Breast Cancer Paradigm Pushes Forward With Novel Agents, Sequencing Strategies, and Dynamic Biomarkers

Aditya Bardia, MD, MPH

As treatment strategies continue to evolve with novel therapies like antibody-drug conjugates (ADCs) in HER2-positive and triple-negative breast cancer (TNBC) and CDK4/6 inhibitors and selective estrogen receptor degraders (SERDs) in hormone receptor–positive breast cancer, sequencing strategies have become a more prominent area of research, said Aditya Bardia, MD, MPH. He added that the rapidly changing field underscores the need for improved molecular testing and identification of dynamic biomarkers like circulating tumor DNA (ctDNA).

“The first [highlight] is the emerging role of ADCs, not only in TNBC, but also in HER2-positive breast cancer. With these newer ADCs, we are seeing outcomes like we have never seen before, including impressive HRs [hazard ratios],” Bardia said in an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

“The first [highlight] is the emerging role of ADCs, not only in TNBC, but also in HER2-positive breast cancer. With these newer ADCs, we are seeing outcomes like we have never seen before, including impressive [hazard ratios],” Bardia said in an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

“The second [highlight] is the development of novel therapies, including SERDs for patients with hormone receptor–positive breast cancer,” Bardia added. “Finally, in terms of germline alterations, we are realizing that other alterations besides BRCA could increase the risk of breast cancer for an individual. More and more, the field is moving toward panel testing rather than just testing single genes.”

In the interview, Bardia discussed key updates in HER2positive, hormone receptor–positive, and triple-negative breast cancers, as well as the evolving clinical application of gene signature assays, liquid biopsies, and genotyping. He was the chair of the IPC meeting, and he is an associate professor of medicine at Harvard Medical School and director of breast cancer research at Massachusetts General Hospital Cancer Center.

OncLive^®: During the IPC meeting, Laura Spring, MD, of Massachusetts General Hospital, discussed updates in HER2-positive breast cancer. How have some of the recent data that emerged in this space changed practice patterns?

Bardia: I want to highlight 2 key updates related to HER2-positive breast cancer. The first is the DESTINY-Breast03 trial [NCT03529110], which showed that fam-trastuzumab deruxtecan-nxki [Enhertu] is superior to ado-trastuzumab emtansine [T-DM1; Kadcyla], with a clear improvement in progression-free survival. That was a practice-changing study. Recently, the sponsor filed for approval [of trastuzumab deruxtecan in the second-line metastatic setting], and [the agent] was given priority review [designation] by the FDA. We anticipate that trastuzumab deruxtecan will be the preferred agent in the second-line setting for a patient with metastatic HER2-positive breast cancer after treatment with first-line trastuzumab [Herceptin], pertuzumab [Perjeta], and paclitaxel.

The second [takeaway from Dr Spring’s presentation] relates to sequencing of agents in metastatic HER2-positive breast cancer. We have multiple agents now, including trastuzumab deruxtecan, T-DM1, tucatinib [Tukysa], neratinib [Nerlynx], and margetuximab-cmkb [Margenza], besides standard trastuzumab plus chemotherapy. We need more understanding of the mechanisms governing resistance to these agents so we can sequence these therapies for an individual to prolong survival.

Seth Wander, MD, PhD, of Massachusetts General Hospital, spoke to the evolving space of hormone receptor–positive, HER2-negative breast cancer. How are CDK4/6 inhibitors and oral SERDs changing the treatment paradigm?

For hormone receptor–positive breast cancer, one of the key highlights from Dr Wander’s presentation includes the use of CDK4/6 inhibitors in the adjuvant setting. We have seen 1 negative trial in PALLAS [NCT02513394] and 1 positive trial in monarchE [NCT03155997]. Abemaciclib [Verzenio] was FDA approved this past year for patients with high-risk hormone receptor–positive breast cancer.

The question is: Should it be used for everyone? What is the role of Ki-67 [expression]? The FDA approval was based on Ki-67 expression of more than 20%. The [American Society of Clinical Oncology] and National Comprehensive Cancer Network guidelines refer to use of adjuvant abemaciclib more [from the] intention-to-treat analysis of patients with more than 4 positive nodes or 1 to 3 positive nodes plus additional features like Ki-67 expression of more than 20%.

