Angela DeMichele, MD, MSCE
Recent findings from clinical trials exploring neoadjuvant treatment in patients with triple-negative breast cancer (TNBC) may provide answers to several questions surrounding early-stage disease, according to Angela DeMichele, MD, MSCE. However, she cautioned, the promising pathologic complete response (pCR) rates observed with some agents in these studies do not necessarily translate into improved survival.
In a presentation during the 2016 International Congress on the Future of Breast Cancer, DeMichele, professor of Medicine & Epidemiology and co-leader of the Breast Cancer Program at the Abramson Cancer Center, University of Pennsylvania, said that having a deeper understanding of how patients with TNBC respond to neoadjuvant regimens helps to further individualize therapy while simultaneously informs adjuvant treatment decisions.
Although knowledge of the many categories of TNBC has advanced, the standard of care in this setting remains anthracycline-based chemotherapy, DeMichele noted. Additionally, she added, nab-paclitaxel is a reasonable alternative for patients who are allergic to paclitaxel, and there is no clear role for bevacizumab. The remaining challenge for clinicians is how to best treat patients who often have a difficult and poor prognosis.
“We do know that a subset of patients with triple-negative breast cancer is actually exquisitely sensitive to chemotherapy,” DeMichele explained. “Yet, our ability to predict who is going to respond is quite limited.”
Role of Platinum-Based Therapy
Long-term outcomes from two neoadjuvant trials evaluating the addition of carboplatin—CALGB 40603 and GeparSixto—were reported at the 2015 San Antonio Breast Cancer Symposium.1,2
In the randomized phase II CALGB 40603 study, patients received weekly paclitaxel followed by dose-dense doxorubicin/cyclophosphamide plus either bevacizumab or carboplatin or a combination of the two. In GeparSixto, paclitaxel remained the backbone, but notably, said DeMichele, it was administered concurrently with nonpegylated liposomal doxorubicin and carboplatin in the experimental arm—all of the drugs given concurrently and all the patients receiving bevacizumab.
These differences in the two trials led to some significant differences in outcomes, she said. Three-year event-free survival in the GeparSixto trial was 85.8% compared with 76.5% in the CALGB 40603 arm, suggesting a better overall prognosis and larger incremental carboplatin effect. However, “when we tease out these data,” said DeMichele, “we could have seen pharmacologic synergy by giving all of these drugs simultaneously [in GeparSixto].”
And, she added, “in both trials, we saw significant toxicity, and this is something we encounter every day in our patients when we try to add carboplatin to these regimens.” Although both trial results suggest benefit, currently not enough data exist to be conclusive, the chemo backbone and carboplatin dose/schedule may be critical to optimal efficacy, and long-term effects of added toxicity are not known, DeMichele said. “We really need to individualize who we’re going to give carboplatin to in the triple-negative setting.”
DeMichele said there is much excitement about PARP inhibitors in the neoadjuvant and adjuvant setting, particularly in patients who have an underlying alteration in DNA repair, either due to a BRCA
mutation or some other abnormality.
She is one of the investigators on the I-SPY2 trial,3
and she noted recently published pCR findings from the TNBC cohort of this trial that indicated the addition of veliparib to carboplatin in the neoadjuvant setting has the potential to be highly successful in a subsequent phase III randomized trial.
In this portion of the I-SPY2 trial, the estimated rates of pCR rate for those with TNBC with veliparib and carboplatin were 51% compared with 26% for a standard neoadjuvant therapy. Adverse events were higher in the veliparib group. Overall, these findings suggest an 88% probably of success for veliparib and carboplatin in a phase III study.
Role of Anthracyclines and Taxanes
Data from a prospective registry study reported at the 2016 ASCO Annual Meeting may shed light on the need for anthracyclines in the neoadjuvant setting. In the PROGECT trial,4
77 patients received neoadjuvant carboplatin (AUC 6) + docetaxel (75 mg/m2
) every 21 days for a total of 4 to 6 cycles.