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The Evolving Role of Neoadjuvant Therapy for Operable Breast Cancer

Laura M. Spring, Yael Bar, and Steven J. Isakoff

The role of neoadjuvant therapy (NAT) for localized breast cancer has evolved tremendously over the past several years. Currently, NAT is the preferred option for high-risk early triple-negative (TN) and HER2-positive (HER2+) breast cancers and is indicated for some estrogen receptor–positive (ER+) breast cancers. In addition to traditional absolute indications for NAT, relative indications such as the assessment of outcomes at the time of surgery and guidance of treatment escalation and de-escalation have greatly evolved in recent years. Pathologic complete response (pCR) and the Residual Cancer Burden (RCB) index are highly prognostic for disease recurrence and survival, mainly in patients with TN or HER2+ disease. Furthermore, post-NAT escalation strategies have been shown to improve long-term outcomes of patients who do not achieve pCR. Additionally, by allowing the direct assessment of drug effect on the tumor, the neoadjuvant setting has become an attractive setting for the exploration of novel agents and the identification of predictive biomarkers. Neoadjuvant trial design has also evolved, using adaptive treatment approaches that enable treatment de-escalation or escalation based on response. However, despite multiple practice-changing neoadjuvant trials and the addition of various new agents to the neoadjuvant setting for early breast cancer, many key questions remain. For example, patient selection for neoadjuvant immunotherapy in TN breast cancer, de-escalation methods in HER2+ breast cancer, and the use of gene expression profiles to guide NAT recommendations in ER+ breast cancer. This article reviews the current approach for NAT in localized breast cancer as well as evolving NAT strategies, the key remaining challenges, and the ongoing work in the field.

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Clinical Outcomes With Abemaciclib After Prior CDK4/6 Inhibitor Progression in Breast Cancer: A Multicenter Experience

Seth A. Wander, Hyo S. Han, Mark L. Zangardi, Andrzej Niemierko, Veronica Mariotti, Leslie S.L. Kim, Jing Xi, Apurva Pandey, Siobhan Dunne, Azadeh Nasrazadani, Avinash Kambadakone, Casey Stein, Maxwell R. Lloyd, Megan Yuen, Laura M. Spring, Dejan Juric, Irene Kuter, Ioannis Sanidas, Beverly Moy, Therese Mulvey, Neelima Vidula, Nicholas J. Dyson, Leif W. Ellisen, Steven Isakoff, Nikhil Wagle, Adam Brufsky, Kevin Kalinsky, Cynthia X. Ma, Joyce O’Shaughnessy, and Aditya Bardia

Background: Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are widely used as first-line therapy for hormone receptor–positive metastatic breast cancer (HR+ MBC). Although abemaciclib monotherapy is also FDA-approved for treatment of disease progression on endocrine therapy, there is limited insight into the clinical activity of abemaciclib after progression on prior CDK4/6i. Patients and Methods: We identified patients with HR+ MBC from 6 cancer centers in the United States who received abemaciclib after disease progression on prior CDK4/6i, and abstracted clinical features, outcomes, toxicity, and predictive biomarkers. Results: In the multicenter cohort, abemaciclib was well tolerated after a prior course of CDK4/6i (palbociclib)-based therapy; a minority of patients discontinued abemaciclib because of toxicity without progression (9.2%). After progression on palbociclib, most patients (71.3%) received nonsequential therapy with abemaciclib (with ≥1 intervening non-CDK4/6i regimens), with most receiving abemaciclib with an antiestrogen agent (fulvestrant, 47.1%; aromatase inhibitor, 27.6%), and the remainder receiving abemaciclib monotherapy (19.5%). Median progression-free survival for abemaciclib in this population was 5.3 months and median overall survival was 17.2 months, notably similar to results obtained in the MONARCH-1 study of abemaciclib monotherapy in heavily pretreated HR+/HER2-negative CDK4/6i-naïve patients. A total of 36.8% of patients received abemaciclib for ≥6 months. There was no relationship between the duration of clinical benefit while on palbociclib and the subsequent duration of treatment with abemaciclib. RB1, ERBB2, and CCNE1 alterations were noted among patients with rapid progression on abemaciclib. Conclusions: A subset of patients with HR+ MBC continue to derive clinical benefit from abemaciclib after progression on prior palbociclib. These results highlight the need for future studies to confirm molecular predictors of cross-resistance to CDK4/6i therapy and to better characterize the utility of abemaciclib after disease progression on prior CDK4/6i.