Dr Wander on Managing HR+ Advanced Breast Cancer in the Clinic

Seth Wander, MD, PhD, instructor, medicine, Harvard Medical School; medical oncologist, Massachusetts General Hospital, discusses how he approaches therapeutic treatment for patients with hormone receptor (HR)–positive advanced breast cancer in the clinic, as well as how ongoing clinical trials and available data affect this decision.

In clinical practice, without definitive data to guide treatment decision-making for different subgroups of patients with HR-positive metastatic breast cancer, Wander says he takes a tailored treatment approach based on patients’disease progression and prior treatment history. For many patients who are newly diagnosed with untreated HR-positive metastatic breast cancer or who have experienced a recurrence after a prolonged period off anti-estrogen therapy, he typically uses a frontline regimen that combines an aromatase inhibitor with a CDK4/6 inhibitor. Ribociclib (Kisqali) is often the CDK4/6 inhibitor of choice in this patient population, due to its proven efficacy and tolerability, Wander explains.

For patients with more aggressive disease, particularly those whose cancer has progressed on or shortly after adjuvant anti-estrogen therapy, the focus shifts to clinical trial opportunities, he continues. These patients likely have a poorer prognosis with standard frontline therapy, and novel approaches are essential, according to Wander. In this context, trials with innovative anti-estrogen agents, targeted therapies, and combination regimens are critical, Wander reports. Until new data become available, the standard of care (SOC) for this subgroup remains fulvestrant (Faslodex) combined with a CDK4/6 inhibitor, he says, noting that the choice between the available CDK4/6 inhibitors can be individualized based on data in the second-line metastatic setting.

However, there is a clear need for improved outcomes for these patients, Wander expands. Genomic sequencing is becoming increasingly important in guiding treatment strategies, he emphasizes. For instance, patients with PI3K pathway alterations may benefit from alpelisib (Vijoice) or capivasertib (Truqap), whereas those with 

 mutations could be candidates for next-generation anti-estrogen therapies, he says. Additionally, some patients may have alterations in other key pathways, such as RAS, Wander explains. For these patients, there may not yet be SOCtreatments, but clinical trials offer promising opportunities, he notes. As research progresses, targeting these pathways will likely become a more integral part of treating patients with metastatic breast cancer, expanding the therapeutic options for these patients, Wander concludes.

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Seth Wander, MD, PhD, discusses how he approaches therapeutic treatment for patients with ER+ advanced breast cancer in the clinic.

Dr Wander on Limitations of First- and Later-Line Therapies in HR+ Breast Cancer

Seth Wander, MD, PhD, instructor, medicine, Harvard Medical School; medical oncologist, Massachusetts General Hospital, discusses the present limitations of first- and later-line therapy for patients with hormone receptor (HR)–positive metastatic breast cancer.

In recent years, significant progress has been made in the development of novel frontline therapies for patients with HR-positive metastatic breast cancer, Wanderbegins. The current standard of care often includes an aromatase inhibitor combined with a CDK4/6 inhibitor, such as ribociclib (Kisqali), a regimen that has generated astatistically significant improvement in overall survival in the first-line setting, he explains.

However, there are still limitations and areas for improvement in treatment, Wandernotes. He says that on one end of the spectrum, patients with more aggressive disease—particularly those who progress shortly after adjuvant anti-estrogen or CDK4/6 inhibitor therapy—represent a high-risk population that requires more effective treatmentstrategies. Recent data from the phase 2/3 INAVO120 trial (NCT04191499) have shown that patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer harboring 

 mutations who have progressed on adjuvant anti-estrogen therapy benefit from a triplet regimen of fulvestrant (Faslodex), palbociclib (Ibrance), and the novel PI3K inhibitor inavolisib (GDC-0077). The positive findings seen in this trial highlight the possibility of developing more effective treatment approaches for these endocrine-refractory patients, he continues.

