The 2022 San Antonio Breast Cancer Symposium

Presenters at the 2022 San Antonio Breast Cancer Symposium (SABCS; December 6–10) reported the latest findings in breast cancer research. NEJM Group was on hand to cover the meeting. Here, NEJM Journal Watch Oncology and Hematology reports on some of the key studies, with clinical perspective provided by Editor-in-Chief Dr. William J. Gradishar and guest author Dr. Erika Hamilton. Dr. Hamilton is Director of Breast Cancer Research for Sarah Cannon Research Institute at Tennessee Oncology, Nashville.

Abstracts are available on the SABCS site; account registration is required to access all abstracts.

In second-line treatment of patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer, overall survival (OS) was longer with trastuzumab deruxtecan (T-DXd) than with trastuzumab emtansine (T-DM1), updated findings from the industry-supported, phase 3, randomized DESTINY-Breast03 trial show.

Among 524 patients, OS was significantly higher with T-DXd than with T-DM1 at 12 months (94% vs. 86%, respectively) and at 24 months (77% vs. 70%, respectively). Neither group reached median OS. Median progression-free survival was 28.8 months with T-DXd versus 6.8 months with T-DM1. Objective response rates were 79% with T-DXd versus 35% with T-DM1; complete response rates were 21% versus 10%, respectively.

Grade 3 or higher treatment-related adverse events were similar between the groups (56% and 52%). Mild-to-moderate drug-related interstitial lung disease (ILD)/pneumonitis occurred in 15% and 3%, respectively.

Summary by Christine Sadlowski, Staff Writer

COMMENT — DR. WILLIAM J. GRADISHAR

The results of DESTINY-Breast03 reaffirm that T-DXd should be the preferred option for most patients with HER2-positive metastatic breast cancer in the second-line setting. Every clinical endpoint is improved with T-DXd compared with T-DM1, while cases of ILD with T-DXd were relatively infrequent and not high grade.

Read more about the study and watch an interview with one of the researchers.

(Editors' note: Dr. Erika Hamilton is a coauthor on this abstract but did not contribute to our coverage of it.)

The benefits of adding abemaciclib to endocrine therapy for hormone receptor (HR)–positive, HER2-negative, node-positive, high-risk early breast cancer persists — and increases — 2 years after stopping abemaciclib, according to an interim analysis from the monarchE trial.

In the industry-funded trial, 5637 patients were randomized to standard adjuvant endocrine therapy for up to 10 years with or without abemaciclib for 2 years. In previously reported analyses at 2 and 3 years, invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) were significantly improved in the abemaciclib group.

Now, at 4 years, with all patients having finished abemaciclib therapy, the absolute IDFS benefit with versus without abemaciclib increased to 6.4%, compared with 4.8% at 3 years and 2.8% at 2 years. The benefit was observed in all subgroups. Similarly, at 4 years the absolute DRFS benefit with abemaciclib increased to 5.9%, compared with 4.1% at 3 years and 2.5% at 2 years. The IDFS and DRFS benefits were observed regardless of Ki-67 index. Mortality was lower in the abemaciclib group at 4 years (5.6% vs. 6.1%), although overall survival data remained immature.

There were no new safety signals.

Summary by Cara Adler, Staff Writer

COMMENT — DR. WILLIAM J. GRADISHAR

The longer follow-up now available in the monarchE dataset offers reassurance that the IDFS curves continue to separate rather than come together. Additionally, the vast majority of patients were able to complete 2 years of treatment while maintaining good quality of life.

COMMENT — DR. ERIKA HAMILTON

With longer follow-up in monarchE, we see that for patients with high-risk ER-positive breast cancer, cure rates continue to increase over time with the addition of abemaciclib to endocrine therapy.

Read more about the study.

