The 2021 San Antonio Breast Cancer Symposium

Presenters at the 2021 San Antonio Breast Cancer Symposium (SABCS; December 7–10) reported the latest findings in breast cancer research. NEJM Journal Watch Oncology and Hematology Editor-in-Chief Dr. William Gradishar summarizes and provides perspective for some of the key studies. Abstracts can be viewed via the SABCS site or the links provided.

Elacestrant monotherapy reduces risk for death and disease progression by 30% compared with standard of care in patients with estrogen receptor–positive, HER2-negative metastatic breast cancer that progressed on endocrine therapy, according to the industry-funded, phase 3 EMERALD trial (abstract GS2-02). Elacestrant is an investigative oral selective estrogen receptor degrader (SERD).

In the international open-label trial, 477 postmenopausal patients with disease progression on one or two lines of endocrine therapy plus a CDK4/6 inhibitor and up to one line of chemotherapy were randomized to elacestrant (400 mg daily) or standard of care (fulvestrant or an aromatase inhibitor).

At 12 months, progression-free survival (PFS) by blinded independent review was significantly higher in the elacestrant group than in the standard-of-care group among all patients (22% vs. 9%) and among those with ESR1 mutations (27% vs. 8%). Treatment-related adverse events — mostly grade 1–2 nausea, vomiting, and fatigue — were more common with elacestrant (25% vs. 9%). No treatment-related deaths occurred.

The authors conclude that elacestrant “has the potential to become the new standard of care” in this patient population.

Summary by Cara Adler, MS, Staff Writer

COMMENT — DR. WILLIAM GRADISHAR

The oral SERDs are a very exciting class of drugs —the first new endocrine agents in 20 years. This class seems to have activity in patients who develop ESR mutations as a result of exposure to prior endocrine therapy. Oral SERDs will likely be combined with CDK4/6 inhibitors with a goal of extending PFS over what can be attained with currently available endocrine therapy partners. The EMERALD trial is the first of several large trials involving oral SERDs to report results.

Watch our interview with the lead author of the EMERALD trial.

The addition of metformin to standard therapies did not confer a survival advantage in patients with estrogen receptor and/or progesterone receptor (ER/PgR)-positive or ER/PgR-negative early breast cancer, according to the international phase 3 MA.32 trial (abstract GS1-08).

Roughly 3650 patients younger than 75, without diabetes, and within 12 months of diagnosis were randomized to oral metformin (850 mg twice daily) or placebo for 5 years. Most patients also received radiotherapy, chemotherapy, or hormonally targeted therapy. Patients were followed for a median of 96 months.

In the primary analysis of patients with ER/PgR-positive and ER/PgR-negative breast cancer, invasive disease-free survival did not differ significantly between the metformin and placebo groups. Other outcomes — including overall survival, breast cancer–free interval, distant relapse–free survival, and breast cancer–specific survival — also did not differ between treatment groups. Rates of toxicity grade 3 or higher were similar with metformin and placebo (21.7% and 18.7%).

An exploratory analysis suggested a survival benefit with metformin in a subset of patients with HER2-positive disease that expresses a C allele of the ATM-associated rs11212617 single-nucleotide polymorphism.

The authors conclude that adjuvant metformin treatment does not improve breast cancer outcomes in patients with ER/PgR-positive or ER/PgR-negative disease.

Summary by Cara Adler, MS, Staff Writer

COMMENT — DR. WILLIAM GRADISHAR

Though the preclinical and clinical data with metformin suggested a potential to affect signaling pathways important for breast cancer, the data from this clinical trial are negative. This is not to suggest that metformin is a bad drug in breast cancer patients. It has utility as an antidiabetic agent and to mitigate the side effects of some cancer therapies, such as alpelisib. Sometimes negative results from clinical research are just as relevant as positive results since negative results provide clinicians with evidence to avoid particular medications for which there is no benefit.

Among premenopausal women with hormone receptor–positive, HER2-negative, node-positive breast cancer with a recurrence score at or below 25, adjuvant chemotherapy continues to be associated with an improvement in invasive disease–free survival (iDFS), according to a follow-up and subanalysis of the SWOG S1007 RxPONDER study (abstract GS2-07).

