2024 Best of ASCO Memphis: Dr Schwartzberg Addresses Five Key Questions in Early and Advanced Breast Cancer

Presenter:

Dr Lee Schwartzberg, Renown Health

Meeting:

Best of ASCO Memphis

At the Total Health Best of ASCO Memphis Conference, Dr Lee Schwartzberg from Renown Health discussed five abstracts from this year’s Annual Meeting of the American Society for Clinical Oncology (ASCO) addressing some key questions in early and metastatic breast cancer.  In his presentation, he highlighted takeaways with implications for changes in clinical practice on Monday morning.

Question: How do I decide what type of chemotherapy to give patients with hormone receptor positive (HR+) Human epidermal growth factor receptor 2 negative (HER2-) breast cancer in the neoadjuvant (pre-surgery) setting?

MammaPrint is a molecular test that can help to inform decisions on the need for chemotherapy to reduce the risk of a distant recurrence (metastasis) in breast cancer patients with HR+/HER2- breast cancer.  Results from the test will classify patients into one of four risk groups, Ultra-Low, Low, High 1, and High2, and based on those results, estimate the overall benefit of chemotherapy and endocrine therapy (ET).  Results presented by O’Shaughnessy and coworkers at ASCO 2024 detailed results from the ongoing FLEX Registry Trial, which showed a benefit for patients in the MammaPrint High2 group who received adjuvant therapy with anthracycline-based chemotherapy (AC-T) versus without anthracyclines (TC). Previous data from FLEX had demonstrated that patients in the High1 group had no difference in the pathologic complete response rate (pCR) when using neoadjuvant AC-T or TC (7.0% vs. 7.7%, respectively), those in the High2 group had a 32% pCR rate with AC-T, while no patients (0%) in the TC group had a pCR. In the current presentation, similarly, patients in the High1 group had no improvement in 3-year relapse-free survival (RFS), while those in the High2 group had an 11.3% improvement in their RFS with the use of AC-T over TC.

Answer: While there were caveats and limitations to the study, Dr Schwartzberg would consider using the MammaPrint test, particularly in those HR+/HER2- patients who may not be good candidates for anthracycline-based chemotherapy (e.g., due to poor performance status or comorbid conditions).

Question: Is there a preferred type of taxane chemotherapy that should be used in Black patients versus White patients?

As compared to their non-Hispanic White counterparts, Black women have been shown to have worse breast cancer survival outcomes and higher rates of treatment related toxicity, due to a wide range of factors such as genetics and biology, as well as access to care and other social determinants of health.  Taxane-induced peripheral neuropathy (TIPN) is a potentially debilitating side effect of taxane-based chemotherapy (CT) that can impact quality of life for breast cancer patients, and previous findings have shown that Black women have significantly higher rates of TIPN when compared to all other races.  The EAZ171 trial reported at ASCO 2024 sought to prospectively assess the incidence of TIPN, specifically in a population of self-identified Black women who were scheduled to receive taxane-based CT, who were treated with either docetaxel or paclitaxel on differing dosing schedules.  The results showed that there was significantly less physician-adjudicated grade 2+ (25% vs. 44%), grade 3 (1.7% vs. 9.4%) or patient reported moderate (24% vs. 40%) and severe (11% vs. 15%) TIPN in the group receiving docetaxel every 3 weeks, as compared to those receiving weekly paclitaxel.

Answer: Dr Schwartzberg noted the importance of ameliorating TIPN as a treatment related toxicity, and based on these findings, and would substitute docetaxel every 3 weeks for paclitaxel when using as an adjuvant CT in Black patients.  He would also consider the same approach when using taxane-based CT in the neoadjuvant (pre-surgery) setting.

Question: In advanced HR+ HER2- breast cancer, what is the benefit of using a cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) as a second-line therapy following an initial treatment with a CDK 4/6i and endocrine therapy (ET)?