It is an evolving area in terms of when to use adjuvant abemaciclib. My personal take is that the risk needs to be balanced with the potential benefits and patient discussions.

The second highlight relates to emerging therapies [in hormone receptor–positive breast cancer], including novel SERDs. At the 2021 San Antonio Breast Cancer Symposium [SABCS], we saw the results of the EMERALD trial [NCT03778931] looking at the novel SERD elacestrant vs standard-of-care endocrine therapy. The trial was positive. Several other SERDs are in development. We are likely to see more development of these novel agents, which will hopefully be better than the current standard of care.

Neelima Vidula, MD, of Massachusetts General Hospital, highlighted updates in TNBC, including adjuvant immunotherapy and ADCs. What are your thoughts on advances in this treatment paradigm?

I’ll continue with the theme of [sharing] 2 key highlights [from my colleagues’ presentations]. The first was [regarding] the use of immunotherapy in the neoadjuvant and adjuvant settings. Historically, we have been using [immunotherapy] in the metastatic setting, but, based on results from the KEYNOTE-522 trial [NCT03036488], we saw that neoadjuvant pembrolizumab [Keytruda] is associated with not only improvement in pathologic complete responses [pCRs] but potentially survival as well, leading to the FDA approval of neoadjuvant and adjuvant pembrolizumab.

In patients with pCRs, do we necessarily need to continue adjuvant pembrolizumab? That is currently an open question. Other questions relate to patients with residual disease: Does capecitabine [Xeloda] have to be combined with pembrolizumab, should we use them sequentially, or should we use only one of these agents? These are some of the open questions.

The second [point] relates to the development of novel ADCs. Currently, sacituzumab govitecan-hziy [Trodelvy] is FDA approved; it targets TROP-2. At the 2021 SABCS, we saw [data with] another ADC called datopotamab deruxtecan, which [also] targets TROP-2. Impressive results were seen in pretreated patients with metastatic TNBC. [Datopotamab deruxtecan] is another ADC to watch out for, and I am sure there are others in development as well.

Moving to the presentation given by Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute, how is the field of breast cancer applying gene signature assays in the clinic?

There are 2 broad themes [that emerged from Dr Burstein’s presentation]. The first is the use of Oncotype DX or the 21-gene signature. It is something that is widely utilized in patients with lymph node–negative disease and lymph node–positive disease. The RxPONDER trial [NCT01272037] showed that even in patients with lymph node–positive disease, the use of Oncotype DX can help select patients who do not need chemotherapy. An open question is whether the chemotherapy benefit in patients who are premenopausal is predominately because of ovarian suppression. That was something beautifully discussed by Dr Burstein [during the IPC meeting] and he also led a debate [on this topic] at the 2021 SABCS. The bottom line is that at least some of the benefit relates to ovarian suppression, which chemotherapy tends to [cause].

The second theme relates to newer and more dynamic biomarkers, such as ctDNA. Oncotype DX, MammaPrint, or Breast Cancer Index are all static biomarkers that we measure at the time of surgery or full biopsy. However, there is interest in looking at dynamic biomarkers that can change over time like ctDNA. Ongoing studies are looking at ctDNA as a dynamic biomarker to identify patients for whom therapy needs to be escalated.

Douglas Micalizzi, MD, PhD, of Massachusetts General Hospital, closed out the IPC meeting by discussing the utility of liquid biopsies and genotyping in breast cancer. How could these technologies be expanded upon to provide further inform treatment selection?

Firstly, in general, liquid biopsies have been used in the metastatic setting for identification of actionable alterations. A classic example is the identification of PIK3CA mutations for selection of PI3K inhibitors. Moving forward, liquid biopsies are also being utilized in early breast cancer to identify evidence of minimal residual disease using ctDNA, which is a sensitive marker to identify evidence of disease. Then, based on the utilization of ctDNA, [we would] select therapies. That is potentially a game changer in the field of adjuvant breast oncology.

Second, in terms of germline mutations besides BRCA, interest in panel testing [is emerging], particularly for PALB2, which seems to be similar to BRCA in terms of risk of breast cancer recurrence. The recommendations are quite similar. It also appears that PARP inhibitors potentially would have a therapeutic role in patients with have germline PALB2 mutations. We need larger studies to look at this from at least a biologic perspective, but if we extrapolate data from the metastatic setting, that is another subgroup of patients for which PARP inhibitors would have a therapeutic role.