Read our coverage of the trial, published in the New England Journal of Medicine (NEJM JW Onc Hematol Dec 16 2021 and N Engl J Med 2021 Dec 16.)

In the original study, roughly 5000 pre- and postmenopausal women with breast cancer were randomized to endocrine therapy (ET) with or without chemotherapy. At a median 5 years' follow-up, premenopausal women saw a 5.2% absolute benefit in invasive disease–free survival with the addition of chemotherapy (94.2% for the ET+CT group vs. 89.0% for the ET group). The postmenopausal women saw no benefit.

In updated data presented at SABCS and covering a median 6 years' follow-up, the absolute benefit for iDFS among premenopausal women who underwent chemotherapy had increased to 5.9%. Chemotherapy was also associated with a 3.3% absolute benefit in distant disease–free survival. With chemotherapy, premenopausal women with a recurrence score of 0–13 had a 2.3% absolute improvement in the distant recurrence–free interval and those with a score of 14–25 had a 2.8% improvement.

Rates of invasive disease–free survival were not statistically different among those who did and did not undergo ovarian function suppression.

Summary by Kelly Young, Staff Writer

COMMENT — DR. WILLIAM GRADISHAR

The RxPONDER trial design was amended to exclude patients with axillary micro-metastases, but prior to the change, 206 premenopausal women with axillary micro-metastases were included, and an exploratory analysis suggested an absolute improvement in 5-year iDFS) with chemotherapy of 7.3%. Furthermore, almost 60% of patients in the endocrine therapy-alone arm and 80% in the chemo-endocrine arm stopped having regular menstrual periods in the first 24 months, with an associated improvement in iDFS in both arms. It remains unclear from these data whether optimal endocrine therapy with ovarian suppression function suppression can substitute for chemotherapy.

The antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) shows “promising” antitumor activity and a “manageable” safety profile in patients with previously treated triple-negative breast cancer (TNBC), according to updated preliminary results from the phase 1, industry-funded TROPION-PanTumor01 study (GS1-05).

The analysis included 43 patients with advanced or metastatic TNBC that relapsed or progressed on standard therapies. Patients received intravenous Dato-DXd at a dose of 6 mg/kg every 3 weeks for a median of 2.8 months. At a median follow-up of 3.9 months, 15 of 38 evaluable patients (39%) had an objective response by blinded independent central review; all responses were partial. The disease control rate was 84%.

Grade 3 and higher treatment-related adverse events occurred in 35% of patients — most commonly stomatitis, fatigue, and vomiting — and were serious in five patients. There were no cases of treatment-related interstitial lung disease, grade 3 and higher diarrhea, or death. Adverse events necessitated dose reductions in nine patients and dose interruptions in three.

Summary by Cara Adler, MS, Staff Writer

COMMENT — DR. WILLIAM GRADISHAR

Dato-DXd is another antibody-drug conjugate with demonstrable activity in TNBC.Q2. In the subset of patients with metastatic TNBC, for whom chemotherapy was the only option just 3 to 4 years ago, there are now an expanding number of options that confer clinically relevant improvements in outcome. The challenge going forward will be how to optimally sequence immunotherapy, PARP inhibitors, antibody drug conjugates such as sacituzumab govitecan and Dato-DXd, as well as standard chemotherapy.

For patients with estrogen-receptor-α–positive, HER2-negative metastatic breast cancer who develop resistance-associated mutations in the estrogen-receptor gene during first-line treatment with an aromatase inhibitor (AI) plus palbociclib, switching to fulvestrant plus palbociclib can double progression-free survival, according to an industry-funded, phase 3 trial (abstract GS3-05).

In PADA-1, over 1000 patients received first-line AI-palbociclib and underwent ESR1 mutation screening every 2 months. Some 170 patients who developed ESR1 mutations and did not experience concurrent disease progression were randomized to either continue AI-palbociclib or switch to fulvestrant-palbociclib. During a median 26 months' follow-up, median progression-free survival was 11.9 months among patients who switched to fulvestrant-palbociclib versus 5.7 among those who continued AI-palbociclib.

