Optimal Personalization of Therapy In TNBC Necessitates Consistent Biomarker Identification

Identifying targetable mutations using germline testing, next-generation sequencing (NGS), and functional assays are vital for navigating the evolving treatment armamentarium in triple-negative breast cancer (TNBC) and accordingly improving patient outcomes with standard therapies, according to Pooja Advani, MBBS, MD.

“After a long time, we are having discussions as to how to sequence medications in TNBC where previously we didn’t have a lot of therapeutic options. It is an exciting yet challenging time,” Advani said in an interview with OncLive® regarding a recent OncLive® State of the Science Summit on breast cancer, which she chaired.

In the interview, Advani highlights the encouraging activity of the antibody-drug conjugates (ADCs) fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) and sacituzumab govitecan-hziy (Trodelvy) in TNBC; the importance of utilizing next-generation sequencing (NGS) to inform treatment selection after progression on CDK4/6 inhibitors in this disease setting; and ongoing efforts to perform functional assays that can best determine patient benefit from standard therapies. Advani, a hematologist/oncologist at the Mayo Clinic Comprehensive Cancer Center in Jacksonville, Florida, also provided further insights from her colleagues presentation in an additional interview.

OncLive: What are some of the key advancements in TNBC that have occurred over the last few years?

Advani: The biggest thing is the analysis of T-DXd in the phase 3 DESTINY-Breast04 trial [NCT03734029]. Although this trial included a relatively small number of patients, there was an improvement in both median progression-free survival [PFS] and overall survival [OS]. The second thing [to emphasize is that] sacituzumab govitecan is also useful and has regulatory approval in TNBC. Activity was seen [with this agent] in a subgroup analysis in both HER2-low and HER2-zero disease and was seen regardless of TROP-2 expression.

When we’re thinking about the ADCs for patients with TNBC, we now have 2 options to choose from for patients in the second-line setting and beyond. [Clinicians should also] always think about testing for germline BRCA1/2 mutations to constantly assess if patients with TNBC in the metastatic setting would be a candidate for PARP inhibitor therapy.

What were you hoping to illustrate with your case discussion of treatment after progression on CDK4/6 inhibitors?

The objective was to highlight that there are several options that we can currently consider for patients who have progressed following a first-line CDK4/6 inhibitor and endocrine therapy. There are 2 things that we [consider] when planning for second-line therapy. First, what was the duration of time that patients remained on CDK4/6 inhibitors [before progression]? The second is that from a scientific perspective, there can be an acute drop in the [survival] curves for patients who have progressed following CDK4/6 inhibitors and endocrine therapy. We need to figure out what the characteristics of those patients are to better develop therapies for them in the future.

When we think about standard-of-care therapies, the idea of the case discussion was to highlight the role of NGS in determining whether patients have any targetable mutations. [These include] ESR1 mutations where elacestrant [Orserdu] can be used, PIK3CA mutations where a combination of alpelisib [Piqray] and fulvestrant [Faslodex] can be used. We also have the recent regulatory approval of the AKT inhibitor capivasertib [Truqap] in combination with fulvestrant for patients that have mutations in the PIK3/AKT/PTEN pathway. There was a very good discussion on how oncologists can use patient characteristics and preferences for toxicity profiles in their decision making.

What exciting research in the breast cancer space is being conducted at your institution?

One thing that I’m passionate about is the personalization of therapy. That can be from both an efficacy perspective and a toxicity perspective. We’ve thought a lot about biomarkers in a manner that is obtainable on tissue or liquid biopsy. We need functional assays to match the right patient to the right treatment.

In this regard, I am excited to be involved in a project where we would be using functional assays to determine if patients are likely to respond to immune checkpoint inhibitors in a tumor-agnostic fashion. Patients will have their tissue biopsies collected, and live tumor fragments will be interrogated via multi-photon imaging to determine whether these patients are likely to respond to immune checkpoint inhibitors or not.