In patients with heavily pretreated, HR-positive, HER-negative metastatic breast cancer, sacituzumab govitecan — a Trop-2–directed antibody–drug conjugate (ADC) — appears to confer a survival benefit regardless of patients' level of Trop-2 expression, according to a subgroup analysis of the industry-supported TROPiCS-02 study.

Roughly 550 patients with inoperable or metastatic breast cancer who had received at least one prior taxane, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, endocrine therapy, and two to four chemotherapy regimens were randomized to receive sacituzumab govitecan (10 mg/kg IV on day 1 and 8, every 21 days) or treatment of physician's choice (eribulin, gemcitabine, capecitabine, or vinorelbine).

Previously, sacituzumab govitecan showed improved progression-free survival (PFS) and overall survival (OS). Now, researchers examined efficacy by Trop-2 expression on archival tumor tissue based on histochemical scores (H-score, with higher scores indicating more Trop-2 expression).

Median PFS and OS were generally improved in the sacituzumab govitecan group, regardless of H-score. For instance, for those with an H-score below 100, median PFS was 5.3 months with sacituzumab govitecan and 4.0 months with treatment of choice, although the difference wasn't statistically significant. For those with an H-score of 100 or more, median PFS was significantly longer with sacituzumab govitecan (6.4 vs. 4.1 months).

Summary by Kelly Young, Staff Writer

COMMENT — DR. ERIKA HAMILTON

This is another ADC where we see that high expression of the target is not required for good activity. With trastuzumab deruxtecan's approval in HER2-low breast cancer and sacituzumab showing benefit across Trop-2 levels, ADCs are stealing the show and are here to stay.

COMMENT — DR. WILLIAM J. GRADISHAR

Like in the ASCENT trial in triple-negative breast cancer, sacituzumab govitecan outperformed standard chemotherapy options and did so regardless of Trop-2 expression. These data support the use of this compound in endocrine refractory patients, where until recently, the only option was standard chemotherapy.

Read more about the study.

Adding palbociclib to the selective estrogen receptor degrader fulvestrant doesn't seem to improve PFS in patients with HR-positive, HER2-negative metastatic breast cancer with prior progression on a CDK4/6 inhibitor, according to results of the phase 2, industry-supported PACE trial.

Some 220 patients whose breast cancer had progressed after an aromatase inhibitor and a CDK4/6 inhibitor (91% received palbociclib) were randomized to receive one of the following regimens:

• Fulvestrant alone
• Fulvestrant plus palbociclib
• Fulvestrant, palbociclib, and the programmed death ligand 1 (PD-L1) inhibitor avelumab

At a median 24 months' follow-up, median PFS was not significantly improved with fulvestrant plus palbociclib compared with fulvestrant alone (4.6 and 4.8 months, respectively). Median PFS was somewhat higher with fulvestrant, palbociclib, and avelumab (8.1 months) than with fulvestrant alone, but the difference was not statistically significant.

Summary by Kelly Young, Staff Writer

COMMENT — DR. ERIKA HAMILTON

This is our first look at the benefits of continuing the same CDK4/6 inhibitor after progression on a CDK4/6 inhibitor. It appears that continuation does not confer additional benefit. This is in contrast to the exploratory trial MAINTAIN, where switching CDK4/6 inhibitors from palbociclib to ribociclib with endocrine therapy at progression showed more benefit than endocrine therapy alone. It appears that novel endocrine therapies are the most promising therapies in the second line.

COMMENT — DR. WILLIAM J. GRADISHAR

The benefit of a different CDK4/6 inhibitor following disease progression while receiving another CDK4/6 inhibitor remains controversial. The PACE trial had a different design than MAINTAIN and is not comparable, but collectively these results do not support this strategy as a standard of care.

Read more about the study.

In patients with HER2-positive unresectable or metastatic breast cancer who've previously received trastuzumab emtansine (T-DM1), treatment with trastuzumab deruxtecan (T-DXd) in the third-line setting improves PFS and OS, as compared with treatment of physician's choice. The findings come from the industry-supported, phase 3 DESTINY-Breast02 trial.