Conversely, there is a subset of patients with slower-growing, indolent disease—such as those with oligometastatic or bone-only HR-positive breast cancer—for whom CDK4/6 inhibitors may not be suitable due to their associated financial burdens, toxicities, and adverse effects, Wander adds. These patients could achieve sufficient disease control with anti-estrogen therapy alone, which highlights the need for a more tailored approach to therapy for this population, he expands.

A key unmet need in this population is identifying which patients can be effectively treated with endocrine therapy alone and which require more aggressive, upfront therapy, potentially including triplet-targeted agents, Wander states. Additionally, advancing biomarker development will be critical for optimizing treatment strategies and personalizing care across this diverse patient population, Wander concludes.

Seth Wander, MD, PhD, discusses the present limitations of first- and later-line therapy for HR+ metastatic breast cancer.

Seth Wander, MD, PhD, discusses the ELAINE-1, ELAINE-2, and ELAINE-3 trials in patients with ER-positive, HER2-negative metastatic breast cancer.

Dr Wander on the ELAINE Trial Portfolio of Lasofoxifene in ER+/HER2– Breast Cancer

Seth Wander, MD, PhD, medical oncologist, Massachusetts General Hospital, instructor, medicine, Harvard Medical School, discusses the data from the phase 2 ELAINE-1 (NCT03781063) and ELAINE-2 (NCT04432454) trials that supported the continued investigation of lasofoxifene plus abemaciclib (Verzenio) in the phase 3 ELAINE-3 trial (NCT05696626) of patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer.

Over the past few years, the potential of lasofoxifene has been extensively explored in clinical research, Wander begins. The initial ELAINE-1 study investigated lasofoxifene monotherapy vs fulvestrant (Faslodex)in patients with 

-mutant, ER-positive metastatic breast cancer who had previously progressed on an androgen inhibitor (AI) with a CDK4/6 inhibitor, he explains. Although lasofoxifene demonstrated notable clinical benefits in terms of improved progression-free survival (PFS) and clinical benefit rate, statisticalsignificance was not fully achieved due to sample size limitations, Wander reports.

Building upon these findings, the ELAINE-2 study subsequently examined the combination of lasofoxifene plus abemaciclib, he continues. The upcoming ELAINE-3 study aims to validate results from ELAINE-2 into a phase 3 setting, he elucidates. This open-label, randomized, multicenter trial will compare lasofoxifene with abemaciclib vs fulvestrant and abemaciclib in patients with ER-positive, HER2-negative metastatic breast cancer, Wander notes. 

Enrolling individuals must have experienced progression on a prior AI with either palbociclib or ribociclib (Kisqali), and will be limited to the 

-mutant population, he continues. With an anticipated sample size of approximately 400 patients, this prospective randomized phase 3 study aims to provide deeper insights into the therapeutic benefits of lasofoxifene with abemaciclib in the post-AI and post-CDK inhibitor setting, Wander states. The ELAINE-3 study is active, and patient screening and enrollment is underway. New sites are joining the study to further advance our understanding and management of metastatic breast cancer, he concludes.

Dr Wander on Genomic Alterations in ER+/HER2– Metastatic Breast Cancer

Seth Wander, MD, PhD, medical oncologist, Massachusetts General Hospital, instructor, medicine, Harvard Medical School, discusses findings from an analysis of baseline genomic alterations in patients with estrogen receptor–positive, HER2-negative metastatic breast cancer who were enrolled in the single-arm, phase 2 ELAINE-2 trial (NCT04432454) of lasofoxifene plus abemaciclib (Verzenio).

Twenty-six of the 29 patients enrolled onto ELAINE-2 harbored baseline 

 mutations and had received prior CDK4/6 inhibitors. In this biomarker subset, the median progression-free survival (PFS) with lasofoxifene plus abemaciclib was 12.9 months, and the clinical benefit rate was 73.1%.

Wander notes that this exploratory analysis was conducted in a relatively small patient cohort, and thus should be used for hypothesis generation and signal finding. The patients with co-occurring 

 mutations (n = 11) had a median PFS of 8.3 months, which was slightly lower than the median PFS in the overall study population. This outcome was expected, as 

 mutations are a potential biomarker of unfavorable outcomes, which may be related to their genomic instability.

