscape, questions about sequencing become pertinent, and this extends to a broad population of patients, Basho expands. Through pan-tumor studies, insights have been gained on understanding how to navigate the complexities of ADC treatments that may potentially benefit a wide array of individuals, Basho concludes.

Reva K Basho, MD, discusses the use of antibody-drug conjugates across the spectrum of breast cancer subtypes at the 2023 Bridging the Gaps in Breast Cancer meeting.


Dr Abdou on Sequencing CDK4/6 Inhibitors in HER2– Metastatic Breast Cancer

Yara Abdou, MD, assistant professor, medicine, Department of Medicine, Division of Oncology, University of North Carolina School of Medicine, discusses findings from the phase 2 MAINTAIN trial (NCT02632045) in patients with HER2-negative metastatic breast cancer, as well as the clinical implications of these trial results.

The MAINTAIN trial evaluated the efficacy of switching endocrine therapy and continuing a CDK4/6 inhibitor in patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer whose disease had progressed on prior endocrine therapy and a CDK4/6 inhibitor. Patients enrolled in the trial switched to treatment with either exemestane [Aromasin] or fulvestrant [Faslodex] depending on which previous endocrine therapy they had received. They were then randomly assigned 1:1 to receive either the CDK4/6 inhibitor ribociclib (Kisqali) or placebo. In total, 86.5% and 11.7% of patients had previously received palbociclib and ribociclib, respectively. Patients who were randomly assigned to the ribociclib arm achieved a median progression-free survival (PFS) of 5.29 months (95% CI, 3.02-8.12) vs 2.76 months (95% CI, 2.66-3.25) in the placebo arm (HR, 0.57; 95% CI, 0.39-0.85; 

The findings from MAINTAIN contrasted those from the phase 2 PACE trial (NCT03147287). In this trial, patients with estrogen receptor–positive, HER2-negative metastatic breast cancer who received palbociclib plus fulvestrant after a prior CDK4/6 inhibitor and endocrine therapy did not experience a significant PFS benefit vs those who received fulvestrant alone. Of those enrolled on the trial, 90% of patients had received prior palbociclib and 4.5%, 4.1%, and 1.4% of patients had received prior ribociclib, abemaciclib (Verzenio), and palbociclib/ribociclib, respectively.

Contrasting findings between MAINTAIN and PACE indicate that switching CDK4/6 inhibitors post-progression may be the most effective treatment approach for patients with HR-positive, HER2-negative metastatic breast cancer who progressed on an initial CDK4/6 inhibitor, Abdou says. Differences between CDK4/6 inhibitors may also contribute to the data discrepancies that favor ribociclib over palbociclib in this setting, Abdou concludes.

Yara Abdou, MD, discusses findings from the phase 2 MAINTAIN trial in patients with HER2-negative metastatic breast cancer, as well as the clinical implications of these trial results.

Dr Jhaveri on Unanswered Questions in Breast Cancer Care

Komal Jhaveri, MD, FACP, section head, Endocrine Therapy Research Program, clinical director, Early Drug Development Service, Patricia and James Cayne Chair for Junior Faculty, Memorial Sloan Kettering Cancer Center, discusses unmet needs for patients with breast cancer, as well as ways to address these needs through discussion and collaboration. Jhaveri was co-chair of the 2023 Bridging the Gaps in Breast Cancer meeting.

Several agents have recently gained FDA approval in the breast cancer space, including novel targeted therapies, such as elacestrant (Orserdu) for patients with 

-positive tumors; PI3K inhibitors; and AKT inhibitors. One novel regimen pending regulatory approval for patients with advanced hormone receptor (HR)–positive breast cancer is the AKT inhibitor capivasertib in combination with the selective estrogen receptor degrader fulvestrant (Faslodex). This combination 

Furthermore, several antibody-drug conjugates (ADCs) are approved for patients with breast cancer. Data from the phase 3 TROPION-Breast01 trial (NCT05104866), which were presented at the 2023 ESMO Congress, also demonstrated the clinical activity of the emerging ADC datopotamab deruxtecan (DS-1062a) in patients with HR-positive, HER2-negative metastatic breast cancer.

Although these new data and novel agents are expanding the breast cancer treatment paradigm, several questions remain regarding their use in clinical practice, Jhaveri says. For instance, the optimal sequencing of therapy for patients with estrogen receptor–positive breast cancer after progression on a CDK4/6 inhibitor is unknown, Jhaveri explains. Furthermore, the presence of 

 mutations may influence these sequencing decisions, and the role of elacestrant vs a PI3K inhibitor in these patient populations is unclear, Jhaveri notes.

