New Options for Patients With Early-Stage Breast Cancer

Originally published by our sister publication Clinical Oncology News.

By Gina Shaw

Multiple recent advances in the management of early-stage breast cancer include updates to treatment options and paradigms for many patient populations, said Jeremy Pappacena, PharmD, BCOP, a clinical pharmacy specialist in hematology and oncology at Allegheny Health Network, in Pennsylvania, during a session at the Hematology/Oncology Pharmacy Association 2022 annual meeting encore presentations on May 13.

New Options for Triple-Negative Disease

Triple-negative breast cancer (TNBC), which is estrogen receptor–negative, progesterone receptor–negative and HER2-negative, is considered particularly aggressive and, until recently, has had limited treatment options beyond traditional cytotoxic chemotherapy (Curr Treat Options Oncol 2019;20[11]:82). But recent trials have demonstrated the potential for immunotherapy as an adjunct to chemotherapy in this population, Dr. Pappacena said.

In November 2020, the FDA approved pembrolizumab (Keytruda, Merck) for the treatment of unresectable locally advanced or metastatic TNBC that is programmed death ligand-1 (PD-L1)–positive. In July 2021, that approval was expanded to include high-risk (stage II-III) early-stage TNBC, whether or not the tumor is PD-L1–positive. The approval was based on the updated results of KEYNOTE-522, a phase 3 clinical trial comparing neoadjuvant pembrolizumab plus chemotherapy versus placebo plus chemotherapy, followed by adjuvant pembrolizumab versus placebo (Ann Oncol Oncol 2021;32[9]:1198-1200).

The pembrolizumab arm showed a statistically significant and clinically meaningful improvement in event-free survival (EFS), with a 36-month EFS rate of 84.5% (95% CI, 81.7%-86.9%) in the pembrolizumab group versus 76.8% (95% CI, 72.2%-80.7%) in the placebo group. The EFS improvement was seen in both PD-L1–positive (hazard ratio [HR], 0.67) and PD-L1–negative (HR, 0.48) patients.

“The benefit was most pronounced in patients with node-positive disease,” Dr. Pappacena said. “There was also a favorable overall survival trend in the pembrolizumab group, with an HR of 0.72, but the data are still immature at this time.”

The adverse event rate for nausea/vomiting, diarrhea, peripheral neuropathy, febrile neutropenia and laboratory abnormalities was similar in both groups, but as expected, the pembrolizumab group had a significantly higher rate of immune-related adverse events than the placebo arm (33.5% vs. 11.3%).

“This regimen is now supported by NCCN [the National Comprehensive Cancer Network] and the American Society of Clinical Oncology [ASCO],” Dr. Pappacena said. He noted that there were two neoadjuvant chemotherapy regimen options:

• paclitaxel 80 mg/m² IV weekly plus carboplatin AUC (area under the free carboplatin plasma concentration versus time curve) 5 mg IV every three weeks or AUC 1.5 mg IV weekly; or
• doxorubicin 60 mg/m² or epirubicin 90 mg/m2 IV every three weeks plus cyclophosphamide 600 mg/m2 IV every three weeks.

“With the platinum-based regimen, clinicians should consider utilizing a weekly carboplatin schedule to reduce significant myelosuppression and maintain dose intensity and density,” he said.

New Answers to Old Questions About Hormone-Positive Breast Cancer

A longstanding question in the management of early-stage hormone receptor–positive breast cancer has been which patients can safely be spared the toxic effects of adjuvant chemotherapy. The use of gene expression assays has helped answer that question, and in February 2022, an interim analysis from the phase 3 RxPONDER trial provided more clarity. The study found that adding chemotherapy to endocrine therapy improved invasive disease–free survival (IDFS) among premenopausal—but not postmenopausal—women with hormone receptor–positive, node-positive breast cancer and a recurrence score of up to 25 on the Oncotype DX 21-gene assay (N Engl J Med 2021;385[25]:2336-2347).

Among premenopausal women, the HR for five-year IDFS with the addition of chemotherapy was 0.60, but much of this benefit was concentrated in the younger age group. Among women younger than 50 years, the HR for five-year IDFS was 0.48, but 0.98 in premenopausal women over 50. And for postmenopausal women, by contrast, the HR for five-year IDFS with the addition of chemotherapy was 1.02.

