The NCCN now recommends the combination of endocrine therapy with a cyclin-dependent kinase (CDK)4/CDK6 inhibitor as first- or second-line therapy as one of the primary options for patients with HR-positive, HER2-negative breast cancer. The updated guideline also suggests that monotherapy with abemaciclib, a CDK4/CDK6 inhibitor, is useful in certain circumstances.
“We’re building on the experience with CDK4/6 inhibitors, combining them with immunotherapy, to determine if we can enhance the effect,” said Dr Gradishar. “We now know that immunotherapy, along with specific kinds of chemotherapy, may be beneficial for a subset of patients with breast cancer.”
One theme that has emerged, Dr Gradishar said, “is that we have to be more refined on how we define the patient populations that are most likely to benefit from a specific therapy, and then consider the notion of precision medicine, tailoring medicine based upon understanding the pathways that are predominant in a specific patient.”
The general approach to sequencing treatment is to try to exhaust endocrine therapy before introducing chemotherapy, said Dr Gradishar. With the introduction of the newer agents, the time until chemotherapy is being prolonged.
The incremental improvement in progression-free survival (PFS) with the addition of CDK4/CDK6 inhibition to endocrine therapy has been realized uniformly with all 3 agents in the class—ribociclib, palbociclib, and abemaciclib. This improvement is more profound when CDK4/CDK6 inhibitors are used in the first-line setting, he added.
Recent data show that the incremental improvement achieved in postmenopausal women by adding a CDK4 or a CDK6 inhibitor is similar in premenopausal women who are rendered postmenopausal by ovarian suppression. Whether the improvement in PFS translates into overall survival (OS) improvement has yet to be determined.
The PI3K/AKT/mTOR pathway is the most altered pathway in breast cancer. The SOLAR-1 clinical trial examined the combination of the investigational drug alpelisib plus fulvestrant in patients with HR-positive, HER2-negative breast cancer. Results showed a doubling of the overall response rate in patients with a PIK3CA mutation compared with fulvestrant alone. “If one were betting, this [alpelisib] is a drug that may very well be approved in the near future and be available for patients with HR-positive disease,” said Dr Gradishar.
“With respect to immunotherapy, we wouldn’t have thought at first blush that this would have been a great strategy for HR-positive disease,” Dr Gradishar said. HR-positive tumors were not thought to be “hot” (ie, immunogenic), but even in patients with HR-positive breast cancer, immunotherapy may prove to be beneficial. The results from ongoing clinical trials in this setting are awaited.
The breast cancer tumors that are the most immunogenic are the HER2-positive and HR-negative tumors, which have a higher rate of tumor-infiltrating lymphocytes (TILs) than other breast cancer types. The amount of TILs is related to the probability of a more favorable outcome in breast cancer.
The NCCN now recommends the new chemoimmunotherapy regimen of atezolizumab and nab-paclitaxel for the subset of patients with advanced triple-negative breast cancer and PD-L1 expression, which was just approved by the FDA in March 2019. This is the first FDA approval of an immunotherapy for this patient population.
This approval was based on the IMpassion130 study, which showed that the addition of atezolizumab to nab-paclitaxel significantly improved PFS as well as OS in patients with triple-negative breast cancer and PD-L1 expression compared with nab-paclitaxel alone.
AT A GLANCE
- ❯ The updated NCCN guideline recommends endocrine therapy plus a CDK4/CDK6 inhibitor as first- or second-line therapy for HR-positive, HER2-negative breast cancer
- ❯ For patients with advanced triple-negative breast cancer with PD-L1 expression, immunotherapy with atezolizumab and nab-paclitaxel is now recommended following the FDA approval
- ❯ Currently, immunotherapy in triple-negative breast cancer is limited to patients with high PD-L1 expression
- ❯ Early-stage HR-positive, HER2-negative breast cancer should be managed by selecting the optimal systemic therapy and individualizing surgical management
The treatment for early-stage HR-positive, HER2-negative breast cancer involves selecting optimal systemic therapy and individualizing surgical management, said Melinda L. Telli, MD, Leader, Breast Cancer Clinical Research Group, Stanford Cancer Institute, CA.
For women who are premenopausal at diagnosis, the updated guideline recommends adjuvant endocrine therapy with tamoxifen (with or without ovarian suppression) or an aromatase inhibitor (with ovarian suppression) for 5 years. Tamoxifen treatment can be considered for an additional 5 years, for a total of 10 years. In a joint analysis of the TEXT and SOFT clinical trials, adjuvant exemestane plus ovarian suppression significantly reduced the recurrence of early-stage HR-positive, HER2-negative breast cancer compared with tamoxifen plus ovarian suppression, resulting in 5-year disease-free survival rates of 91% versus 87%, respectively.
In women who are postmenopausal at diagnosis, the updated guideline recommends upfront aromatase inhibitor or tamoxifen treatment for 5 years, or sequential treatment with either agent for 2 to 3 years. “There is high-level evidence to continue therapy for 5 additional years of an adjuvant aromatase inhibitor,” said Dr Telli.
Axillary disease management considers whether patients have positive or negative lymph nodes at the time of diagnosis, with further decisions (ie, axillary dissection or sentinel lymph node biopsy) dependent on the initial clinical stratification.