In the multicenter, open-label trial, roughly 600 patients were randomized to T-DXd or treatment of physician's choice (trastuzumab + capecitabine or lapatinib + capecitabine). The primary outcome was PFS.

During a median follow-up of roughly 20 months, patients in the T-DXd group were 64% less likely than those in the physician's choice group to experience disease progression. Median PFS was 17.8 months versus 6.9 months, respectively. OS also favored T-DXd, with a median duration of 39.2 months versus 26.5 months.

Grade 3 or higher adverse events occurred in 53% of T-DXd recipients and 44% of physician's choice recipients. Adjudicated drug-related interstitial lung disease (usually low grade) occurred in 10.4% and 0.5% of patients, respectively.

Summary by Amy Herman, Staff Writer

COMMENT — DR. WILLIAM J. GRADISHAR

The antibody–drug conjugate T-DXd has dramatically improved outcomes in multiple settings: in the second-line setting as treatment for HER2-positive breast cancer, for those developing disease progression following treatment with T-DM1, and in those with HER2-low disease. With greater experience by clinicians using T-DXd, the concerns regarding T-DXd–associated interstitial lung disease, particularly high-grade, have diminished. We await the results of other trials exploring the use of T-DXd as a first-line therapy as well as combination strategies.

COMMENT — DR. ERIKA HAMILTON

It is extremely reassuring to see how well T-DXd outperformed standard chemotherapy in DESTINY-Breast02 in terms of PFS and OS. However, these data are really only practice-confirming at this point, and in fact, most patients are likely to receive T-DXd in the second-line setting with the results of DESTINY-Breast03 instead of third-line.

Read more about the study.

A new analysis from the RxPONDER trial finds worse breast cancer survival in Black compared with white women despite similar recurrence scores (RS), and a second new analysis finds greater cancer-related cognitive impairment (CRCI) with chemoendocrine therapy (CET) compared with endocrine therapy (ET) alone.

In RxPONDER, which received some industry support, roughly 5000 women with HR-positive, HER2-negative breast cancer with 1 to 3 positive axillary lymph nodes and 21-gene RS ≤25 were randomized to chemotherapy followed by ET or ET alone.

The analysis of racial/ethnic disparities involved some 4000 participants; 70% were non-Hispanic (NH) white, 6% NH Black, 15% Hispanic, and 8% Asian. The 21-gene RS was similar across groups, as was tumor size and number of positive nodes. High-grade tumors were more common among NH Black and Hispanic patients. Five-year invasive disease-free survival was significantly lower in NH Black than in NH white patients overall (87% vs. 92%) and in premenopausal and postmenopausal subgroups.

The analysis of CRCI involved cognitive function questionnaires completed by roughly 100 premenopausal and 400 postmenopausal participants at baseline through 36 months. Scores were similar in the CET and ET groups at baseline and decreased (indicating worse cognitive function) in both groups at 6 and 12 months, with greater decreases in the CET group. At 36 months, impairment scores had returned to baseline with ET but not CET. Results were similar in premenopausal and postmenopausal women.

Summary by Cara Adler, Staff Writer

COMMENT — DR. WILLIAM J. GRADISHAR

Although the subset of Black patients in RxPONDER was quite small compared with white patients, who account for the majority of patients in the study, the results suggest that the molecular tools we utilize (RS) do not necessarily “level the playing field.” Even when the biology of the disease is evaluated at a molecular level, beyond clinical features alone, disparities between white and Black patients exist both in terms of outcome and toxicity.

COMMENT — DR. ERIKA HAMILTON

Black and Hispanic patients did worse than white patients in terms of cancer recurrence in RxPONDER even when tumor size, number of positive nodes, and recurrence scores were similar. This really underscores disparities across racial/ethnic groups and makes it even more important to have higher representation of underserved populations in the clinical trials that determine standards of care.

