Clinicians Discuss New Directions in the Treatment of Breast Cancer

At the National Comprehensive Cancer Network (NCCN) 23rd Annual Conference, held March 22-24 in Orlando, Florida, Sharon H. Giordano, MD, MPH, the University of Texas MD Anderson Cancer Center, Anthony D. Elias, MD, University of Colorado Cancer Center, and William J. Gradishar, MD, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, provided an update on the NCCN guidelines for the treatment of breast cancer and discussed new directions in breast cancer therapy.

HER2-Postive Breast Cancer

Giving an overview of treatment options for HER2-positive breast cancer, Giordano said that recent years have seen an explosion of new drugs, and that “these drugs have made a tremendous impact on the survival” of patients.

In advanced disease, the phase 3 CLEOPATRA study defined the standard of care for HER2-positive metastatic breast cancer as pertuzumab plus trastuzumab with docetaxel. In second-line therapy, the standard has become trastuzumab emtansine (TE); the EMILIA study showed an improvement in overall survival (OS) with TE versus capecitabine plus lapatinib, and “these are fairly substantial and meaningful improvements in survival,” she said.

Dual-targeted therapies have made their way into the NCCN guidelines, with preferred regimes for HER2-postive stage IV disease being pertuzumab plus trastuzumab with docetaxel or pertuzumab plus trastuzumab with paclitaxel.

In the early-stage neoadjuvant setting, dual-targeted therapy has been demonstrated to lead to better pathological complete response (pCR); in the TRYPHAENA study, Giordano noted, pCR ranged from 50% to the mid-60% range with dual-targeted therapy.

However, as the KRISTINE study demonstrated,¹ attempts to de-escalate therapy by reducing chemotherapy and relying on trastuzumab and pertuzumab without the use of docetaxel or carboplatin are associated with lower pCR (44% versus 56% for a regimen including chemotherapy agents).

In the early-stage adjuvant setting, dual-targeted therapy has been disappointing, as demonstrated by the ALTTO trial, though the APHINITY trial’s invasive disease-free survival subset analysis led to an FDA approval for pertuzumab for adjuvant HER2-positive breast cancer.

Neratinib has shown to give a somewhat modest benefit after a year of standard therapy with trastuzumab; in the ExteNet adjuvant trial, neratinib met its primary endpoint of 2-year invasive disease-free survival, and in a subgroup analysis, hormone receptor (HR)-positive patients derived somewhat more benefit than HR-negative patinets.

Another de-escalation study, APT, demonstrated after 7 years of follow-up that adjuvant paclitaxel and trastuzumab were associated with good outcomes for patients with stage T1 node-negative HER2-postive breast cancer. The use of adjuvant chemotherapy with trastuzumab and endocrine therapy has now made its way into NCCN’s guidelines for patients with this disease type.

Triple-Negative Breast Cancer

Elias noted in his presentation that “there aren’t any substantive additions to the NCCN guidelines for triple-negative breast cancer.” In this very aggressive tumor type, with the exception of olaparib for the treatment of tumors with the germline BRCA mutation, no targeted therapies are approved, leaving only chemotherapy as an option.

Yet, in the future, immune-checkpoint therapy may become a viable options; currently, a number of studies are underway for pembrolizumab, atezolizumab, and avelumab for triple-negative breast cancer. “We have numerous numbers of combinations” being investigated now, and “a major direction is moving to earlier phase disease.”

Other drugs of interest include SGN-LIV1A (a humanized IgG1 anti‐LIV1 monoclonal antibody linked to monomethyl auristatin E), glembatumumab vendotin, and sacituzumab govitecan. Also of interst is targeting the androgen receptor pathway; 12% to 55% of triple-negative breast cancers express the androgen receptor, and “it’s unclear what it’s doing” in this disease.

Hormone-Sensitive Breast Cancer

Finally, Gradishar discussed the treatment of hormone-sensitive breast cancer, saying that we are now in the “era of the [cyclin-dependent kinase] CDK 4/6 inhibitors,” including palbociclib, ribociclib, and abemaciclib. These drugs, said Gradishar, show “a fairly striking improvement” when used with aromatase inhibitors. “Regardless of the clinical characteristics … you can’t really identify any group that doesn’t benefit” from these combinations.

In fact, in the MONARCH 3 subset analysis, presented in abstract at the San Antonio Breast Cancer Symposium in 2017, the worse a patient’s prognosis based on some clinical features, the greater the magnitude of the benefit from the CDK 4/6 inhibitor.

In the adjuvant setting, there is growing interest in the question of whether extended adjuvant therapy with aromatase inhibitors could result in a better outcome. “There’s sort of a mixed bag,” said Gradishar, but there may be the possibility of an incremental improvement in outcomes with with longer therapy.

However, “What you do see with time, with longer durations of therapy, [is that] you’re also buying more of the side effects,” including osteoporotic fractures. Reduced adherence is also an issue in longer courses of treatment, and clinicians should be cognizant of some of these longer-duration effects in determining an appropriate therapy.

Reference

1. Hurvitz SA, Martin M, Fraser Symman W, et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2017;19(1):115-126. doi: 10.1016/S1470-2045(17)30716-7.