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Answers to Burning Questions in Breast Cancer - Part 2: Advanced Breast Cancer

Presentation by Dr Lee Schwartzberg, Renown Cancer Institute

At the 2023 Total Health Spring Oncology Review and Renew Conference, Dr Lee Schwartzberg from Renown Cancer Institute provided an update on treatment for advanced stage and/or metastatic breast cancers, with answers to some key questions in the field and practice-changing results, mainly as presented at the 2022 San Antonio Breast Cancer Symposium (SABCS).

Should I use chemotherapy or a CDK4/6i + endocrine therapy for visceral disease in 1st line HR+ HER2- metastatic breast cancer?

In the setting of advanced and/or metastatic breast cancer, the first question which Dr Schwartzberg addressed was whether or not patients with hormone-receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer whose cancer had spread to the visceral organs and was causing symptoms (also known as “visceral crisis”) should use chemotherapy, or combination therapy with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) as a first line treatment. He discussed findings from the ‘RIGHT Choice’ trial, a phase II study of premenopausal patients with aggressive, HR+/HER2- advanced breast cancer treated with ribociclib, a CDK4/6i, in combination with ET, as compared with a physician’s choice of a ‘combination’ chemotherapy, which, as Dr Schwartzberg noted, constituted a very valid comparison, as these are some of the most aggressive chemotherapy regimens in use for patients with advanced breast cancer.

The results for the primary endpoint of progression-free survival (PFS) showed a significant benefit of ribociclib + ET over chemotherapy, with a median PFS of 24.0 versus 12.3 months, and a hazard ratio (HR) of 0.54 (P=0.0007). Additional findings from the trial showed that, while the overall response rate (ORR) and the clinical benefit rate (CBR) was largely similar between the ribociclib +ET and combination chemotherapy arms (ORR, 65.2% vs. 60.0%; CBR, 80.4% vs. 72.7%), the overall toxicity profile favored the ribociclib + ET arm, with mainly asymptomatic neutropenia and leukopenia as the main adverse events, while symptoms like nausea, vomiting, diarrhea, alopecia, and fatigue were much less than that seen with combination chemotherapy.

Should I consider changing the endocrine therapy or the CDK 4/6i agent following a 1st line treatment with an AI and CDK 4/6?

In line with the above-described results from RIGHT Choice supporting the first line use of a CDK4/6i + ET for patients with HR+/HER2- advanced breast cancer, another question which Dr Schwartzberg considered was whether patients with progression following a first line (1L) treatment with a CDK4/6i and ET with an aromatase inhibitor (AI) should consider changing the AI, or changing the CDK4/6i. He noted that, while a definitive answer is not available as yet, results presented at the 2022 American Society for Clinical Oncology (ASCO) Meeting from the phase II MAINTAIN trial suggested that switching out both the CDK4/6i (mostly palbociclib  ribociclib) and the ET (mostly from an AI  fulvestrant) might be a good strategy, with a modest benefit of 2.5 months for the endpoint of PFS with a hazard ratio of 0.57 (P=0.006). Another phase II trial, PACE, presented at SABCS 2022, examined the impact of a similar approach, maintaining the CDK4/6i, palbociclib, while switching the ET from an AI to fulvestrant, and this trial showed no apparent benefit of the ET switch. In view of these data, Dr Schwartzberg suggested that further study is needed to answer the question more definitively.

Which patients are the best candidates for single agent oral SERDs?

A third question which Dr Schwartzberg considered was which patients are the best candidates for monotherapy with an orally administered selective estrogen receptor degrader (SERD). SERDs are a type of endocrine therapy (ET) that is useful for patients who have progression while on other types of ET such as the aromatase inhibitors (AIs). Although another SERD (fulvestrant) has been approved since 2002, its use has been limited by the need for intramuscular administration, and as such, there has been a considerable interest in developing oral SERDs which are more convenient to administer. Dr Schwartzberg noted that there are a number of oral SERDs under development, most notably elacestrant, which was recently approved for use in breast cancer based on the results of the EMERALD trial.