Patients with disease progression on continued AI-palbociclib were allowed to cross over to fulvestrant-palbociclib. In this group, median progression-free survival was just 3.5 months over a median 15 months' follow up — showing limited benefit with fulvestrant when used after progression on AI-palbociclib.

Summary by Amy Herman, Staff Writer

COMMENT — DR. WILLIAM GRADISHAR

PADA-1 is interesting as it suggests we have tools that allow clinicians to identify at an earlier time point patients who are destined to have an early relapse. What remains to be determined is whether a change in systemic therapy prior to clinical evidence of disease progression, based on a change in a molecular marker, will alter outcome in a clinically meaningful way.

In patients with treatment-naive, nonmetastatic, triple-negative breast cancer, the benefits of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab are seen across a range of patient subgroups, according to new analyses from the industry-funded, phase 3 KEYNOTE-522 study (abstract GS1-01).

Nearly 1200 patients were randomized to receive pembrolizumab (200 mg every 3 weeks) or placebo, both given with four cycles of paclitaxel plus carboplatin, then with four cycles of doxorubicin or epirubicin plus cyclophosphamide. Participants then underwent definitive surgery, after which they received pembrolizumab or placebo for nine cycles. In the primary analysis, event-free survival over a median 39 months' follow-up was significantly improved in patients randomized to pembrolizumab (hazard ratio, 0.63).

Now, the benefits have held up in subanalyses according to various definitions of event-free survival, in women with nodal involvement (HR, 0.65) and without (HR, 0.58), and in premenopausal (HR, 0.62) and postmenopausal women (HR, 0.64). Benefits were also observed in subgroups according to overall disease stage, HER2 expression level, and lactate dehydrogenase level, but these did not always achieve statistical significance.

Summary by Amy Herman, Staff Writer

COMMENT — DR. WILLIAM GRADISHAR

In general these results are reaffirming, showing that pembrolizumab confers improvement in event-free survival in this population of patients with metastatic TNBC as well as in specific subsets of patients of TNBC. Evaluation to determine eligibility for pembrolizumab (CPS >10) should be an initial step in treating patients with metastatic TNBC.

Black women with breast cancer who undergo axillary lymph node dissection are four times more likely to develop lymphedema than white women, regardless of other risk factors, according to a prospective cohort study (abstract GS4-01).

Some 270 women undergoing breast cancer-related axillary lymph node dissection had their arm volume and body-mass index (BMI) assessed at baseline and at least once after surgery. Lymphedema was defined as a relative arm volume change of 10% or more from baseline.

The cohort comprised 62% white, 21% Black, 11% Asian, and 6% Hispanic women. Black women were older and had higher baseline BMI and likelihood of node positivity than the other groups.

At 18 months, incidence of lymphedema was 31% in Black, 20% in Hispanic, 12% in white, and 11% in Asian women. In multivariable analyses, Black race was the strongest predictor of lymphedema, with an odds ratio of 4.4 compared with white women. Other independent predictors were neoadjuvant therapy, older age, greater number of lymph nodes removed, and longer time since surgery. Lymphedema was also more likely to be severe in Black women.

Summary by Cara Adler, MS, Staff Editor

COMMENT — DR. WILLIAM GRADISHAR

Long-term quality-of-life issues differ according to a number of clinical and demographic parameters. Lymphedema is one of the toxicities of therapy that patients fear and that not infrequently goes unrecognized. Now, data from this large registry study at Memorial Sloan Kettering reveals a markedly increased risk for lymphedema in Black patients as well as a trend for the same in Hispanic compared to white patients. Additionally, it appears that patients receiving neoadjuvant therapy experience a several-fold increase in the risk of developing lymphedema. Patients should be counseled appropriately about increased risk for lymphedema and measures to mitigate its severity.

For premenopausal women with hormone receptor–positive early breast cancer, adjuvant therapy with exemestane plus ovarian function suppression (OFS) is superior to tamoxifen plus OFS at 12 years, according to an updated analysis of roughly 4700 participants in the TEXT and SOFT trials (GS2-05).