Patients with disease harboring co-occurring 

 mutations (n = 8) also had a lower median PFS than that of the overall population, at 7.8 months. Additionally, a small number of these patients had received prior PI3K inhibitors. These findings necessitate further investigation to determine which patients with 

 mutations had received prior PI3K inhibition, given that the armamentarium of PI3K and AKT inhibitors is evolving both in the United States and around the world, Wander says.

 amplifications (n = 5) had a higher median PFS than that of the overall population, at 16.6 months in both subgroups. One patient in this study had disease harboring an 

 mutation. This patient had a median PFS similar to that of the overall population, at 11.0 months, Wander concludes.

Seth Wander, MD, PhD, discusses findings from an analysis of baseline genomic alterations in patients with estrogen receptor–positive, HER2-negative metastatic breast cancer who were enrolled in the single-arm, phase 2 ELAINE-2 trial of lasofoxifene plus abemaciclib. 

Seth Wander, MD, PhD, instructor, medicine, Harvard Medical School, medical oncologist, the Massachusetts General Hospital, discusses the evaluation of vepdegestrant (ARV-471), a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, in patients with advanced ER-positive/HER2-negative breast cancer.

The ongoing, global, randomized, phase 3 VERITAC-2 trial (NCT05654623) is evaluating the PROTAC vs fulvestrant (Faslodex) in patients with ER-positive/HER2-negative advanced breast cancer. This PROTAC has exhibited significant promise in its clinical progression, Wander begins. Investigators hope to drive the investigation of vepdegestrant forward in several different clinical trials, Wander says, noting that this agent targets the ER for degradation within the cell. Both preclinically and in early-phase clinical trials, this agent has been well tolerated and demonstrated preliminary efficacy, even in heavily pretreated patients, Wander emphasizes.

The mechanism of action of the drug allows the ubiquitin proteasome system to target the ER, resulting in efficient degradation, Wander expands. This holds true for mutant forms of the ER, for example, in patients who develop 

 wild-type disease. The phase 2 expansion portion of the phase 1/2 VERITAC trial (NCT04072952) evaluated vepdegestrant a group of heavily pretreated patients with locally advanced or metastatic ER-positive/HER2-negative breast cancer, most of whom had received prior antiestrogen agents and CDK4/6 inhibitors, Wander explains. Many of these patients had also received prior cytotoxic chemotherapy, he notes. These data revealed that this agent conferred a clinical benefit rate (CBR) of 38.9% (95% CI, 23.1%-56.5%) in the cohort of patients who received the agent at 500 mg once daily. In the subgroup of patients with 

 mutations, a traditionally difficult subgroup to treat, the CBR was 54.5% (95% CI, 32.2%-75.6%) in the 500 mg cohort, Wander adds.

This agent is progressing in several related phase 3 trials, both alone and in combination with other agents, Wander continues. Notably, the VERITAC-2 trial is ongoing.

Regarding toxicities, vepdegestrant is associated with low-grade adverse effects (AEs), including fatigue, hot flashes, and nausea. Overall, however, this agent was well tolerated in VERITAC, he says. Investigators did not see high rates of bradycardia, cardiac abnormalities, or visual disturbances, which are some AEs associated with some of the newer agents in development over recent years, Wander concludes.

Seth Wander, MD, PhD, discusses the evaluation of vepdegestrant (ARV-471), a proteolysis targeting chimera estrogen receptor degrader, in patients with advanced estrogen receptor/HER2-negative breast cancer.


Dr Wander on the Evaluation of Vepdegestrant in ER+/HER2– Breast Cancer

Seth Wander, MD, PhD, medical oncologist, Massachusetts General Hospital; instructor, medicine, Harvard Medical School, discusses challenges related to the ongoing platinum chemotherapy shortage for patients with breast cancer and other malignancies, as well as ways that oncologists and cancer centers can operate during the shortage to continue to provide appropriate care for patients.