Read more about the racial/ethnic disparities and cognitive impairment.

Adding capivasertib to fulvestrant improves PFS in patients with HR-positive, HER2-negative advanced breast cancer that has become resistant to aromatase inhibitor therapy, according to findings from the CAPItello-291 trial. Capivasertib is an investigational AKT inhibitor.

In the industry-supported, phase 3 trial, roughly 700 patients were randomized to receive fulvestrant with either capivasertib (400 mg twice daily; 4 days on, 3 days off) or placebo. Some 41% of participants had AKT-pathway–altered tumors. Among patients' prior treatments for advanced disease: 87% had received at least one prior line of treatment, 69% had received a CDK4/6 inhibitor, and 18% had received chemotherapy.

Overall, median PFS was twice as long with fulvestrant plus capivasertib compared with fulvestrant plus placebo (7.2 vs. 3.6 months), representing a 40% reduction in risk of disease progression with capivasertib. Findings were similar in the subgroup with AKT-pathway–altered tumors (7.3 vs. 3.1 months; hazard ratio for progression, 0.50).

The most frequent adverse events with fulvestrant plus capivasertib were diarrhea, rash, and nausea; these occurred much more often with capivasertib than with placebo. Roughly 13% of the capivasertib group and 2% of the placebo group discontinued treatment owing to adverse events.

Summary by Amy Herman, Staff Writer

COMMENT — DR. ERIKA HAMILTON

Novel endocrine strategies after endocrine therapy or CDK4/6 inhibitors are a huge unmet clinical need, with standard endocrine agents showing poor activity. Here we see data for fulvestrant plus an AKT inhibitor showing a doubling in PFS from 3.6 to 7.2 months, at a cost of moderately more toxicity in terms of nausea, diarrhea, and rash. Endocrine therapy with AKT blockade may be one strategy to overcome endocrine resistance.

COMMENT — DR. WILLIAM J. GRADISHAR

Partnering endocrine therapy with targeted therapy improved clinical outcomes for patients with metastatic, ER+/HER2-negative breast cancer. Typically following disease progression on a CDK4/6 inhibitor, clinicians will determine if a PIK3CA mutation is present, allowing for the use of alpelisib. The results from CAPItello may offer yet another targeted option for patients with pathway-altered mutations, or not, extending the time until chemotherapy is required.

Read more about the study.

Pausing endocrine therapy to attempt pregnancy is not associated with worse breast cancer outcomes, suggest results from the POSITIVE study.

Researchers enrolled over 500 premenopausal women aged 42 or under who hoped to become pregnant and who'd had 18–30 months of adjuvant endocrine therapy for stage I–III HR-positive breast cancer. Women stopped endocrine therapy for up to 2 years to attempt pregnancy, delivery, and breastfeeding. Patients were strongly encouraged to resume endocrine therapy after pregnancy to complete 5–10 years' therapy.

At 3 years, the rate of local, regional, or distant recurrence or new invasive contralateral breast cancer, the primary endpoint, was 8.9% in the POSITIVE cohort, compared with 9.2% in a historical cohort of 1500 patients whose endocrine therapy was not interrupted. Nearly three quarters of women in POSITIVE had at least one pregnancy, and 86% of these had at least one live birth. The rate of birth defects was low, around 2%.

Summary by Kelly Young, Staff Writer

COMMENT — DR. ERIKA HAMILTON

This is a really reassuring study regarding those patients who wish to stop adjuvant endocrine therapy to have children. It appears that after at least 1.5 years of therapy, temporary cessation of endocrine therapy was not associated with any clinically significant detriment in terms of relapse.

COMMENT — DR. WILLIAM J. GRADISHAR

These data address a critically troubling issue to both patients and their physicians, that is, whether interruption of adjuvant endocrine therapy in young women to get pregnant will raise the risk of recurrence. POSITIVE reassures all that it is safe to allow interested women to pursue pregnancy without compromising breast cancer outcomes, with the caveat that resumption of endocrine therapy is a necessity to complete a full course. Longer follow-up of this trial will continue.