The postMONARCH Trial evaluated the impact of using a CDK4/6i (abemaciclib), in combination with a selective estrogen receptor degrader (SERD), fulvestrant, versus fulvestrant alone, for patients with HR+/HER2- advanced breast cancer, following progression on first line CDK4/6i + ET therapy.  A majority of patients in the trial were “endocrine sensitive”, Dr Schwartzberg noted, with 71% and 77% of patients in the combination and fulvestrant alone arms having a prior duration of CDK4/6i + ET of over 12 months.  The results showed a modest, but statistically significant benefit in progression-free survival (PFS) when comparing the abemaciclib versus the placebo arms (6.0 vs. 5.3 months; P=0.02). Among those with one year or more on their prior CDK4/6i + ET, however, the overall benefit of adding abemaciclib was greater (7.0 months vs. 5.4 months). In addition, those without visceral metastases in the trial (i.e., without lung or liver metastases) had a greater benefit of the combination therapy versus fulvestrant alone (11.1 vs. 5.1 months).

Answer: Based upon findings from postMONARCH, Dr Schwartzberg noted he will be using a CDK 4/6i after initial CDK 4/6i + ET, specifically in those patients who have had a prolonged response to their initial therapy, and in those patients without visceral metastases. It is also important to ensure such patients do not have an actionable genomic alteration (and therefore are not candidates for a targeted therapy).

Question: What is the most effective first line chemotherapy for patients with HR+/HER2- metastatic breast cancer?

The DestinyBreast06 trial investigated the use of trastuzumab deruxtecan (T-Dxd) as compared to the physician’s choice of chemotherapy (TPC) in patients with HR+ metastatic breast cancer having ‘HER2-Low’(defined as IHC 1-2+), or ‘Ultra-Low’ (defined as IHC detectable but less than 1+) status who had received prior endocrine therapy.  The results showed a significant progression-free survival (PFS) benefit of T-Dxd over TPC in the HER2-Low group of patients (median 13.2 mo vs. 8.1 mo), with a similar improvement seen in the overall population.  There was also benefit with T-Dxd over TPC in overall response rate (ORR) in the HER2-Low (56.5% vs. 32.2%) and HER2-Ultra-Low (61.8% vs. 26.3%) patients, and the overall population (57.3% vs. 31.2%). Overall survival also trended in favor of T-Dxd. In terms of safety, those patients in the T-Dxd group experienced somewhat higher rates of adverse events such as nausea, fatigue, alopecia (hair loss) and neutropenia (reduced white blood cell counts) relative to those on CT.  Interstitial lung disease (ILD), as well as drop in left ventricular ejection fraction (LVEF) were also seen in 11% and 8% of patients, respectively, although these events were generally mild (grade 1 or 2).

Answer: Based upon findings from DestinyBreast06, Dr Schwartzberg would consider using T-Dxd for higher risk patients with visceral metastases as a first line chemotherapy following initial endocrine therapy.  Another option for less aggressive disease he noted, is capecitabine, an oral chemotherapy that many patients may prefer from the perspective of better tolerability, and ease of administration.

Question: Can a poly-ADP Ribose Polymerase Inhibitor (PARPi) be used in patients who have genetic alterations other than a germline BRCA mutation (gBRCAm)?

The TBCRC 048 trial examined the use of a PARPi (olaparib) beyond its approved indication for patients having a germline (inherited) mutation in the breast cancer genes BRCA1 or BRCA2.  In this phase II trial, patients having metastatic breast cancer and a germline PALB2 mutation (gPALB2) or a somatic mutation (meaning found in the tumor and not inherited) in BRCA1 or BRCA2 (sBRCA) were treated with olaparib.  Dr Schwartzberg noted that most patients in the study had HR+, HER2- disease, and most had not had prior chemotherapy for their disease.  The results showed, for patients with gPALB2 (n=24) an ORR of 75%, and an  overall clinical benefit rate (CBR) of 83%.  In those patients with sBRCA1/2 (n=30), the ORR was 37%, with a CBR of 53%.

Answer: Based upon these findings, Dr Schwartzberg notes he will be testing all metastatic breast cancer patients for both somatic mutations (in the tumor) as well as germline (inherited) mutations to determine if they are candidates for olaparib therapy.  Candidates would now include those with gPALB2 as well as somatic BRCA1/2 mutations, and such testing would typically be done before chemotherapy to determine if PARPi is an option.

Speaker Disclosure information: Dr Schwartzberg reported the following disclosures for this presentation: Consultant: Genentech, Foundation Medicine, Novartis, Daiichi Sankyo, AstraZeneca, GSK. Speaker Bureau: AstraZeneca, Daiichi Sankyo, Merck