Continued Research Underscores the Need to Explore New Approaches Across the Breast Cancer Armamentarium


Stephanie L. Graff, MD, expands on treatment options available for patients with premenopausal breast cancer who are trying to conceive, highlighting the POSITIVE trial in women with endocrine-responsive breast cancer.

Stephanie L. Graff, MD

Stephanie L. Graff, MD

Better understanding of optimal treatment options for patients with premenopausal breast cancer is necessary to improve outcomes in this population, according to Stephanie L. Graff, MD, who added that expanding this armamentarium remains vital as additional research is done regarding treatment during pregnancy as well as the effects ovarian suppression or ablation may have on this group.

“I was able to present on premenopausal breast cancer at our [event]. My premenopausal breast cancer presentation focused on an EBCTCG [Early Breast Cancer Trialists’ Collaborative Group] meta-analysis that looked at ovarian function suppression and the benefits for premenopausal women,” Graff said in an interview with OncLive® following a State of the Science Summit™ (SOSS) on breast cancer, which she chaired.

In the interview, Graff expanded on treatment options available for patients with premenopausal breast cancer who are trying to conceive, highlighting the POSITIVE trial (NCT02308085) in women with endocrine-responsive breast cancer, and discussed ongoing and planned research at the Lifespan Cancer Institute at Rhode Island Hospital in Providence.

Graff is the director of breast oncology at the Lifespan Cancer Institute, associate professor of medicine at Brown University, and coleader of the Breast Cancer Translational Research Disease Group.

OncLive: Could you expand on the goals for your presentation, pulling out key points that highlight the POSITIVE study?1

Graff: I reviewed the POSITIVE trial, [which is] looking at withholding endocrine therapy for up to 2 years to allow for breast cancer survivors to move into pregnancy.

The POSITIVE trial looked at patients who were premenopausal at the time of their breast cancer [diagnosis], and participants were all under [aged 42 years] and had been on endocrine therapy for at least 18 months. These patients all had an early-stage breast cancer and hormone receptor [HR]–positive breast cancer. Although the design allowed for stage I, II, or stage III breast cancer, only 1% of the participants had stage III disease, which makes this a little bit harder to generalize to a stage III population. Moreover, 62% of the patients had prior chemotherapy, and the median age was 37 years.

Patients who participated were allowed any time after 2 years of endocrine therapy to take an interruption of their endocrine therapy for up to 2 years. During those 2 years, they were allowed to attempt to conceive, conceive, deliver, [and] breastfeed, and they were also given a 3-month washout from the initial medications. If patients hadn’t achieved pregnancy by 1 year, a fertility consultation was encouraged.

What results of the POSITIVE trial were shared at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting?

The results of the POSITIVE trial showed that patients had an excellent breast cancer-free interval and a distant relapse-free interval that compared with the historical cohort of patients who had been enrolled in the SOFT and TEXT trials [NCT00066690; NCT00066703], where despite this 2-year interruption with endocrine therapy, we didn’t see a worse breast cancer outcome. The [investigators also] reported the specific outcomes for the pregnancies.

We saw that 74% of patients who participated were able to have 1 pregnancy, and 64% of all women—86% of those who became pregnant—had at least 1 live birth, with a relatively low rate of pregnancy complications considering the age of the participants and their prior history of childbirth. Globally, the results of the POSITIVE trial tell us that it’s very safe and appropriate for us to be considering endocrine therapy interruption after 2 years for patients who are still hoping to have another pregnancy or birth.

Looking at the EBCTCG meta-analysis, what highlights of this study were shared at the 2023 ASCO Annual Meeting?2

The EBCTCG analysis was a patient level meta-analysis of 14,993 patients, all of whom were premenopausal in over 25 randomized trials. The analysis looked at the individual patient level data and included patients who were premenopausal at the time of randomization on the study. The question posed was whether ovarian suppression or ablation affect premenopausal women in a variety of different situations as it pertains to their breast cancer recurrence, and overall survival [OS].

What we saw was that for patients who were premenopausal after chemotherapy, ovarian ablation or suppression significantly reduced their risk of recurrence at 15 years with a 15-year gain in improved outcome of 9.8%. Specifically, looking at the risk of mortality for patients who had ovarian ablation or suppression among those who had no chemotherapy or were premenopausal after chemotherapy, their breast cancer mortality was reduced by 10.9%, supporting the use of ovarian suppression or ablation.

Notably, investigators also looked at all-cause mortality and we did not see an increased risk of all-cause mortality among the patients who had ovarian ablation or suppression. Despite historical assumptions, [these data] support that ovarian ablation or suppression didn’t increase secondary causes of death, like heart disease. Altogether I think that the EBCTCG meta-analysis further supports the value of ovarian function suppression, [particularly] in patients under [aged 45 years].

You also discussed antibody-drug conjugates (ADCs) in breast cancer on behalf of Aditya Bardia, MD, of Massachusetts General Hospital Cancer Center. How has the implementation of treatment with ADCs affected patients with this disease?

This is the age of the ADCs in breast cancer and we’re seeing a flourishing of ADCs. We did have a review during our SOSS on sacituzumab govitecan-hziy [Trodelvy], which is now approved for both triple-negative breast cancer, based on the results of the phase 3 ASCENT trial [NCT02574455], and HR-positive breast cancer, based on the results of the phase 3 TROPiCS-02 trial [NCT03901339].

