Genomic Predictors Inform the Evolving Role of Chemotherapy in Breast Cancer Management

Kari Wisinski, MD

Treatment individualization is at the core of adjuvant therapy optimization for patients with breast cancer across the spectrum of hormone receptor (HR) positivity and HER2 expression, according to Kari Wisinski, MD.

In an interview with OncLive®, Wisinski highlighted treatment options for patients with node-positive and -negative HR-positive, HER2-negative breast cancer, where chemotherapy fits into the triple-negative breast cancer (TNBC) treatment paradigm, and the evolving role of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) for patients with HER2-positive breast cancer with brain metastases.

She shared her insights on the use of CDK4/6 inhibitors in patients with HR-positive metastatic breast cancer in another article.

Wisinski is the Endowed Professor of Hematology and Oncology and chief of the Division of Hematology, Medical Oncology and Palliative Care in the Department of Medicine at the University of Wisconsin (UW) School of Medicine and Public Health in Madison. She is also the associate director of Clinical Research and co-lead of the Breast Cancer Disease Oriented Team at the UW Carbone Cancer Center.

OncLive: What is the current treatment strategy regarding the use of adjuvant regimens in patients with premenopausal HR-positive, HER2-negative breast cancer?

Wisinski: For premenopausal women, the decision about when to add chemotherapy is still an evolving area. For lymph node–negative breast cancer, use of a genomic predictor, such as Oncotype DX or the 21-gene recurrence score, can be a useful tool in making these decisions. There are clear-cut points for where we should recommend chemotherapy and where [a patient] likely does not need it.

However, then there’s this middle range, between [the Oncotype DX scores of] 16 and 25, where [this decision] becomes more nuanced and difficult. There needs to be a discussion with the patient regarding the other tumor features, the tumor size, the grade, what might be the absolute benefit of chemotherapy for that patient, and whether we know if that’s a chemotherapy benefit vs an ovarian suppression benefit from the chemotherapy. I have those conversations in the clinic and then try to make an individualized decision with each patient about whether to layer in the chemotherapy to their adjuvant endocrine therapy. The National Comprehensive Cancer Network guidelines support that; they [recommend] both options, which gives us the discretion to have these types of conversations and individualize patient decisions.

The second question is: What do we do for premenopausal women who have HR-positive, HER2-negative, node-positive disease, especially if it’s in the range of 1 to 3 positive nodes? At this point, that is also a difficult group to make decisions for. The phase 3 RxPONDER trial [NCT01272037] findings indicate that there’s potentially some chemotherapy benefit in those patients, but there remain questions about whether that is truly chemotherapy benefit vs suppression of the ovaries and effect on endocrine efficacy. The current standard is to consider chemotherapy for premenopausal patients who have node-positive disease. The phase 3 OFSET study [NCT05879926] is an important study that we are doing nationally to address this question, and I’m hopeful that the outcomes of that study comparing chemotherapy plus ovarian function suppression [OFS] and endocrine therapy vs OFS plus endocrine therapy alone will help address this question in the future.

What is the significance of the final overall survival (OS) data from the phase 3 KEYNOTE-522 trial (NCT03036488)?

The KEYNOTE-522 data, when they first came out, demonstrated improvement in pathologic complete response and then event-free survival. This was exciting information for the management of advanced TNBC, and the recent OS data have helped us clearly understand that this treatment is having the effect we had hoped for: that it is preventing recurrences and improving survival for a disease that affects many people, especially at young ages, and can have devastating outcomes. Our next question, because there’s always a next question, is: Do we need all the chemotherapy that is part of the KEYNOTE-522 regimen: anthracyclines, cyclophosphamide, carboplatin, and taxanes? It’s a lot of chemotherapy. There’s good work going on nationally, including the scarlet study, that is trying to evaluate whether [treatment] de-escalation with an anthracycline-free regimen can have the same efficacy as the KEYNOTE-522 regimen.

Lastly, one of the key challenges we face still with immunotherapy is lifelong adverse effects that can happen in the setting of these agents. Developing better predictors for which patients are going to benefit from these agents again, or who might develop toxicities and in whom we might want to avoid [these agents], continues to be a high priority.

How might the data from the phase 3 DESTINY-Breast12 trial (NCT04739761) influence clinical practice for patients with HER2-positive brain metastases?

In HER2-positive breast cancer, brain metastases remain one of our biggest challenges. Although we can often control the systemic disease well elsewhere in the body, brain metastases often develop and become a life-limiting consequence of the disease. At the same time, we’ve also had difficulty identifying newer systemic therapies that can effectively control or shrink brain tumors. Therefore, we’ve relied for many years on radiation and surgery as primary treatments [for these patients].

However, we’ve seen advances in the past few years, with agents like tucatinib [Tukysa], with some central nervous system [CNS] activity. As T-DXd has come into the realm of treatment for [patients with] HER2-positive breast cancer, there have been interesting observations that [this agent could] have activity also in patients who are affected by brain metastases. The results of the DESTINY-Breast12 study are further evidence that T-DXd seems to have CNS activity, and that this agent can be considered as one of our approaches for patients who have HER2-positive breast cancer with brain metastasis.

What is your main message for colleagues about individualized breast cancer management?

Treatment for breast cancer needs to be individualized based on discussions with the patient about their preferences and understanding their underlying other medical issues. The other consideration that is important in this individualization is considering how we use our tools, [such as] molecular testing like Oncotype DX or next-generation sequencing [NGS], to look for tumor mutations to help identify a treatment strategy that makes sense for what’s going on in that patient’s tumor. [We are making] important advances with both circulating tumor DNA and NGS but we also need to understand some of the limitations of those tests when we’re interpreting them and discussing treatment options for patients, making sure we’re putting that all into context.