“ASCO has just updated their guidelines to strongly recommend the use of Oncotype DX in all node-negative and the majority of node-positive early-stage breast cancer patients,” Dr. Pappacena said.

“Although RxPONDER confirms no benefit from chemo in postmenopausal patients with lower Oncotype, sparing a large portion of the breast cancer patient population exposure to chemotherapy, the results in premenopausal patients are controversial,” said Erica Mayer, MD MPH, the director of breast cancer clinical research and an institute physician at Dana-Farber Cancer Institute, in Boston, in a separate interview. “Although there appeared to be benefit from chemotherapy in these patients regardless of Oncotype score, some of the apparent ‘benefit’ seen with chemotherapy may have been due to chemotherapy-induced ovarian suppression, a strategy which can provide substantial benefit in reducing risk of cancer recurrence. Use of Oncotype should be encouraged in post-menopausal patients and can be considered in select premenopausal patients with node-positive disease to guide decisions around use of chemotherapy.”

Another perennial question in the management of early-stage hormone-positive breast cancer has been duration of endocrine therapy. “In this population, we know that the most important systemic therapy to reduce the risk of cancer recurrence is adjuvant endocrine therapy,” Dr. Mayer said. “Years ago, the duration of adjuvant endocrine therapy with either tamoxifen or an aromatase inhibitor was established at five years; however, risks of cancer recurrence can extend beyond those initial five years, and multiple recent trials have studied extended therapy durations ranging from seven to 10 years.”

The most recent of those trials is ABCSG-16/SALSA, which found no difference in disease-free survival (HR, 0.99) or overall survival (HR, 1.02) between women who received seven years of treatment and those who continued treatment for a total of 10 years (N Engl J Med 2021;385:395-405). SALSA randomized postmenopausal women younger than 80 years of age with early-stage hormone-positive breast cancer who had already received five years of adjuvant endocrine therapy to either an additional two years or an additional five years of aromatase inhibitor therapy. In addition to the comparable survival outcomes, there was no difference in the risk for a contralateral or secondary primary cancer between the two groups. The risk for clinical bone fracture, by contrast, was significantly increased in the group that received an additional five years (HR, 1.35).

“This is a very important study, and the data are very reassuring that seven years is a good target to aim for. For many patients, it doesn’t appear that there is much more to be gained by going beyond that duration,” Dr. Mayer said. She noted, however, that the patient population in this study was overall a lower-risk group, with approximately 73% tumor stage I and approximately 67% having no lymph node involvement. “For individual patients with higher-risk breast cancer, who are tolerating therapy well and are interested in a longer duration of therapy, it may be reasonable to extend up to 10 years. We do need to continue to personalize therapy.”

People with high-risk hormone-positive breast cancer also have a new treatment option, Dr. Pappacena reported. In October 2021, the FDA approved abemaciclib (Verzenio, Eli Lilly) in combination with endocrine therapy for the treatment of these patients, provided that they score at least 20% on a companion assay for the proliferation marker Ki-67. This approval was based on the monarchE trial, in which patients who received abemaciclib plus endocrine therapy had significantly improved two-year IDFS (92.2% vs. 88.7%; P=0.01) and two-year distant recurrence–free survival (93.6% vs. 90.3%; P=0.01) compared with those who received standard endocrine therapy alone (J Clin Oncol 2020;38[34]:3987-3998).

“The primary additional side effect was diarrhea, which occurred in 82.2% of the patients in the abemaciclib arm and 7.1% of patients in the standard endocrine therapy arm,” Dr. Pappacena said. “The median onset of diarrhea was eight days, and the duration of grade 2 to 3 diarrhea was five to six days. Dose adjustments occurred in 68.1% of patients, and 16.6% discontinued treatment because of adverse effects, so it is important to prepare patients for this side effect.” He noted that neutropenia was also increased in the abemaciclib group (44.6% vs. 5%), but the increase in neutropenia did not increase rates of infection.

Dr. Mayer served as a consultant to AstraZeneca, Eli Lilly, Gilead and Novartis.

Dr. Pappacena reported no relevant financial disclosures.