[Results showed that] OS improved from 11.2 months to 14.4 months for patients with HR-positive breast cancer treated with sacituzumab govitecan.3 This is a new indication for all of us and really expands our options. Patients in the TROPiCS-02 trial were also very heavily pretreated, therefore, that benefit is notable.

Additionally, we reviewed other ADCs including fam-trastuzumab deruxtecan-nxki [Enhertu], which is shaking up the landscape of metastatic breast cancer, including HR-positive disease as well as the new entity of HER2-low breast cancer. We’re able to use trastuzumab deruxtecan in either of those [scenarios].

[Upcoming interests] that we discussed included how trastuzumab deruxtecan is being explored in earlier lines of therapy for metastatic HR-positive breast cancer, as well as in metastatic HER2-positive breast cancer. Notably, it is also being explored for refractory disease after neoadjuvant chemotherapy, similar to the previously reported phase 3 KATHERINE study [NCT01772472]. Therefore, we may start to see the indications for trastuzumab deruxtecan continue to expand.

Mary Ann Fenton, MD, of the Lifespan Cancer Institute, discussed the use of CDK4/6 inhibitors in HR-positive breast cancer. How have the use of these inhibitors for patients affected their treatment?

Dr Fenton reviewed the role of CDK4/6 inhibitors in HR-positive early-stage breast cancer. She walked us through both the phase 3 NATALEE trial [NCT03701334], looking at ribociclib [Kisqali], as well as the phase 3 monarchE study [NCT03155997], looking at abemaciclib [Verzenio].

There’s quite a bit of nuance between the 2 trials in terms of the populations of patients that were included, differences in the way that the medications are prescribed and scheduled, and dosing length of time, particularly as compared with the metastatic setting and even compared with one another in this earlier-stage indication. It was great to get a comprehensive snapshot of that data.

Komal Jhaveri, MD, FACP, of Memorial Sloan Kettering Cancer Center, discussed new strategies for targeting the estrogen receptor. What did you take away from this talk?

Dr Jhaveri offered a tour de force of the evolving landscape of metastatic HR-positive breast cancer. There are many selective estrogen receptor degraders [SERDs], selective estrogen receptor modulators, selective estrogen receptor covalent antagonists, and now a new class of medications coming into the metastatic HR-positive landscape, making it beneficial to get a review of those medications, where they currently stand in terms of trial development, and potential adverse effects, risks, and benefits of the available agents.

The key takeaway is that we’re probably at phase 1 of at least a phase 2 process where, right now, many of the trials that have reported are looking at things like SERDs as a single agent. Because they’re designed to be safe in combination with other therapies, even other hormone-targeted therapies, I expect to see a second phase or round of data as we start to learn how to use the new generation of medications in combination with other treatments for targeting and precision therapy for HR-positive metastatic breast cancer.

Ann H. Partridge, MD, MPH, of Dana-Farber Cancer Institute, spoke in place of Sara M. Tolaney, MD, MPH, of Dana-Farber Cancer Institute, on the HER2-positive treatment arena. What updates have been across the landscape that you believe have had the greatest effect on clinical practice?

The landscape for HER2-positive metastatic breast cancer has been exciting over the past several years. We’ve seen the FDA approvals of trastuzumab deruxtecan and the approval of tucatinib [Tukysa], both of which are now being explored in earlier lines of treatment. Both FDA-approved agents have continual emerging data, looking at the drugs in combination with other therapies and even in the curative intent, adjuvant [and] neoadjuvant setting.

What we’re seeing as we look through these data is we’re starting to get more of the translational science data that can help us understand who may be getting maximal benefit or how mechanisms of resistance [in] those different populations are developing. Additionally, we’re starting to see emerging data on how all these medications work for patients with brain metastasis, which is a very important consideration in this community.

Are you participating in any ongoing or upcoming research that you would like to highlight?

I am proud to be a part of the upcoming phase 3 [ADJUVANT] WIDER study [NCT05827081]. WIDER is a study that’s going to look at the use of ribociclib for the adjuvant treatment of [patients with] high-risk, HR-positive breast cancer. We’ve already seen the results of the NATALEE study, and those data will continue to mature and continue to report additional end points. By following NATALEE with the WIDER study, it will allow us to expand the knowledge and understanding of how adjuvant ribociclib benefits an even broader population of patients with HR-positive early-stage breast cancer. That is a great opportunity for patients to participate [in].

A second project that we’re really excited to be working with SWOG on is the phase 3 SWOG 2205 trial [NCT05642611], which is looking at a new device to hopefully reduce the risk of developing chemotherapy induced peripheral neuropathy. This clinical trial is randomly assigning patients to compression, cryocompression (meaning ice and pressure), or a placebo arm. The question will be how those different therapies might reduce patients’ risk of developing peripheral neuropathy. This is a tremendous opportunity to continue to provide better care to the patients we take care of.


  1. Partridge AH, Niman SM, Ruggeri M, et al. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023; 388(18):1645-1656. doi:10.1056/NEJMoa2212856
  2. Gray RG, Bradley R, Braybrooke J, et al. Effects of ovarian ablation or suppression on breast cancer recurrence and survival: patient-level meta-analysis of 14,993 pre-menopausal women in 25 randomized trials. J Clin Oncol. 2023;41(suppl 16):503. doi:10.1200/JCO.2023.41.16_suppl.503
  3. FDA approves sacituzumab govitecan-hziy for HR-positive breast cancer. News release. US Food and Drug Administration. February 3, 2023. Accessed September 6, 2023.
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