Similar questions arise in the management of HER2-positive breast cancer, according to Jhaveri. For example, patients with HER2-positive disease and certain risk factors may benefit from increased doses of immunotherapy or targeted therapy, Jhaveri says.

Overall, the goal of the Bridging the Gaps in Breast Cancer meeting is to facilitate conversations between breast cancer experts regarding controversies arising from current clinical data, Jhaveri emphasizes. Identifying these areas of ongoing debate is the first step toward addressing the needs of patients with breast cancer and improving outcomes in this disease space, Jhaveri concludes.

Editor's Note: Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.

Komal Jhaveri, MD, FACP, discusses unmet needs for patients with breast cancer, as well as ways to address these needs through discussion and collaboration. 

Dr Conlin on Targeting CNS Metastases in the Treatment of Breast Cancer

Alison K. Conlin, MD, medical oncologist, Providence Cancer Institute Franz Clinic, discusses the importance of targeting central nervous system (CNS) metastases in the treatment of patients with breast cancer, highlighting ongoing treatment investigations for this population.

Over the past 5 years, there has been significant progress in the treatment paradigm for patients with HER2-positive breast cancer with CNS metastases, particularly since the phase 2 HER2CLIMB study (NCT02614794) demonstrated the efficacy of tucatinib (Tukysa) in this population, Conlin begins. This efficacy was specifically noted in patients with untreated or progressive disease, he states. Recent data from a pooled analysis of the phase 2 DESTINY-Breast01 (NCT03248492), phase 3 DESTINY-Breast02 (NCT03523585), and phase 3 DESTINY-Breast03 (NCT03529110) trials presented at the 2023 ESMO Congress showed that fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) elicited an ORR of 45.2% in patients with treated or stable CNS metastases and an ORR of 45.5% in those with untreated or active CNS metastases Conlin explains. Although the presentation involved pooled data and lacked a randomized prospective study design, the results were notably impressive, she adds. These findings indicate that there are viable options for effectively controlling untreated CNS disease in patients with HER2-positive breast cancer, expanding the choices available for their treatment, Conlin says.

The evolving understanding of HER2-positive breast cancer with CNS metastases is prompting a reassessment of available treatment strategies, she continues. Notably, insights from the phase 3 KATHERINE study (NCT01772472) have highlighted that although patients with high-risk HER2-positive disease experience improved outcomes with ado-trastuzumab emtansine (Kadcyla; T-DM1) vs trastuzumab, they still experience CNS recurrence rates comparable withthose experienced by patients who receive trastuzumab if they don't achieve a pathologic complete response to T-DM1, Conlin emphasizes. As the oncology field recognizes the CNS as a site where disease recurrences can occur, research focuses are shifting toward exploring preventive measures, she elucidates.

Ongoing National Cancer Institute–sponsored research is investigating the potential of using an oral TKI, such as tucatinib, to prevent CNS disease in patients deemed cured of their breast cancer, Conlin expands. Existing data support the use of neratinib (Nerlynx), another oral TKI,for the prevention of secondary CNS disease, she explains. The phase 2 BRIDGET study (NCT05323955) is actively examining the feasibility of treating isolated CNS recurrence with local therapy and exploring the addition of a TKI to trastuzumab plus pertuzumab or T-DM1 to prevent future CNS metastases or overall disease progression, Conlin adds. This trial’sperspective underscores the evolving view of the CNS as a distinct consideration, not only as a potential separate entity but also as an integral part of overall systemic disease control strategies, she concludes.

Alison K. Conlin, MD, discusses the importance of targeting central nervous system metastases in the treatment of patients with breast cancer, highlighting ongoing treatment investigations for this population.


Dr Mamounas on Surgical De-Escalation Strategies in HER2+ Breast Cancers

Terry P. Mamounas, MD, medical director, Comprehensive Breast Program, University of Florida Health, Health Cancer Center at Orlando Health, discusses surgical de-escalation strategies in the treatment of patients with HER2-positive breast cancer.

