(in the her2+er- subgroup)
benefit of dual her2 blockade w herceptin & lapatinib and chemo or just hercepton +chemo BOTH very high for her2+er-s
I simplif(or innuied by equating her2+er- with her2 enricjed subtype--but the point made here is that molecular subtyping may save $$$ by giving dual blockade w lapatinib only to those more likely to obtain added benefit
This study will hopefully be superceded by siilar studise with other combos with pertuzumab, tdm1 etc to determine which molecular subtypes are best treated with which combos, but molecular heterogeneity may be such that treatment may still need to be individualized
or immunotherapy added (see my previous post)
HER2-Enriched Molecular Subgroup Highly Sensitive to Breast Cancer Regimens
- See more at:
http://www.onclive.com/web-exclusive....njiaWbPM.dpuf
Lisa Carey, MD
The primary analysis of the phase III CALGB 40601 trial found that pathologic complete response (pCR) to dual HER2 blockade was not statistically higher than anti-HER2 monotherapy. However, there was a high level of intertumoral heterogeneity, and patients with the HER2-enriched subtype had a high pCR with both single and dual anti-HER2 therapy, according to data recently published in the Journal of Clinical Oncology.
“This trial paves the way for integrating molecular analyses into other trials in HER2-positive breast cancer, and may allow us to take a less-is-more approach for women who are selected to be highly sensitive to targeted treatments and to have a good prognosis,” said lead study author Lisa Carey, MD, a UNC Lineberger member, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research at the University of North Carolina School of Medicine, and the physician-in-chief of the North Carolina Cancer Hospital, in a statement.
The phase III CALGB 40601 study examined the efficacy of combining trastuzumab (Herceptin) and lapatinib (Tykerb) with chemotherapy versus trastuzumab combined with chemotherapy in 295 randomly assigned patients with stage II or III HER2-positive breast cancer.
Eligibility criteria included newly diagnosed, histologically confirmed, untreated clinical stage II or III HER2-positive disease, were aged more than 18 years old, had tumors greater than 1 centimeter in size, and had a pretreatment left ventricular ejection fraction greater than 50%. All patients enrolled in the study agreed to have 16-gauge core biopsies taken prior to the start of therapy.
Patients received paclitaxel at 80 mg/m2 IV once weekly for 16 weeks, with the addition of trastuzumab or both agents. Trastuzumab was given at 4 mg/kg IV in week 1 with a subsequent dose of 2 mg/kg IV afterward. Lapatinib was administered orally at 1500 mg daily when given concurrently with trastuzumab.
The trial’s primary endpoint was pCR in the breast, correlative endpoints focused on molecular features identified by gene expression–based assays. Secondary endpoints included adverse events and pCR in the breast and ipsilatereal axillary lymph nodes.
The pCR rate was 56% for those in the dual HER2 blockade plus chemotherapy arm (n = 118; 95% CI, 0.47-0.65) versus 46% for the single-agent plus chemotherapy arm (n = 120; 95% CI, 0.37-0.55; P = .13). An investigational arm of paclitaxel plus lapatinib (n = 67) was closed early, due to reports of inferiority and greater toxicity of lapatinib-only regimens.
Through molecular profiling, researchers found that the HER2–enriched subgroup were highly sensitive to the treatment, regardless of whether they received one or two agents. In this group, the pCR was 70%; patients with luminal A or luminal B subtypes had a pCR of 34% and 36%, respectively (P <.001).
There was no effect of dual therapy in the hormone receptor–positive subset; however, there was a significant increase in pCR with dual therapy in those with hormone receptor–negative disease (P = .01).
PIK3CA mutations were detected in 36 patients (20%), including 14 (25%) of 57 HER2-enriched, 4 (7%) of 55 luminal A, and 16 (31%) of 51 luminal B tumors. Ninety-three percent of the mutations were in exons 9 and 20. The pCR rate was 39% among tumors with PIK3CA mutations and 47% among those with wild-type PIK3CA (P = .5).
Grade 3/4 adverse events differed between the two arms, with 25 and 16 patients experiencing diarrhea and rash in the trastuzumab, lapatinib, and paclitaxel arm versus 2 and 2 patients experiencing the toxicity in the trastuzumab and paclitaxel arm, respectively.
“These are important findings because we treat all of these tumors the same—with multiple chemotherapy drugs and now often 2 anti–HER2 drugs at a cost of more than $100,000,” Carey said. “These findings suggest that we may be able to be more sophisticated in determining up front which tumors need more aggressive treatment and which will do well with a less aggressive therapy.”
Trastuzumab has reduced death in stage I to III HER2-positive breast cancer by 37% when combined with adjuvant chemotherapy. Trastuzumab-based regimens often exceed $5000 per month, while dual therapy regimens can exceed $10,000 per month.
Carey LA, Berry DA, Cirrincione CT, et al. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib [published online November 2, 2015]. J Clin Oncol. doi:10.1200/JCO.2015.62.1268.
- See more at:
http://www.onclive.com/web-exclusive....B4wmONge.dpuf
another adjuvant study with stats shows pcr of her2+er-s twice that of her2+er+&
Linear Mode
