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guide to treatment deescalation: her2 heterogeneity predicts response2 preop tdm1 &
pertuzumab combo
ASCO Reading Room 09.17.2019 HER2 Heterogeneity and Response to Neoadjuvant Therapy Study confirms lower rates of HER2 expression, pCR in HER2+ breast cancer treated with T-DM1 and pertuzumab by Wayne Kuznar Contributing Writer This Reading Room is a collaboration between MedPage Today® and: Medpage Today Expert Critique FROM THE ASCO READING ROOM David Hermel, MD David Hermel, MD Oncology/Hematology Fellow Scripps Clinic La Jolla, CA Aberrant overexpression of the human epidermal growth factor receptor 2 (HER2) gene results in constitutive activation of receptor tyrosine kinase signaling and unmitigated cell proliferation in breast cancer cells. Common diagnostic assays used to characterize HER2 expression include fluorescence in situ hybridization (FISH) of HER2 gene amplification and immunohistochemistry to detect protein overexpression. It is not uncommon (10-30% of the time) to detect heterogeneity in HER2 gene amplification and expression within breast cancer tumor specimens, which is thought to arise from multiple genetically distinct proliferating clones within a single tumor. Though HER2-positivity is a known poor prognostic factor in breast cancer, whether HER2 heterogeneity is a biomarker of response to HER2-directed neoadjuvant treatment has not been validated clinically. A prospective, single-arm phase II study of 164 patients with stage II and III HER2-positive breast cancer treated with trastuzumab emtansine and pertuzumab in the neoadjuvant setting found a positive association between HER-2 heterogeneity (defined according to specific criteria with FISH positivity from 5% to 50% of tumor cells, or an area of tumor that tested HER2 negative, in multiple core biopsies) and lack of pathologic complete response. Though premature, the study findings suggest that stage II and III breast cancer patients with HER2 heterogeneity may benefit from alternative agents in addition to HER2-directed therapy. The results also highlight the need to develop improved diagnostic assays to better quantify the degree of HER2 expression, so as to integrate and tailor HER2 therapy more effectively based on the degree of amplification/expression. Full Critique HER2 heterogeneity is defined as the presence of at least two distinct clones of cells with different levels of HER2 amplification within a tumor. "When we think about HER2-positive disease, in general, at the tumor level, we expect that the majority of cells would be HER2-positive," said Otto Metzger Filho, MD, of Dana-Farber Cancer Institute in Boston, speaking at the 2019 ASCO annual meeting. He noted that the estimates of the prevalence of HER2 heterogeneity from retrospective series have varied from 10% to 30%, depending on the definition and the population studied. Whether HER2 heterogeneity influences the response to targeted anti-HER2 therapies for patients diagnosed with HER2-positive breast cancer is not clear. To answer this question, Metzger Filho and co-investigators conducted a study that included patients with stages II and III HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1) and pertuzumab before surgery. "We think this is a clinically important question, considering HER2 heterogeneity cases may have lower pathologic complete response (pCR) rates when treated with highly effective targeted HER2 therapies," he said. "Investigating the impact of HER2 heterogeneity is particularly important as we try to de-escalate chemotherapy in HER2-positive disease and rely more often on the effective targeted HER2 therapies. To my knowledge, this is the first clinical trial designed and conducted to evaluate prospectively the effect of HER2 heterogeneity on response to therapy in HER2-positive disease." The 164 patients enrolled in the single-arm phase II study were treated with T-DM1 and pertuzumab for a total of six doses prior to surgery. HER2 heterogeneity was evaluated on two different geographic areas of each tumor using ultrasound-guided biopsies. In each of the core biopsy sites, HER2 heterogeneity was evaluated using fluorescent in situ hybridization (FISH), counting approximately 50 cells in each of the core biopsy areas. HER2 heterogeneity was defined as the presence of HER2 positivity in 5-50% of tumor cells, according to the American College of Pathologists guideline, or an area of tumor that tested HER2-negative. The assessment was performed by a central laboratory and blinded to treatment outcome. The primary objective was to determine the relationship between pCR, defined as a residual cancer burden of 0, and intra-tumor heterogeneity of HER2 amplification. A total of 163 of the 164 patients enrolled were evaluable for safety, and 157 for efficacy (HER2 heterogeneity testing failed in five patients). Median tumor size at baseline was 2.8 cm. About two thirds (68.7%) of patients had hormone receptor (HR)-positive breast cancer. The vast majority (84.7%) had stage II disease. HER2 by immunohistochemistry (IHC) was 2+ in 24.5% of the patients and 3+ in 74.1% (data were missing in 1.2% of patients). T-DM1 given in combination with pertuzumab for six cycles was found to be safe; the most