The initial focus of surgical de-escalation strategies in this patient population revolved around de-escalating the primary tumor surgery by inducing a robust response to neoadjuvant chemotherapy, potentially shifting patients from needing mastectomy to being eligible for breast-conserving surgery, Mamounas begins. In some ongoing trials, investigators are exploring the possibility of omitting formal surgical resection, though this is not standard practice yet, he states. Notably, prospective trials are addressing this question by using imaging to identify a strong response to neoadjuvant chemotherapy in the breast, Mamounas says, adding that core biopsies of the tumor bed are employed to confirm the absence of residual disease. In cases without residual disease, there is consideration for avoiding surgery, although this is not the current standard, Mamounas expands. A recent study conducted out of The University of Texas MD Anderson Cancer Center demonstrated promising local control rates with this approach, showcasing its potential, especially as systemic therapy advances, he emphasizes.

In more recent years, another approach aims to de-escalate surgery for axillary nodes, Mamounas states. For patients with subclinically or clinically involved axilla, traditional surgical methods often involve more extensive procedures to determine whether lymph node dissection is necessary, he adds. However, by sterilizing the lymph nodes and ensuring residual disease negativity at the time of surgery, surgeons can perform a sentinel lymph node (SLN) biopsy alone, avoiding a comprehensive axillary dissection, Mamounas continues. This minimizes the risk of lymphedema and reduces axillary morbidity. Notably, investigators have improved false negative rates in SLN biopsy by employing techniques such as clipping nodes that were positive before neoadjuvant chemotherapy and removing them with the clip after treatment, he explains.

This approach has lowered SLN biopsy false negative rates to be comparable with those seen when conducting SLN biopsies in upfront settings, Mamounas says. The goal of this strategy is to decrease the morbidity associated with axillary surgery by adopting an equally effective yet less invasive approach, he concludes.

Terry P. Mamounas, MD, discusses surgical de-escalation strategies in the treatment of patients with HER2-positive breast cancer.

Oral selective estrogen receptor degraders (SERDs) in patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer

Dr Bardia on the Continued Investigation of Elacestrant in ER+/HER2– Breast Cancer

Aditya Bardia, MD, MPH, attending physician, medical oncology, Massachusetts General Hospital; associate professor, medicine, Harvard Medical School, discusses the continued investigation of oral selective estrogen receptor degraders (SERDs) in patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer. 

Several ongoing clinical trials are focused on oral SERDs, which can be categorized into 3 groups, Bardia begins. The first category pertains to elacestrant (Orserdu), an FDA-approved agent, he states. 

This oral SERD was approved by the regulatory agency in January of 2023

 for the treatment of postmenopausal women or adult men with ER-positive, HER2-negative, 

-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy. This approval was supported by the phase 3 EMERALD trial (NCT03778931). Furthermore, the phase 1/2 ELEVATE trial (NCT05563220) is investigating elacestrant in combination with other agents, such as PI3K inhibitors and CDK4/6 inhibitors, in patients with metastatic breast cancer, Bardia explains. Notably, the second category of oral SERD clinical trials involves first-line studies comparing combinations of oral SERDs and CDK4/6 inhibitors with combinations of aromatase inhibitors (AIs) and CDK4/6 inhibitors, he adds

Furthermore, the third category includes trials examining circulating tumor DNA (ctDNA), where therapy may be altered based on elevated ctDNA levels, Bardia continues. An example is the phase 3 SERENA-6 trial (NCT04964934), a hybrid second-line study using ctDNA as a marker for switching therapy from an AI to camizestrant (AZD9833) in patients with 

-mutant, hormone receptor–positive, HER2-negative metastatic breast cancer, he explains. Positive data from this trial could influence the utilization of ctDNA and genotyping in breast cancer.

Resistance to conventional endocrine therapies, such as tamoxifen, AIs, and fulvestrant(Faslodex), often occurs because of mutations in the ER, which render the tumor estrogen independent, Bardia continues. Although drugs directly targeting ERs are often effective in these cases, conventional doses of fulvestrant and tamoxifen are not potent ER blockers in the presence of 

 mutations, he emphasizes. Novel agents, however, can degrade ERs and have demonstrated superior activity compared with fulvestrant and AIs in this scenario, Bardia says. Additionally, the appeal of these oral agents lies in their convenience for patients compared with intramuscular fulvestrant injections, he concludes.

Aditya Bardia, MD, MPH, discusses the continued investigation of oral selective estrogen receptor degraders in patients with estrogen receptor-positive, HER2-negative metastatic breast cancer.  