In June 2023, the National Comprehensive Cancer Network released a statement with results from a survey conducted by its Best Practices Committee, revealing that 93% and 70% of cancer centers in the United States are experiencing carboplatin and cisplatin shortages, respectively. 

This platinum chemotherapy shortage affects the management of several tumor types, as platinum agents are often used in both early-stage and metastatic settings, Wander says. For example, within the breast cancer realm, patients with early-stage HER2-positive or triple-negative breast cancer often receive carboplatin as preoperative chemotherapy, Wander notes.

This drug shortage affects patients and cancer centers across the United States and requires daily decision making by oncologists, Wander explains. The oncology community, in collaboration with the United States government, should work together to develop a safe solution to this shortage as quickly as possible, so patients with cancer who are eligible for platinum chemotherapy can have uninterrupted access to appropriate treatment, Wander emphasizes.

In response to this shortage, oncologists at cancer centers across the country, including Massachusetts General Hospital, are making thoughtful decisions about when they use platinum chemotherapy, he says. Administration of carboplatin and cisplatin is being prioritized for when they are critical for a patient’s care and cannot be safely replaced with an alternative treatment, Wander says. As every patient has unique treatment needs, oncologists need to consider all available standard therapeutic options in case there are regimens beyond platinum chemotherapy that are equally effective and safe for a given patient, Wander explains.

As the chemotherapy shortage continues to evolve, the availability of these drugs will fluctuate, Wander notes. In the future, the leadership teams at cancer centers across the country may need to develop policies to guide oncologists in the safe and effective distribution of platinum chemotherapy, Wander concludes.

Seth Wander, MD, PhD, discusses challenges related to the ongoing platinum chemotherapy shortage for patients with breast cancer and other malignancies, as well as ways that oncologists and cancer centers can operate during the shortage to continue to provide appropriate care for patients.

Dr Wander on Using Platinum Chemotherapy Wisely in Breast Cancer

Seth Wander, MD, PhD, medical oncologist, the Massachusetts General Hospital, instructor in Medicine, Harvard Medical School, discusses the investigation of resistance to CDK4/6 inhibitors and the role of 

At the 2022 San Antonio Breast Cancer Conference, investigators presented data on an institutional retrospective study, where they identified 26 patients metastatic hormone receptor (HR)–positive/HER2-negative breast cancer harboring 

 mutations who had 1 or more circulating tumor DNA samples sequenced at variable time-points as part of routine care. They concluded that 

 mutations may be associated with resistance to CDK4/6 inhibitors, and mutant NF1 allele fraction in HR-positive could be predictive of CDK4/6 inhibitor susceptibility.

The growing knowledge of the biology of HR-positive breast cancer has suggested that the genomic and molecular landscape of resistance to CDK4/6 inhibitors is heterogeneous, with a number of different potential driver alterations potentially affecting resistance, Wander explains. Many of these alterations fall into genomic or molecular changes that affect the mechanisms of cell cycle division and oncogenic signal transduction pathways, Wander adds.

The RAS/MAPK pathway may be a critical and common pathway that can be altered in patients who develop CDK4/6 inhibitor resistance, leading investigators to examine 

 mutations as a potential route that the RAS/MAPK pathway can be activated, Wander explains.

New data continue to emerge on the use of CDK4/6 inhibitors in HR-positive/HER2-negative breast cancer, including information on the role that the immune system plays in interacting with different regulatory components that could affect response and resistance to CDK4/6 inhibitors, Wander says. Moreover, new data were also presented on different cellular models of resistance that may demonstrate unilateral resistance to one CDK4/6 inhibitor vs another. These data could help determine whether individual patients can respond to a different CDK4/6 inhibitor after developing resistance to a prior agent, Wander concludes.

Seth Wander, MD, PhD, discusses the investigation of resistance to CDK4/6 inhibitors and the role of NF1 mutations in breast cancer.

Seth Wander, MD, PhD

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