common adverse events of any grade were fatigue (occurring in 76.6% of patients), diarrhea (64%), and nausea (60%). There were no grade 4 or higher adverse events, and approximately 95% of patients were able to complete all six cycles of treatment. HER2 heterogeneity was detected in 16 evaluable patients (10%), of whom 13 (81%) had HR-positive disease and three (19%) were HR-negative. The study met its primary endpoint by demonstrating a significant association between HER2 heterogeneity and pCR after preoperative therapy, when adjusted for estrogen receptor (ER) status. In the nonheterogeneous cohort of 141 patients, the pCR rate was 55%, compared with 0% in the 10 patients with HER2 heterogeneity (P<0.001). There was also a significant association between heterogeneity and residual cancer burden class 0 or 1, adjusted for ER status. In the nonheterogeneous population, 67% of patients had a residual cancer burden score of 0 or 1 compared with 25% of the HER2 heterogeneous population (OR 5.6, P=0.004). The pCR rate was 49% overall, and by HR status was 65% in those who were HR-negative versus 42% in those who were HR-positive (P=0.01). In an exploratory analysis, the association between HER2 heterogeneity and pCR remained significant when adjusted for ER status and HER2 IHC status (P=0.002), with a pCR achieved in 56% who were HER2 3+ and 27% who were HER2 2+. The researchers said that if cases that were classified as HER2 heterogeneous are excluded, 58% of patients with HER2 3+ expression and 40% with HER2 2+ expression achieved pCR, a difference that did not achieve significance (P=0.10). Digital spatial profiling of at least four regions in core biopsy sites 1 and 2 was performed in 30 patients, with a selection of heterogeneous and nonheterogeneous cases with or without pCR, in an attempt to quantify HER2 at the protein level in multiple areas of the same tumor. Across the 13 patients with intratumor heterogeneity of HER2 expression, heterogeneity was more diverse than expected with the classic pathologic evaluation, he said. The HER2 protein level in the heterogeneous cases was lower than in the nonheterogeneous cases, regardless of pCR. "HER2 heterogeneous cancers may represent a distinct subset of HER2-positive breast cancer associated with lower rates of pCR and lower levels of HER2 protein expression," concluded Metzger Filho. "The findings suggest a means of identifying a subset of HER2-positive patients who may need chemotherapy or novel treatment approaches." Discussant: 'Data Make Compelling Argument' The discussant for the study, Mark Pegram, MD, director of the Breast Oncology Program at Stanford University in California, said the study results independently confirm that HER2 heterogeneity is a distinct clinical entity with lower levels of HER2 expression and pCR rates in patients with HER2-positive breast cancer treated with T-DM1 and pertuzumab. The findings support those of the I-SPY 2 study in which quantitative measurement of HER2 protein was positively associated with response to the same treatment regimen in patients already identified as HER2-positive by central IHC and FISH testing. Those data were also reported at ASCO19 in poster format. "While our results need to be validated in larger prospective trials, they indicate that new approaches to measure more quantitatively the amount and activation state of HER2 ... may more effectively identify patients that respond to HER2-targeted therapies than HER2 IHC and FISH alone," concluded Julia Dianne Wulfkuhle, PhD, of George Mason University in Columbia, Maryland, and colleagues. "Taken together, these data make a compelling argument that HER2 expression levels are important in the action of T-DM1 in the metastatic and neoadjuvant settings," Pegram said. "Future directions in addressing the heterogeneity issue may include use of antibody-drug conjugates with activity in HER2-low states, antibody-drug conjugates whose payloads have bystander effects, and combinations of antibody-drug conjugates targeting epitopes expressed in heterogeneous tumor cell populations." Filho Metzger reported financial relationships with Grupo Oncoclinicas and Roche Brasil and institutional funding from AbbVie, Cascadian Therapeutics, Eisai, Pfizer, Roche/Genentech, and Susan G. Komen for the Cure. Pegram reported financial relationships with Daiichi Sankyo, Genentech/Roche, MacroGenics, and Seattle Genetics. Primary Source American Society of Clinical Oncology Source Reference: Metzger Filho O, et al "HER2 heterogeneity as a predictor of response to neoadjuvant T-DM1 plus pertuzumab: Results from a prospective clinical trial" J Clin Oncol 2019; 37 (suppl; abstr 502). Secondary Source American Society of Clinical Oncology Source Reference: Wulfkuhle JD, et al "HER family protein expression and activation predicts response to combination T-DM1/pertuzumab in HER2+ patients in the I-SPY 2 TRIAL" J Clin Oncol 2019; 37; abstr 3133. © 2019 MedPage Today, LLC. All rights reserved. Medpage Today is among the federally registered trademarks of MedPage Today, LLC and may not be used by third parties without explicit permission. Accessibility Statement At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email. |
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