In TEXT, patients were randomized within 12 weeks of surgery to 5 years of either exemestane or tamoxifen, plus OFS; chemotherapy was optional. In SOFT, patients were similarly randomized within 12 weeks of surgery, or within 8 months of completing chemotherapy. After a median 9 years' follow-up, disease-free survival and distant recurrence-free interval were both improved with exemestane plus OFS versus tamoxifen plus OFS.

In the latest analysis, 12-year disease-free survival continued to favor exemestane over tamoxifen (80.5% vs. 75.9%). Secondary outcomes, including 12-year invasive breast cancer–free interval and distant recurrence–free interval, also favored exemestane. Overall survival was high in both groups and did not differ significantly between the two (90.1% and 89.1%, respectively). The benefits of exemestane plus OFS were more consistent in patients with HER2-negative disease and in those with high-risk disease features.

Summary by Amy Herman, Staff Writer

COMMENT — DR. WILLIAM GRADISHAR

In patients with high-risk features, particularly those for whom adjuvant chemotherapy is deemed necessary, optimal endocrine therapy with an aromatase inhibitor and OFS confers a clinically relevant improvement in outcome. Since late occurrence still may be anticipated, these patients will be followed for another 5 years. In addition, clinicians will need to have a discussion with patients regarding potential toxicities associated with OFS, including menopausal symptoms and risk of fractures.

When combined with ovarian suppression, aromatase inhibitors (AIs) are more effective than tamoxifen in reducing breast cancer recurrence — but not mortality — in premenopausal women with early-stage, estrogen receptor–positive disease, a meta-analysis shows (abstract GS2-04.

Investigators analyzed patient-level data from four randomized trials that included roughly 7000 women who received ovarian suppression/ablation and either AIs or tamoxifen for 3 or 5 years. Patients were followed for approximately 8 to 10 years.

In the pooled analysis, breast cancer mortality did not differ between the AI and tamoxifen groups. Women randomized to AIs had significantly lower annual rate of recurrence (relative risk, 0.79), with a 5-year absolute risk of recurrence of 6.9% for AIs versus 10.1% for tamoxifen. The risk of distant recurrence was also lower with AIs (RR, 0.83). The AI recurrence benefit was most pronounced during the first 4 years and plateaued or disappeared thereafter. The recurrence reduction was independent of age, body-mass index, tumor size, tumor grade, histologic subtype, and chemotherapy. AI recipients had a higher rate of fractures (5.0% vs. 3.8%).

AIs showed no benefit over tamoxifen in patients with N4+ disease — a finding the authors call “surprising” because it contrasts with findings in postmenopausal women.

Summary by Cara Adler, MS, Staff Writer

Watch our interview with two of the investigators.

First-line treatment with ribociclib plus letrozole may offer a survival benefit to postmenopausal women with hormone receptor (HR)–positive, HER2-negative advanced breast cancer, regardless of the site or number of metastases, according to exploratory analyses from an industry-supported, phase 3 trial (abstract GS2-01).

In MONALEESA-2, women with HR-positive, HER2-negative, locoregionally recurrent or metastatic disease were randomized to receive first-line ribociclib or placebo, both with letrozole. In the previously reported primary analysis, median overall survival was significantly improved with ribociclib compared with placebo (63.9 vs. 51.4 months).

In the new exploratory analyses among roughly 670 participants, the benefits of ribociclib over placebo appeared to persist across all subgroups studied, including those with or without bone-only metastases, liver involvement, liver or lung involvement, or three or more metastatic sites at baseline. The findings are considered hypothesis-generating, as the analyses were not powered for statistical significance.

Summary by Amy Herman, Staff Writer

COMMENT — DR. WILLIAM GRADISHAR

The use of CDK4/6 inhibitors is well established, and they should be a go-to choice for treatment of metastatic breast cancer in combination with either an aromatase inhibitor or fulvestrant. There should be few patients for whom this combination is not viewed as the best choice to confer a meaningful benefit to clinical outcomes.