4 days ago
Optimizing Therapies for HR+ Early-Stage Breast Cancer
Hormone receptor-positive (HR+) early-stage breast cancer is one of the most common types of breast cancer, characterized by tumor cells that have receptors for estrogen or progesterone hormones. Although significant progress has been made in screening, treatment, and surgery, the risk of recurrence still remains. To explore therapies for managing HR+ early-stage breast cancer, Medscape spoke with Hope S. Rugo, MD, FASCO, division chief of breast medical oncology and a professor of medical oncology and therapeutics research at City of Hope Comprehensive Cancer Center, Duarte, California, and professor emeritus at the University of California San Francisco. Read on for her insights.
What role does risk stratification play in determining therapy for HR+ early-stage breast cancer?
Hope S. Rugo, MD, FASCO
This is a critical area. It is a key aspect of determining appropriate treatment and extent of treatment, and we are still learning more about how to appropriately stratify based on clinicopathologic and genomic characteristics. Gene expression tests are used widely to understand prognosis and benefit from chemotherapy, but there are ongoing issues in HR+ disease including disease heterogeneity and how to optimally treat very young women with HR+ disease.
We use clinicopathologic data in combination with gene expression tests to stratify risk, but this approach doesn't always provide us with the necessary information for determining the optimal adjuvant or neoadjuvant treatment. The adjuvant CDK4/6 inhibitor trials will be helpful, as they will allow for longer follow-up of patients with high- and intermediate-risk disease.
Additionally, newer predictors, such as gene expression signatures that may estimate the benefit from immunotherapy, are also being evaluated.
What factors influence your choice between endocrine therapy and chemotherapy for HR+ early-stage breast cancer?
Multiple factors have an influence on the choice of therapy, including the extent of disease and tumor biology. We have also learned that the intensity or extent of estrogen positivity plays a role in endocrine sensitivity. In terms of tumor biology, understanding tumor proliferation and chemotherapy sensitivity is critical.
We are currently using gene expression tests, but it is clear that these are insufficient, even within the context of age and tumor burden. Additional markers that help to identify up-front or emerging resistance to endocrine therapy are critical. Data from the CDK4/6 inhibitor adjuvant trials has further complicated this question — as now the issue is where optimal outcome can be achieved in less chemotherapy-responsive, higher-risk disease with the addition of abemaciclib or ribociclib.
Considering recent research, is extended endocrine therapy actually beneficial?
I believe it is, but careful consideration needs to be given to the decision to extend therapy. Disease burden is of course our first consideration, but sensitivity to endocrine therapy, development of resistance, and response to chemotherapy in appropriate cases need to be taken into consideration. Interestingly, several analyses have suggested that patients with low proliferative and genomic risk, but a higher disease burden, might be most likely to benefit from extended duration endocrine therapy due to the long natural history of this disease. We are now exploring the use of switching the type of endocrine therapy in the high-risk adjuvant setting and the use of circulating tumor DNA (ctDNA) to optimize therapy.
What role do CDK4/6 inhibitors play in the adjuvant setting for HR+ early-stage disease?
Both abemaciclib and ribociclib have reduced the risk of recurrence and the risk of distant recurrence in patients with intermediate or high-risk early-stage breast cancer. The duration of therapy varies, and eligibility criteria overlap; however, the recent NATALEE trial included a diverse population, including an intermediate-risk group (stage II, node-negative with additional risk factors) to evaluate the role of the CDK4/6 inhibitors among such populations. The striking aspect of this trial was the carry-over effect, shown most clearly in the monarchE study with 5-year follow-up. Even 3 years after completing treatment with abemaciclib, the data showed an increasing impact on disease-free survival and distant disease-free survival. Although there has been no overall survival impact yet, fewer patients with abemaciclib in monarchE are living with metastatic disease.
What are the most critical research gaps or upcoming trials that could reshape how we manage HR+ early-stage breast cancer in the upcoming years?
A few main things to address are improving risk stratification, how to use ctDNA to improve outcome, and understanding if use of oral selective estrogen receptor degrader (SERDs) in sequence improve outcome and their optimal therapy duration.
So far, studies using ctDNA to assess risk and guide therapy changes have been challenging due to the low number of positive ctDNA results. Moreover, ctDNA detection has sometimes coincided with metastatic disease already visible on scans in case of several aggressive cancers. We still don't know the optimal treatment approach when molecular evidence of disease is found, which is making studies focus on adding targeted therapy or changing endocrine therapy.
Several trials are evaluating oral SERDs in the early stage setting for the treatment of high-risk disease. While these trials will also collect ctDNA, patient eligibility is not based on these tests.
One very important area that requires additional research is understanding early-stage breast cancer in young women, where tumors seem to behave poorly — particularly in women under the age of 40 — even when patients are treated with optimal therapy. Understanding optimal therapy is a key research focus, and further investigation of biological drivers in both ductal and lobular cancers is warranted.
The OFFSET trial aims to determine the value of adjuvant chemotherapy vs ovarian function suppression in conjunction with standard endocrine therapy and CDK4/6 inhibitors as indicated. However, this study is challenging to enroll in.
Hope S. Rugo, MD, FASCO, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Chugai; Puma; Sanofi; Napo; Mylan
Received research grant from: AstraZeneca; Daiichi Sankyo, Inc.; F. Hoffmann-La Roche AG/Genentech, Inc.; Gilead Sciences, Inc.; Lilly; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Pfizer; Stemline Therapeutics; OBI Pharma; Ambrx