Read more about the study.

Two new trials offer promising results for novel estrogen receptor degraders in patients with HR-positive, HER2-negative advanced breast cancer.

First, in the industry-supported, phase 2 SERENA-2 trial, 240 postmenopausal patients with disease progression or recurrence after no more than one endocrine therapy or chemotherapy regimen in the advanced setting were randomized either to camizestrant, an investigational next-generation oral selective estrogen receptor degrader (SERD), or to fulvestrant, an FDA-approved injectable SERD. During a median 17 months' follow-up, the proportion of patients with disease progression was significantly lower with 75- or 150-mg camizestrant (68%–70%) than with fulvestrant (80%). Median PFS was twice as long with camizestrant (roughly 7.5 months) as with fulvestrant (3.7 months).

Next, VERITAC, a phase 2, industry-supported trial, enrolled 71 patients with locally advanced or metastatic disease who had received at least one prior endocrine therapy, at least one CDK4/6 inhibitor, and no more than one chemotherapy regimen. Patients received oral ARV-471, an investigational proteolysis targeting chimera (PROTAC) estrogen receptor degrader, at either 200 mg or 500 mg daily. The clinical benefit rate — combining rates of confirmed complete response, partial response, and stable disease at 24 weeks — was 37%–39% with the two doses.

In both trials, drug discontinuations due to adverse events were rare.

Summary by Amy Herman, Staff Writer

COMMENT — DR. WILLIAM J. GRADISHAR

The new oral estrogen receptor degraders offer the promise of greater convenience (oral versus intramuscular injection) as well as greater efficacy compared to fulvestrant. Additionally, these drugs may be superior to fulvestrant in certain tumors where molecular markers of resistance have developed. Though not all oral estrogen receptor degrader candidates have been successful, camizestrant and ARV-471 appear promising.

Read more about SERENA-2 and VERITAC.

(Editors' note: Dr. Erika Hamilton is a coauthor on both of these trials but did not contribute to our coverage of them.)

For patients with multiple ipsilateral breast cancer, lumpectomy followed by radiotherapy has a low rate of recurrence, suggests the ACOSOG (Alliance) Z11102 trial.

In this phase 2, single-arm prospective trial, researchers studied nearly 200 patients with 2 or 3 foci of biopsy-proven breast cancer, with each site less than 5 cm and at least one invasive site. Sites were separated by more than 2–3 cm of normal breast tissue, and disease was limited to two breast quadrants. Patients underwent lumpectomy followed by whole breast radiation with boosts to the lumpectomy beds.

At 5 years, the estimated cumulative incidence of local recurrence was 3.2%, which is in line with the historical rate among patients with a single breast tumor who undergo lumpectomy. Of note, patients who did not undergo a presurgery breast MRI had a higher rate of recurrence (23% vs. 2% for those with MRI).

Summary by Kelly Young, Staff Writer

COMMENT — DR. ERIKA HAMILTON

This abstract suggests that even patients with multifocal cancer may be able to be managed with breast-conserving surgery. This has previously been considered a high-risk factor that could possibly necessitate more radical surgery techniques. This finding comes on the heels of an increasing body of data suggesting that some patients may need less to have good outcomes.

COMMENT — DR. WILLIAM J. GRADISHAR

Mastectomy was frequently recommended for patients with more than one primary tumor in the breast. This study should reassure patients, and surgeons, that with appropriate preoperative evaluation (MRI), patients meeting the criteria of this study do not have a higher rate of recurrence with lumpectomy than those with a single breast tumor. The issue of cosmetic outcome may be the primary driver when considering removal of more than one tumor.

Read more about the study.

An investigational 16-gene molecular signature identifies patients with breast cancer who might safely forego local radiotherapy after breast-conserving surgery, according to a validation study.

