I am encouraged by these results. despite my own proclivity for Triple Negative tumors.
ASCO 2016 Report — Breast Cancer
ASCO 2016 Report — Breast Cancer
- William J. Gradishar, MD
Highlights of the latest treatments
- William J. Gradishar, MD
At this year's annual meeting of the American Society of Clinical Oncology (ASCO 2016), held June 3 to 7 in Chicago, investigators discussed the latest findings in cancer research. The editors of NEJM Journal Watch Oncology and Hematology were on hand to report highlights of the conference. Here, Editor-in-Chief William J. Gradishar, MD, reviews key presentations on new breast cancer treatments. All meeting abstracts can be viewed in the ASCO meeting library).
Extending Adjuvant Letrozole for Early-Stage Breast Cancer
A study by Goss and colleagues presented in the Plenary session suggested that extending the duration of treatment with the aromatase inhibitor letrozole for as long as 10 years may further reduce the risk for disease recurrence in postmenopausal patients with estrogen receptor (ER)-positive, early-stage breast cancer (abstract LBA1). The data were derived from the NCI-Canada MA-17R trial, an outgrowth of the MA-17 trial, which demonstrated that after 4 to 6 years of adjuvant tamoxifen, administration of letrozole for 5 years versus placebo significantly improved disease-free survival (DFS). In MA-17R, 1918 postmenopausal patients who had received letrozole for 5 years were re-randomized to receive an additional 5 years of letrozole or placebo.
At a median follow-up of 6.3 years, 165 DFS events had occurred, including 42 distant recurrences in the letrozole group and 53 distant recurrences in the placebo group. Of note, contralateral breast cancer occurred in fewer patients receiving letrozole than placebo (13 vs. 31). Overall survival (OS) was identical between the two groups. Extended letrozole therapy resulted in further reduction in the odds of a breast cancer event; 5-year DFS was 95% for the letrozole arm and 91% for the placebo arm, but only about 1% of the difference was accounted for by distant recurrences.
These results raise the issue of whether extended therapy should be recommended for all patients. Although quality-of-life data suggest equivalence between the two treatment arms, self-selection may have occurred, as patients able to complete the first 5 years of letrozole with few side effects may have been willing to be re-randomized for further treatment. Additionally, there may be tumors for which this strategy is most relevant, based on grade, size, nodal involvement, etc. As is often the case, these data suggest that recommendations must be individualized.
Abemaciclib for ER-Positive/HER2-Negative Metastatic Breast Cancer
A study by Dickler and colleagues (MONARCH 1) evaluated the monotherapy activity of the CDK4/6 inhibitor abemaciclib in 132 postmenopausal patients with ER-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who had progressed on or after endocrine therapy and chemotherapy (abstract 510). Patients had received a median of three prior lines of therapy for advanced disease, including two chemotherapy regimens. Abemaciclib was administered orally every 12 hours (200 mg) on a continuous schedule.
An objective response rate of 19.7% and a clinical benefit rate of 42.4% were observed with a PFS of 6 months. These results compare favorably to what chemotherapy drugs such as eribulin and capecitabine would achieve in a similar clinical scenario, although abemaciclib is not being developed to be a standalone drug, but rather to be combined with other endocrine agents. Currently, there is not sufficient data to draw comparisons with the approved CDK 4/6 inhibitor palbociclib. However, there appear to be differences in toxicities between the two agents, as hematologic toxicity was observed with palbociclib, and low-grade diarrhea was observed with abemaciclib. Key abemaciclib registration trials (Monarch 2 and 3) and the Monaleesa trials of a third drug in this class, ribociclib, will generate much data for consideration during the next few years.
Palbociclib for Patients with Metastatic Disease and ESR1 Mutations
ER mutations (ESR1) tend to be more common in metastatic breast cancer than in early-stage disease. Several reports have shown that following aromatase inhibitor therapy for metastatic disease, ESR1 mutations — which can be detected by so-called liquid biopsies using digital droplet polymerase chain reaction (PCR) — occur in as many as 30% of tumors and portend poorer prognosis than that associated with tumors without ESR1 mutations.
