Mark D. Pegram
MIAMI — A high unmet need still exists in the treatment of HER2-positive early breast cancer, according to a presenter at Miami Breast Cancer Conference.
“Most clinicians thought that the problem with HER2-positive early breast cancer had been cured in 2005, but this was not the case,” Mark D. Pegram, MD, director of the breast cancer oncology program at Stanford Women’s Cancer Center and co-director of Stanford’s molecular therapeutics program, said during a presentation. “What is perhaps more sobering is that, with longer follow-up — about 10 years — there is a 25% risk for relapse in these patients. With this being said, our work is not yet done in the HER2-positive setting.”
Vasmatzis and colleagues determined chromoanasynthesis — a common mechanism leading to HER2 amplification at the ERBB2 locus — may have important prognostic implications in this setting.
“Chromosome 8 is commonly involved in the same chromoanasynthesis with 17,” Pegram said. “Moreover, when chromosome 8 is involved, NRG1 fusions, NRG1 amplification, FGFR1 amplification and ADAM32 or ADAM5 fusions have been observed. ERBB3 overexpression is associated with NRG1 fusions, and EGFR and ERBB3 expression are anti-correlated. In one instance, a small duplication fully encompassing the ERBB2 gene was accompanied by a pathogenic mutation.”
Pegram additionally discussed the theoretical pitfalls of ado-trastuzumab emtansine (Kadcyla, Genentech), often referred to as T-DM1, in patients with HER2-positive breast cancer.
“The failure of T-DM1 plus pertuzumab (Perjeta, Genentech) in I-SPY 2 and in the phase 3 MARIANNE trial can be attributed to the fact that T-DM1 has theoretical deficiencies. T-DM1 retains all the mechanisms of action of trastuzumab, which may explain the lack of activity in both the first-line metastatic disease setting and in the neoadjuvant setting,” he said.
However, there is enthusiasm following the release of 7-year follow-up data from the APT trial, in which researchers observed an overall 7-year DFS rate of 93.3% among patients with small, HER2-positive breast cancer.
“This is fantastic data and we cannot lose sight of this for our patients with smaller tumors that are clinically node-negative,” Pegram said.
Additionally, there is the possibility of one day being able to use a nonchemotherapy regimen in a certain subset of low-risk patients. Researchers for the ATEMPT trial are working to replace the low-dose paclitaxel backbone completely with a non-chemotherapy option with T-DM1 in patients with HER2-positive breast cancer.
Pegram cautioned clinicians when interpreting the data from the PERSEPHONE trial, which showed that 6 months of trastuzumab (Herceptin, Genentech) is noninferior to 12 months in HER2-positive, early-stage breast cancer.
“Be aware of subsets of patients,” he said. “When treating older HER2-positive patients with small lymph node-negative tumors with inferior chemotherapy, and [given] sequentially, then 6 months trastuzumab might be OK. However, in most cases, all other patients should receive 1 year trastuzumab.” – by Jennifer Southall
Pegram MD. Controversies in the optimal management of HER2-positive breast cancer. Presented at: Miami Breast Cancer Conference; March 7-10, 2019; Miami.
Vasmatzis G, et al. BMC Cancer. 2018;doi:10.1186/s12885-018-4594-0.
Disclosure: Pegram reports advisory roles with Genentech/Roche and MedImmune/AstraZeneca, as well as a scientific advisory board role with Zymeworks.