In ASCO's most recent Clinical Cancer Advances report, the breast cancer-related developments highlighted included an antibody-drug conjugate for HER2-positive cancer, an immunotherapy-chemotherapy combination for triple-negative cancer, and an internet-based cognitive behavioral therapy program that improved treatment-induced menopausal symptoms.
In the following interview, the report's breast cancer specialty editor, Jane Lowe Meisel, MD, of Emory University Winship Cancer Institute in Atlanta, elaborated on the advances and discussed future research priorities.
For the advance of the year in the report overall, ASCO chose the "refinement of surgical treatment of cancer" -- how has this advance impacted treatment of patients with breast cancer?
Meisel: The choice reflects not just advances in surgery itself but also advances in systemic therapy that have changed, in many instances, how and when surgery is performed. This has been particularly true in the case of the melanoma and pancreatic cancer studies included in the report. In breast cancer, there has been a shift towards neoadjuvant therapy for more patients in recent years because of the growing body of data showing that response to neoadjuvant therapy not only informs prognosis but can also predict benefit from the addition of other therapies in the adjuvant setting.
The CREATE-X study showed that for patients with triple-negative breast cancer who do not achieve a pathologic complete response (pCR) to neoadjuvant chemotherapy, six to eight cycles of adjuvant capecitabine can improve outcomes compared with observation. The KATHERINE study showed that for patients with HER2-positive breast cancer who do not achieve a pCR to modern neoadjuvant anti-HER2 therapies, completing a year of anti-HER2 therapy with adjuvant trastuzumab emtansine improves outcomes compared with standard-of-care trastuzumab.
In this way, surgery for breast cancer is not only part of the path to potential cure, but has also become a critical tool, allowing the multidisciplinary team to obtain critical information about response to therapy in order to choose the best path forward for their patients. Additionally, more clinical trials are underway that will allow us to better understand how to optimize pCR as a predictive and prognostic tool and how to use genomic information from residual disease found at the time of surgery to personalize subsequent adjuvant therapy for patients.
The clinical advances associated with breast cancer in the report mostly had to do with combination therapies, such as the PD-L1-targeted immunotherapy atezolizumab combined with chemotherapy for triple-negative breast cancer. Why do you think so many breast cancer advances were related to combination therapy rather than other types of therapy this time around?
Meisel: I think this all has to do with disease biology. The immunotherapy story in breast cancer is one that is rapidly evolving, but studies have shown fairly consistently that responses to single-agent PD-1 and PD-L1 antagonists occur in less than 10% of patients with metastatic breast cancer.
Chemotherapy may augment immunity by relieving immune-suppressive signals in the tumor microenvironment and/or by enhancing immune priming through antigen release. Two phase III trials, IMpassion130 and more recently KEYNOTE-355 (not yet presented, but referred to in a Feb. 2020 press release from Merck), showed improved progression-free survival in patients with PD-L1-positive triple-negative breast cancer with the addition of atezolizumab (IMpassion130) or pembrolizumab (KEYNOTE-355) to chemotherapy, suggesting proof of this principle.
As is often the case, strategies that are successful in the metastatic setting usually are brought to the curative setting for evaluation, and this has happened with chemoimmunotherapy in breast cancer. The I-SPY study has shown that pembrolizumab improves pCR rates as part of neoadjuvant therapy for ER-positive and triple-negative breast cancers, and the KEYNOTE 522 study very recently showed the benefit of this approach in triple-negative disease. It is likely that immunotherapy may become part of the standard of care for some of our early-stage breast cancer patients.
Additional efforts are now focusing on developing immunotherapy combinations that can convert non-responders to responders, deepen the responses that some patients are seeing, and surmount acquired resistance to immunotherapy.
I suspect that in 2021 we will see more novel combinations of targeted therapies and immunotherapies in breast cancer, and perhaps these will lead to opportunities to postpone or minimize the use of chemotherapy in certain breast cancer patient populations.
Another advance related to breast cancer was internet-based cognitive behavioral therapy that improved treatment-induced menopausal symptoms in women with breast cancer. Why is treating these symptoms important?