Turner and colleagues conducted an analysis of ESR1 mutations in 265 plasma samples from the Paloma 3 trial, which compared fulvestrant plus palbociclib with fulvestrant plus placebo in pre- and perimenopausal women with ER-positive/HER-negative metastatic breast cancer (abstract 512). ESR1 mutations were present in 27% of the study population. Adding palbociclib to fulvestrant improved PFS whether an ESR1 mutation was present or not. This treatment option may be optimal for patients with ESR1 mutations who continue to receive an endocrine agent rather than switch to an alternative aromatase inhibitor, with which the benefit would be expected to be low in patients harboring an ESR1 mutation.
Anthracyclines for Early-Stage Disease
In patients with early-stage breast cancer, for whom a decision has been made to offer chemotherapy, a trend in recent years has been to avoid anthracyclines, when possible, to minimize the potential for cardiac toxicity and long-term bone-marrow disorders, such as leukemia and myelodysplasia. Blum and colleagues compared the outcomes of patients with high-risk, HER2-negative disease receiving docetaxel and cyclophosphamide (TC) regimens with those receiving anthracyclines and taxane (AT) regimens (abstract 1000).
Data from NSABP and US Oncology Research (USOR) trials were combined to include more than 4000 patients, of whom approximately 70% were ER-positive and two thirds had node-positive disease. An analysis, triggered by a predetermined number of invasive events, showed superior DFS for patients receiving an AT regimen (either anthracyclines and cyclophosphamide followed by a taxane or concurrent anthracyclines, taxane, and cyclophosphamide) compared with those receiving TC (90.7% vs. 88.2%).
This result begs the question of whether the trend in recent years toward anthracyclines-free regimens is wise. This analysis suggested that DFS rates in both groups were high, but somewhat higher for those receiving AT regimens. An exploratory analysis suggested that there was little benefit from AT in patients with ER-positive, node-negative disease. Additionally, a small benefit was seen with AT in patients with ER-positive disease, those with 1 to 3 positive nodes and ER-negative disease, and those with node-negative disease (DFS improved 2.0%–2.5%), whereas a very large benefit was seen with AT in patients with ER-positive disease and ≥4 positive nodes and those with ER-negative disease with any positive node (DFS improved 5.8%–11.0%). Acute leukemia occurred in five patients receiving AT and none receiving TC. Further work on biomarkers may help identify at a molecular level those patients most likely to benefit from an anthracycline and those who can avoid them.
A Biosimilar Trastuzumab
Biosimilars are a very active area of drug development that offer the possibility of lower-cost drugs in the U.S., but also open the door to these therapies in resource-restricted countries around the world. One of the concerns is whether the efficacy, tolerability, and pharmacokinetics are similar to the original drug.
To that end, Rugo and colleagues conducted a phase III, randomized, double-blind trial (Heritage; abstract LBA 503) comparing trastuzumab with the trastuzumab biosimilar Myl-1401O in patients with metastatic HER2-positive breast cancer receiving first-line therapy. HER2-directed therapy was combined with a taxane, either docetaxel or paclitaxel. At 24 weeks, as outlined in the study, equivalence was observed in terms of efficacy, safety, immunogenicity, and pharmacokinetics between the two treatment arms.
Whether Myl-1401O can be viewed as a complete substitute for trastuzumab in all stages of disease will be debated, but there is little doubt that if a drug such as Myl-1401O could be provided at a significantly reduced cost, the number of HER2-positive patients around the world who may be able to receive what is viewed as optimal therapy would significantly increase.
Editor Disclosures at Time of Publication
Disclosures for William J. Gradishar, MD at time of publication Consultant / Advisory board Eisai Editorial boards Clinical Breast Cancer; Oncology Leadership positions in professional societies National Comprehensive Cancer Network (Chair, Breast Cancer Panel)