Uptake of New Therapies Pushes Treatment Paradigm Forward in Breast Cancer

Angela DeMichele, MD, MSCE

The standard of care continues to evolve in all lines of therapy across the breast cancer paradigm, with new agents emerging in the treatment of HER2-positive disease, hormone receptor (HR)–positive disease, and triple-negative breast cancer (TNBC). Recent developments include the utilization of fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with metastatic HER2-positive breast cancer, plus neoadjuvant treatment strategies in TNBC, according to faculty from an OncLive^® Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

The event, chaired by Angela DeMichele, MD, MSCE, co-leader of the Breast Cancer Research Program, director of the Breast Cancer Clinical Trials Unit, co-director of the 2-PREVENT Breast Cancer Translational Center of Excellence, and the Alan and Jill Miller Professor in Breast Cancer Excellence at the Perelman School of Medicine at the University of Pennsylvania, Penn Medicine, highlighted updates across TNBC, including the affect of the phase 2 I-SPY 2 trial (NCT01042379) and the phase 3 KEYNOTE-522 trial (NCT03036488), plus the potential role of minimal residual disease (MRD) in the space.

DeMichele was joined by her colleagues:

• Rachel C. Jankowitz, MD, director of the Rena Rowan Breast Center and associate professor of Clinical Medicine at the Perelman School of Medicine at the University of Pennsylvania, Penn Medicine
• Amy S. Clark, MD, MSCE, deputy director of Breast Cancer Clinical Trials and assistant professor of Medicine at the Hospital of the University of Pennsylvania, Penn Medicine
• Oluwadamilola “Lola” Fayanju, MD, MA, MPHS, FACS, surgical director of the Rena Rowan Breast Center, The Helen O. Dickens Presidential Associate Professor, Innovation fellow at the Penn Center for Cancer Care Innovation, senior fellow at The Leonard Davis Institute of Health Economics, University of Pennsylvania, and chief of Breast Surgery at Penn Medicine

Below, DeMichele, Jankowitz, Clark, and Fayanju summarize the main messages of their presentations.

Neoadjuvant Treatment Strategies in TNBC

DeMichele: Neoadjuvant therapy is now the standard of care for TNBC that is greater than T1. [Treatment in the neoadjuvant setting] gives us insight into the response of the tumor and how patients [with TNBC] will ultimately do over time. It gives us the opportunity for a second shot [at treatment] with adjuvant therapy and gives [clinicians] the opportunity to try new agents in the neoadjuvant setting, such as in the I-SPY 2 trial, where we have the opportunity to test these agents in patients and they have the opportunity to be cured.

The optimal neoadjuvant regimen in TNBC is still in evolution. The KEYNOTE-522 trial, as the only positive trial [in the neoadjuvant setting in TNBC], has set the bar for giving the ‘kitchen sink’ to patients, and I’m not sure that this is truly necessary. In the coming years, we will be trying to understand whether patients need pembrolizumab [Keytruda] with an anthracycline, whether we need to add the carboplatin, and what the duration of pembrolizumab should be.

In addition, we now have post-neoadjuvant therapies that are standard of care, and we do not know yet whether patients who have had a pathological complete response can forgo this therapy, and we don’t know the best way to combine [these agents]. We do have some safety data, but we do not know whether we need to combine [pembrolizumab with olaparib (Lynparza) or capecitabine].

Finally, MRD may play an important role when finding the patients who are destined for relapse, but this is still not standard of care in [TNBC].

Updates in HER2-Positive Breast Cancer

Jankowitz: We have many new therapeutic options for patients with HER2-positive breast cancer. Trastuzumab deruxtecan is now a new standard of care in the second line [of metastatic breast cancer].

Both antibody-drug conjugates and TKIs appear to have central nervous system activity and can help treat patients with brain metastases. It will be interesting to see whether [those agents] can potentially start to play a role in preventing brain metastases.

Adjuvant Therapy Updates in HR-Positive/HER2-Negative Breast Cancer

Clark: The phase 3 RxPONDER trial [NCT01272037] randomized patients with 1 to 3 positive lymph nodes and a recurrence score equal to or less than 25 to receive chemotherapy with endocrine therapy vs endocrine therapy alone, and [the study] did not dictate whether patients who were premenopausal received ovarian function suppression.

The results of RxPONDER, which were presented [in 2021], showed that there was a difference between pre- vs postmenopausal patients. Postmenopausal patients did not benefit from chemotherapy; however, all premenopausal patients did. There are a lot of [clinicians] that postulate that the reason that premenopausal patients are benefiting from chemotherapy is that [the treatment] is causing amenorrhea, or it is functionally causing ovarian function suppression.

However, the trial wasn’t designed to look at that question. Because the investigators didn’t dictate whether premenopausal patients received ovarian function suppression, only a minority of patients received ovarian function suppression. One of the analyses that was done was to tease out whether patients who became amenorrheic had a lower risk of recurrence.

The bottom line is that you cannot draw any conclusions, and you also cannot conclude from this trial that we can use ovarian function suppression in place of chemotherapy for premenopausal patients. It is important for patients who are premenopausal with 1 to 3 positive lymph nodes to still be offered chemotherapy.

Factors to Consider in Locoregional Management of Breast Cancer

Fayanju: Axillary lymph node dissection is considered a fairly morbid procedure. [Patients] have risks of lymphedema that range between 10% and 45%. There is also a slightly increased risk of injury to the long thoracic thoracodorsal nerve, which can affect arm and shoulder movement. Increasingly, when we think about whether [a patient] needs axillary lymph node dissection, we are working to balance the benefit that can be provided to patients by removing the gross disease from the axilla [vs] the possibility of injury.

When managing the axilla, there are 3 primary things we are trying to work on. One of which is in whom axillary surgery can be minimized, given that we are concerned about long-term sequelae. Second, [we must consider how we] manage the axilla based on how a patient presents or how she might end up after receiving neoadjuvant systemic therapy. Finally, [we need to consider] how we can mitigate the adverse sequelae in axillary surgery.