Meisel: The most common type of breast cancer is hormone receptor-positive breast cancer, and the most effective treatments we have for this cancer are anti-estrogen therapies -- otherwise known as endocrine therapy. We know that these therapies can cut the risk of breast cancer recurrence down by one third to one half, but because they must be taken daily for 5-10 years for optimal effect and can cause significant menopausal side effects, many women are not able to complete the recommended course of therapy. Hot flashes, night sweats, sexual dysfunction, insomnia, and psychological distress are a few examples of side effects that can significantly impact quality of life and interfere with treatment adherence. There are ways to treat some of these side effects (antidepressants, sleep aids, etc.), but these treatments often come with their own side effects and can be expensive and are often not as effective as desired.
The internet-based study showed that a 6-week cognitive behavioral therapy (CBT) program improved hot flashes, night sweats, and sleep quality compared with no intervention and also helped menopausal symptoms in general. This is intriguing because if this benefit of CBT is validated in larger studies, patients would have a cost-effective, easily accessible, and nontoxic option for managing endocrine therapy-related side effects. Patients could enjoy better quality of life on endocrine therapy and possibly be more likely to stay on endocrine therapy for the recommended duration of treatment. If this were the case, CBT might be an intervention that improves not only quality of life, but also disease-related outcomes as well.
The report also identified research priorities to accelerate progress against cancer. Can you discuss how one of these research priorities could improve breast cancer treatment?
Meisel: There are a number of research priorities identified in the report that will help improve breast cancer treatment: identifying strategies to predict response and resistance to immunotherapy; limiting the extent of surgery by optimizing systemic therapy; optimizing care for older adults; reducing the adverse consequences of cancer treatment; and reducing obesity's impact on cancer incidence and outcomes, to name a few. For breast cancer, the call to increase equitable access to cancer clinical trials is critical.
Pivotal breast cancer clinical trials are often large in number and take several years to enroll and even longer to lead to results that change clinical practice. However, some of the most vulnerable populations of patients with breast cancer -- those with the most aggressive and difficult-to-treat malignancies -- are from racial and ethnic minorities, lower socioeconomic groups, and younger age brackets.
As pointed out in the report, decreased representation of these groups in trials can not only limit early access to the promising treatments offered through these trials but also mean that the study results and conclusions may not take into account the many biologic, social, and cultural factors at play in the real world.
To improve access to clinical trials for these diverse populations, multiple interventions may be necessary. We will need to work on developing both community-based and internet-based educational tools to improve awareness and education about trials; evaluate ways to remove some of the economic barriers to clinical trial participation (such as time away from work for additional visits, and/or the need for child or elder care during that time, or inadequate Medicaid coverage of routine care costs); and work as an oncology community to bring more promising studies to institutions that treat a significant proportion of underrepresented patients.
If we can do this, we will be able to provide earlier access to novel therapies to many of the patients with breast cancer who need them the most -- and also ensure that the outcomes of the trials that change clinical practice are more generalizable to our highest-risk populations.
Finally, what would you most like oncologists to take away from this report?
Meisel: Taking care of cancer patients is one of the most emotionally and intellectually demanding livelihoods one could imagine. As oncologists, we care deeply about our patients, and yet are faced with the challenge of having to recommend difficult-to-tolerate treatments in order to give patients the best chance of survival. We celebrate the triumphs, help with the struggles, and cope with the loss of a patient.
However, the future of cancer care is bright. Advances in targeted therapy, immunotherapy, and multidisciplinary combination therapies are abundant, and research in cancer prevention is also becoming more robust. We are able to use genomic tests and other tools now to offer more accurate predictions about prognosis and to be able to better personalize therapy.
The report offers example after example of promising research that has improved and will continue to improve the way we provide care for our patients ... I look forward to seeing what the next advances will be in the 2021 report.
Read the article abstract here and expert commentary about the clinical implications here.
Disclosures
Meisel disclosed relationships with Total Health Conferencing, Pfizer, Seattle Genetics, and Puma Biotechnology.
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