Abstract
HER2 persistence after treatment with T-DXd in breast and gastrointestinal cancers.
Author
person
Joshua Z. Drago
Memorial Sloan Kettering Cancer Center, New York, NY
info_outline
Joshua Z. Drago, Fresia Pareja, Komal L. Jhaveri, Elaine M. Walsh, Geoffrey Yuyat Ku, Steven Brad Maron, Yelena Y. Janjigian, Mark E. Robson, Jorge S. Reis-Filho, Shanu Modi, Pedram Razavi, Sarat Chandarlapaty
Full text
Authors
person
Joshua Z. Drago
Memorial Sloan Kettering Cancer Center, New York, NY
info_outline
Joshua Z. Drago, Fresia Pareja, Komal L. Jhaveri, Elaine M. Walsh, Geoffrey Yuyat Ku, Steven Brad Maron, Yelena Y. Janjigian, Mark E. Robson, Jorge S. Reis-Filho, Shanu Modi, Pedram Razavi, Sarat Chandarlapaty
Organizations
Memorial Sloan Kettering Cancer Center, New York, NY, Memorial Sloan Kettering - Breast and Imaging Center, New York, NY, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
Abstract Disclosures
Research Funding
U.S. National Institutes of Health
U.S. National Institutes of Health
Background:
T-DXd is a HER2-targeted antibody drug conjugate approved for treatment of advanced HER2-positive breast and gastroesophageal cancers and HER2-low breast cancers. The prevalence of HER2 loss after exposure to T-DXd is unknown and has implications for treatment strategies in refractory patients.
Methods:
We investigated clinically reported HER2 immunohistochemistry (IHC) scoring on post-treatment tissue biopsies from patients who received at least 2 cycles of T-DXd as of 2/2023. IHC was performed using mAB clone 4B5 (Ventana) and scored by ASCO/CAP guidelines on a scale of 0 to 3+. MSK-IMPACT next generation sequencing (NGS) was performed on paired pre- and post-treatment samples when available. Statistics are descriptive.
Results:
A total of 62 patients with breast, gastroesophageal, or colon cancer had available post-treatment biopsies. The majority (n = 51) had breast cancer, including 32 with HER2-positive and 19 with HER2-low disease. Median time on therapy was 30 weeks in HER2-positive and 21 weeks in HER2-low breast cancer. All 32 patients with HER2-positive breast cancer had detectable HER2 expression by IHC on post-treatment biopsies (median IHC score 2+; range 1+ to 3+). Of those with HER2-low breast cancer, 12 (63.1%) patients had detectible IHC after treatment. Of the 7 with IHC scores of zero, 3 also had scores of zero on the most proximal pre-treatment biopsies. Seven patients with gastroesophageal and 3 with colorectal cancer were included, with a median time on therapy of 12 and 9 weeks respectively, of which 1 (9%) exhibited HER2-loss after treatment. Among all patients with HER2-positive cancers, the rate of complete HER2-loss by IHC after exposure to T-DXd was 2.3%. Thirty-two patients had paired genomic analysis, including 25 breast and 7 gastrointestinal cancers. No change was observed in the fraction of genome altered (p = 0.0736, q = .327) or tumor mutational burden (p = 0.139, q = .487) with T-DXd exposure. Changes in
ERBB2
copy number did not show clear directionality, with 15 patients (46.7%) exhibiting
ERBB2
amplification pre-treatment and 12 (37.5%) post-treatment, the sum of 3 temporal gains and 6 losses of
ERBB2
amplification across the threshold of 1.8.
Conclusions:
HER2 remained detectable by IHC in the majority of patients treated with T-DXd in this cohort, especially those with HER2-positive cancers. These findings suggest that resistance to T-DXd may occur via target-independent factors, and that HER2 could still be exploited therapeutically in these populations. Further prospective studies using quantitative assays are needed to confirm these hypotheses.
Tumor Type
N
Median Time on Tx (Wks)
Median HER2 IHC Post-Tx
IHC 0 Post-Tx
N (%)
HER2-Positive Breast Cancer
32
30
2+ (1-3)
0 (0)
Her2-Low Breast Cancer
19
21
1+ (0-2)
7 (36)*
Gastroesophageal Cancer
7
12
3+ (0-3)
1 (14.2)
Colorectal Cancer
4
9
2+ (2-3)
0 (0)
Total
62
23.5
2+ (0-3)
8 (12.9)
*3 of these 7 patients had IHC scores of 0 pre-treatment.
3 organizations
1 drug
1 target
Organization
Memorial Sloan Kettering Cancer CenterTarget
HER2 (ERBB2)