DAY 3: Less Chemo, Fewer Pregnancies, and a Setback for Ipatasertib

by Chase Doyle

Day 3 of the 2020 San Antonio Breast Cancer Symposium (SABCS) virtual meeting featured advances in how to optimally use adjuvant chemotherapy for early-stage breast cancer (EBC), a setback in the metastatic setting of triple-negative breast cancer (TNBC), and mixed news for survivors looking to conceive post-treatment.

No Adjuvant Chemo Needed for Postmenopausal Women with EBC and Low Recurrence Score

Many women with the most common form of breast cancer can safely avoid chemotherapy and still achieve similar outcomes with endocrine therapy alone, according to an interim analysis of the SWOG S1007 RxPONDER trial (Abstract GS3-00).

Findings from the study, which evaluated the role of chemotherapy in more than 5,000 women with hormone receptor (HR)-positive, HER2-negative breast cancer with 1 to 3 positive nodes and a recurrence score (RS) ≤25, suggest that postmenopausal women can forgo adjuvant chemotherapy without compromising invasive disease-free survival (iDFS).

“This will save tens of thousands of women the time, expense and potentially harmful side effects that can be associated with chemotherapy infusions,” said lead study author Kevin Kalinsky, MD, director of the Glenn Family Breast Center at Winship Cancer Institute of Emory University, Atlanta.

At 54% of the anticipated iDFS events in the overall population, the analysis showed that postmenopausal women with an RS score ≤25 did not benefit from adjuvant chemotherapy in any subgroup.

Conversely, investigators observed a five-year iDFS improvement with the addition of chemotherapy followed by endocrine therapy in all premenopausal subsets. Although the follow-up is still limited, investigators also identified a 5-year survival benefit of 1.3% favoring chemotherapy followed by endocrine therapy versus endocrine therapy alone in premenopausal women with positive nodes and an RS score ≤25.

Although the results of the study are clear, the explanation for the findings may be less so, according to Kent Osborne, MD, Dudley and Tina Sharp Chair for Cancer Research, Baylor College of Medicine, in Houston.

“The results clearly show no benefit to adding chemotherapy to standard endocrine therapy in post-menopausal patients, despite having positive nodes,” said Dr. Osborne. “This emphasizes that node positivity, while an important prognostic marker, is not a predictive marker of chemotherapy sensitivity. In premenopausal patients, a different result was obtained.”

Dr. Osborne explained the majority of premenopausal patients in this study received tamoxifen as endocrine therapy. The standard approach today, however, would be ovarian suppression plus either tamoxifen or an aromatase inhibitor, which would have been superior to tamoxifen alone in this subgroup.

“Since adjuvant chemotherapy causes ovarian suppression in many premenopausal patients, the patients in this study actually received ovarian suppression plus tamoxifen, while tamoxifen alone was the endocrine therapy for the no-chemotherapy arm,” he concluded. “We may never know whether the difference in outcome in this subset is due to the endocrine effects of chemotherapy.”

Ipatasertib Shows No PFS Benefit in Advanced TNBC

Findings of a Phase 3 study could cast doubt on the future of AKT and PI3K inhibition in triple-negative breast cancer (TNBC).

The addition of AKT inhibitor ipatasertib to paclitaxel in patients who harbored PIK3CA, AKT1, or PTEN alterations did not significantly improve progression-free survival (PFS) in the first-line setting of advanced TNBC, according to primary results from IPATunity130 Cohort A (Abstract GS3-04).

With a median follow-up of 8.3 months, data from the double-blind, placebo-controlled, randomized Phase 3 trial showed a PFS of 6.1 months in patients receiving paclitaxel alone versus 7.4 months with ipatasertib. However, the stratified PFS hazard ratio of 1 was not statistically significant, said Rebecca Dent, MD, associated professor at the National Cancer Center Singapore, in Singapore.

Confirmed overall response showed a slight improvement from 35% with paclitaxel compared to 39% with the addition of ipatasertib, and similar rates of clinical benefit.

Safety was consistent with previously reported results for this combination, which showed higher rates of diarrhea in the ipatasertib combination arm.

Dr. Dent highlighted the surprising differences in results between this Phase 3 study and the randomized Phase 2 LOTUS trial of ipatasertib, which showed “impressive improvement in overall survival and a modest improvement in PFS.”

“The question on everybody’s mind is, ‘Why after such amazing data from both randomized Phase 2 trials with AKT inhibition in advanced TNBC have we gotten these [negative] results?’” said Dr. Dent. “I think it’s important to recognize that TNBC is very heterogeneous. It’s really just an overarching term to describe a breast cancer that has several different pathways that are upregulated.”

As for the future of AKT or PI3K inhibitors in TNBC, Dr. Dent noted that translational work exploring potential biomarkers of benefit from ipatasertib is ongoing as researchers continue to learn about this disease.

“I don’t think the story is over yet,” said Dr. Dent. “I think it’s only just beginning.”

Meta-Analysis Finds Significantly Reduced Odds of Pregnancy after Breast Cancer  

New research highlights the significant impact of breast cancer and its treatment on subsequent chance of pregnancy.

Results of the systematic review and meta-analysis of 39 studies that identified women who had been pregnant after a breast cancer diagnosis and included data on 114,573 breast cancer patients showed a 60% lower chance of getting pregnant post-treatment in breast cancer survivors compared with the general population (Abstract GS3-09). In fact, only survivors of cervical cancer had lower odds of subsequent pregnancy.

“While results of this meta-analysis provide reassuring evidence on the feasibility and safety of conceiving in women with prior history of breast cancer, the reduced chances of future conception among breast cancer survivors should raise awareness about the importance of offering complete oncofertility counseling,” said Lead study author, Eva Blondeaux, MD, a medical fellow in oncology at IRCCS Policlinico San Martino Hospital.

Dr. Blondeaux and colleagues also identified higher risk of delivery and fetal complications, particularly in women exposed to prior chemotherapy. Compared with women in the general population, breast cancer survivors had 50% higher risk of having a baby with low birth weight, 16% higher risk of having a baby that was small for gestational age, a 45% higher risk of preterm labor, and a 14% higher risk of having a caesarean section.

Importantly, however, the researchers found no significant increased risk of congenital abnormalities or other delivery complications. Although there is a need for closer monitoring of these pregnancies, said Dr. Blondeaux, the lack of negative effects on survival indicate that many women can successfully go through pregnancy after breast cancer.

“Returning to a normal life after cancer should be considered a crucial ambition in cancer care in the 21st century,” said Dr. Blondeaux. “This study shows the need for deeper consideration of patients’ pregnancy desire as a crucial component of their survivorship care plan and wish to return to a normal life.”

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