Researchers identify mechanisms of resistance to drug for triple-negative breast cancer 藥物如何使三陰性乳腺癌對治療產生耐藥性

Editor’s note:  The biggest challenge to the current conventional treatments is that they can induce drug-resistance of cancer cells.  When drug resistance develops and all drugs lose their efficacy, the cancer cells become more aggressive and lethal.  At this stage, cancer patients face a greater risk of dying from cancer. This risk is sped up by the treatment. The conventional treatments cause 1) injury or death of cancer cells, 2) drug resistance of cancer cells, 3) stem cell like cancer cells, 4) new mutation in otherwise healthy cells which become the root of new cancer, and 5) loss of cancer patients’ natural immunity against cancer.  Cancer needs to be treated gently to avoid damage to the healthy cells, and get cancer cells under control without injuring them.  Injury of cancer cells by treatments such as chemotherapy and radiotherapy causes mutations which lead to drug resistance.

編者按：當前常規治療面臨的最大挑戰是癌症會產生耐藥性。 當產生耐藥性並且所有藥物都失去效力時，癌細胞變得更具侵略性和致命性。 在這個階段，癌症患者面臨更大的死於癌症的風險。 這種風險會因治療而加速。 常規治療會導致 1) 癌細胞的損傷或死亡，2) 癌細胞的耐藥性，3) 幹細胞像癌細胞，4) 其他健康細胞的新突變，成為新癌症的根源，以及 5) 喪失癌症患者對癌症的天然免疫力。 癌症需要溫和治療，以避免損害健康細胞，並在不傷害癌細胞的情況下控制癌細胞。 化療和放療等治療對癌細胞造成的損傷會導致突變，從而導致耐藥性。

17-Aug-2021

The finding could help to improve therapy and prolong survival for patients with triple-negative breast cancer.

Peer-Reviewed Publication
Massachusetts General Hospital

BOSTON – Massachusetts General Hospital (MGH) researchers have identified for the first time how a highly aggressive form of breast cancer can evade one of the most powerful and effective drugs used to treat it, reporting their findings in Cancer Discovery, a journal of the American Association for Cancer Research. The findings could help improve therapy and ultimately prolong survival for patients with metastatic triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is notoriously difficult to treat because it lacks the receptors or “docking sites” for the hormones estrogen and progesterone and the growth factor HER2, all three of which can be targeted with effective cancer therapies. Standard chemotherapy regimens provide limited benefit against TNBC, and patients with metastatic disease – disease that has spread to other parts of the body – have a very poor prognosis and short survival.

But as Aditya Bardia, MD, MPH, from the Mass General Cancer Center and colleagues previously reported, patients with metastatic TNBC treated in a large clinical trial with the compound sacituzumab govitecan (SG; tradename Trovdely) lived nearly twice as long as patients treated with chemotherapy alone.

SG is an antibody-drug conjugate, consisting of an antibody targeted to a receptor called Trop2 found on the surface of most breast cancer cells, plus a cancer-killing compound known as SN-38 (topoisomerase I inhibitor). SG is designed to specifically seek out breast cancer cells and deliver SN-38 as its toxic “payload.”

Yet some patients with metastatic TNBC either do not benefit from treatment with SG or have an initial response to treatment but then develop drug-resistant disease.

Now, Bardia, with Leif Ellisen MD, PhD, director of Breast Medical Oncology at Mass General Cancer Center, and MGH colleagues, report that they have identified for the first time two separate alterations in the genome of TNBC cells that allow them to develop resistance to the antibody-drug conjugate in patients with triple-negative breast cancer.

“We undertook a study to look at the mechanisms of acquired resistance,” says Ellisen.

“In terms of de novo resistance, the data supported prior studies which suggested that the complete absence of Trop2 could be an important predictor of primary resistance. But the really remarkable part of the study had to do with acquired resistance,” he says.

When they studied the genomic profiles of tissues sampled both before treatment and after disease progression, they found that in multiple metastatic lesions from one woman who had an initial robust response to SG but later had disease progression and died from the disease, there were different molecular mechanisms of resistance in different metastatic lesions.

“All of the resistance mechanisms were driven by genetic changes in the metastatic tumor cells that were not present in the primary tumor. Remarkably, in one set of metastatic lesions there was a mutation in the Trop2 target of the antibody, and in another set of lesions there was actually a mutation in the target of the cytotoxic [cell-killing] payload,” says Ellisen.

“This is the first report describing mechanisms of acquired resistance to sacituzumab govitecan,” adds Bardia. “The findings have potential clinical significance for guiding antibody-drug conjugate sequencing for patients with breast cancer.”

The study was supported by grants from the National Institutes of Health, the DoD Breast Cancer Research Program, the Terri Brodeur Breast Cancer Foundation Fellowship, MGH ECOR Fund for Medical Discovery Fellowship, Susan Eid Tumor Heterogeneity Initiative, Tracey Davis Breast Cancer Research Fund and by the Broad/IBM Cancer Resistance Research Project.

About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2021, Mass General was named #5 in the U.S. News & World Report list of “America’s Best Hospitals.”

Journal

Cancer Discovery

Method of Research

Experimental study

Subject of Research

Cells

Article Title

Parallel genomic alterations of antigen and payload targets mediate polyclonal acquired clinical resistance to sacituzumab govitecan in triple-negative breast cancer

Article Publication Date

17-Aug-2021

COI Statement

AB has received research support (paid to institution) from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, Inc., Mersana, Innocrin, and Biotheranostics Inc.; has served as a consultant to Bio theranostics Inc., Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Inc., Spectrum Pharma, Taiho, Sanofi, Daiichi Pharma/AstraZeneca, Puma, Philipps, and Eli Lilly; and has received travel support from Biotheranostics Inc., Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Inc., Spectrum Pharma, Taiho, Sanofi, and Philipps. DJ has served as a compensated consultant for Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Turning Point Therapeutics, and Elevation Oncology; received honorarium and travel support from Pfizer; received institutional research funds from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, and Novartis; received CME funding from OncLive, MedStar Health, and Northwell Health. GG receives research funds from IBM and Pharmacyclics, and is an inventor on patent applications related to MuTect, ABSOLUTE, MutSig, MSMuTect, MSMutSig, POLYSOLVER and TensorQTL. He is also a founder, consultant, and holds privately held equity in Scorpion Therapeutics. IL is a Consultant for PACT Pharma, Inc. and eNOV1, LLC KR, FU, CL, and LP are employees of IBM. The other authors declare no potential conflicts of interest.