The molecular signature, called Profile for the Omission of Local Adjuvant Radiotherapy (POLAR), includes genes involved in cellular proliferation and immune response that are expressed differently in patients with and without locoregional recurrence (LRR) after breast-conserving surgery.

The meta-analysis included 623 patients with ER-positive, HER2-negative, node-negative breast cancer who were enrolled in three randomized, controlled trials evaluating breast-conserving surgery with or without local radiotherapy. Using tumor samples from each patient, investigators assigned a POLAR score and used modeling to examine the effects of radiotherapy in patients with high versus low scores.

Among patients with low scores, rates of LRR were similar with and without radiotherapy (10-year cumulative incidence of LRR, 7% and 5%, respectively). Among patients with high scores, the LRR rate was reduced by 63% with radiotherapy compared to without radiotherapy (10-year cumulative incidence, 7% vs. 20%, respectively).

Noting that further validation is needed, the authors conclude, “To our knowledge, POLAR is the first genomic classifier that is not only prognostic for LRR but also predictive.”

Summary by Cara Adler, Staff Writer

COMMENT — DR. ERIKA HAMILTON

This goes along with the theme of “right sizing” therapy for the individual patient and discusses a POLAR score that can help make the decision whether patients need radiation to improve outcomes — or whether they have a good enough prognosis that radiation therapy is excessive and they can be spared this intervention.

COMMENT — DR. WILLIAM J. GRADISHAR

The POLAR study suggests that clinicians may be able to identify patients, based on a molecular signature, who can safely avoid radiation therapy. These data were generated from a meta-analysis of three separate trials. It will be important to determine how well clinical features suggesting a good or poor outcome track with the results of the molecular signature.

Read more about the study.

Prometastatic changes to the tumor microenvironment in response to neoadjuvant chemotherapy may contribute to the worse breast cancer prognosis in Black patients compared with white patients with HR-positive, HER2-negative disease, according to a multicenter, retrospective study. Prior research suggests that neoadjuvant chemotherapy can induce prometastatic changes in some patients.

Roughly 200 patients who had residual disease after neoadjuvant chemotherapy underwent residual tumor tissue analysis. Tumor microenvironment of metastasis (TMEM) doorways — portals for tumor cell dissemination to distant sites — were visualized by triple immunohistochemistry for macrophages, tumor cells, and endothelial cells.

Overall, Black patients were more likely than white patients to develop a distant recurrence (50% vs. 34%). Black patients' tumors had more macrophages and higher TMEM scores in the entire study population and also in the HR-positive, HER2-negative subgroup — but not in the triple-negative subgroup. After multivariable adjustment, high TMEM score was a significant predictor of worse distant recurrence-free survival in the overall cohort and showed a trend toward significance in the HR-positive, HER2-negative subset — but not in the triple-negative subset.

The study's senior author notes, “Our study provides a potential explanation for the persistent racial disparities in ER-positive/HER2-negative breast cancer outcomes that are not fully explained by disparities in social determinants of health.”

Summary by Amy Herman, Staff Writer

COMMENT — DR. WILLIAM J. GRADISHAR

Though seemingly counterintuitive, the effects of preoperative therapy may create an environment that actually promotes the development of metastatic disease. The differences in outcome between white and Black patients with similar clinical disease characteristics as well as treatment speak to a more complex interplay between cellular players in the microenvironment that differ between populations.

COMMENT — DR. ERIKA HAMILTON

The disparities that exist in breast cancer care across racial/ethnic groups represent a huge unmet clinical need, with Black patients being 41% more likely to die from breast cancer than their white counterparts.

Beyond social differences and treatment disparities, this study identifies biologic possibilities to account for some of the disparity in breast cancer outcomes. Identifying differences in biology is the first step in potentially developing a strategy to overcome any related outcome disparities.

Read more about the study.