Frequently those patients with progression on AIs will develop a mutation in the gene for the estrogen receptor, ESR1, which causes it to become constitutively activated, driving breast cancer growth even in the absence of estrogen. In the EMERALD trial, patients with HR+/HER2- advanced breast cancer who had progression following prior ET, at least one line of which included combination therapy with a CDK4/6i, were randomized to either elacestrant, or to the investigator’s choice of a standard of care therapy (one of the available AIs, or fulvestrant). The overall results, as summarized by Dr Schwartzberg, showed that patients with the longest duration of progression-free survival while on a CDK4/6i (considered the most “endocrine responsive patients”) had a greater benefit of elacestrant, and those with mutations in ESR1 had the greatest degree of benefit. Similar results were seen in the SERENA trial of camizestrant, another oral SERD, with a greater benefit over fulvestrant observed in patients who had a prior CDK4/6i, and the greatest benefit was again observed in those with ESR1 mutation. Accordingly, Dr Schwartzberg noted that, based on the current data, oral SERDs are most useful for those patients with ESR1 mutations, and he recommended, as a general standard of care, that all patients with progression following a CDK4/6i with an AI should undergo genetic testing for an ESR1 mutation.

Does TDxd have survival benefit in refractory HER2+ breast cancer?

The final question which Dr Schwartzberg considered was whether there is any survival benefit for patients treated with trastuzumab-deruxtecan (TDxd) over the standard of care, trastuzumab emtansine (TDM1). In this regard, he noted earlier results which showed a remarkable benefit for TDxd in patients with human epidermal growth factor receptor 2 positive (HER2+) as well as the more recently defined subtype of “HER2-Low” breast cancer. He reviewed the updated results from the Destiny-Breast 03 trial, which showed a four-fold increase in PFS over TDM1 (28.8 versus 6.8 months) with a hazard ratio (HR) of 0.33 (P<0.000001), clearly establishing TDxd as the new standard of care in the second line treatment setting, following 1 or 2 prior lines of chemotherapy and anti-HER2 therapy. Notably, results for the key secondary endpoint of overall survival (OS) also showed a significant benefit of TDxd with an HR of 0.64 (P=0.0037), and Dr Schwartzberg suggested that based on the available data, a patient diagnosed with metastatic HER2+ breast cancer can now expect a median survival in excess of 8 years, which is among the best survival outcomes of all the breast cancer subtypes. Overall response rate (ORR) also favored the use of TDxd in the study, with an ORR of 78.5% and 35.0% in the TDxd and TDM1 groups, respectively. Lastly, he noted the adverse event of interstitial lung disease (ILD) is important to monitor for when using TDxd; this event occurred in 15.2% and 3.1% of patients in the TDxd and TDM1 groups, respectively, after an average of 2 years of therapy, although most of the observed ILD was of grade 1 or 2.

Quick Summary

· Using a CDK4/6i + endocrine therapy as a 1st line therapy was more effective than combination chemotherapy for patients with symptomatic visceral disease in advanced/metastatic HR+/HER2- breast cancer.

· For patients with progression while on combination CDK4/6i + endocrine therapy, switching both the CDK4/6i and the type of endocrine therapy may be a valid option for continuing treatment.

· Orally administered selective estrogen receptor degraders (SERDs) such as the recently approved elacestrant, appear to be most effective in patients with ESR1 mutations, and in those who have a prolonged PFS while on a CDK4/6i with endocrine therapy.

· Results from the Destiny-Breast 03 trial show that TDxd, the new standard of care for advanced HR+/HER2+ metastatic breast cancer, has a significant PFS benefit, as well as an overall survival advantage, as compared to TDM1.

Speaker Disclosure Information: Dr Schwartzberg lists his disclosures as follows: Consultant: AstraZeneca, Daiichi Sankyo, Genentech, Novartis, Pfizer, Seagen, Spectrum, Coherus. Speaker Bureau: AstraZeneca, Seagen, Merck.


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