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Deciphering resistance mechanisms in cancer: final report of MATCH-R study with a focus on molecular drivers and PDX
Damien Vasseur1,2, Ludovic Bigot3, Kristi Beshiri4
1Medical Biology and Pathology Department, Gustave Roussy, Villejuif, France.
Background:
Understanding the resistance mechanisms of tumor is crucial for advancing cancer therapies. The prospective MATCH-R trial (NCT02517892), led by Gustave Roussy, aimed to characterize resistance mechanisms to cancer treatments through molecular analysis of fresh tumor biopsies. This report presents the genomic data analysis of the MATCH-R study conducted from 2015 to 2022 and focuses on targeted therapies.
Methods:
The study included resistant metastatic patients (pts) who accepted an image-guided tumor biopsy. After evaluation of tumor content (TC) in frozen tissue biopsies, targeted NGS (10 < TC < 30%) or Whole Exome Sequencing and RNA sequencing (TC > 30%) were performed before and/or after the anticancer therapy. Patient-derived xenografts (PDX) were established by implanting tumor fragments into NOD scid gamma mice and amplified up to five passages.
Results:
A total of 1,120 biopsies were collected from 857 pts with the most frequent tumor types being lung (38.8%), digestive (16.3%) and prostate (14.1%) cancer. Molecular targetable driver were identified in 30.9% (n = 265/857) of the patients, with EGFR (41.5%), FGFR2/3 (15.5%), ALK (11.7%), BRAF (6.8%), and KRAS (5.7%) being the most common altered genes. Furthermore, 66.0% (n = 175/265) had a biopsy at progression on targeted therapy. Among resistant cases, 41.1% (n = 72/175) had no identified molecular mechanism, 32.0% (n = 56/175) showed on-target resistance, and 25.1% (n = 44/175) exhibited a by-pass resistance mechanism. Molecular profiling of the 44 patients with by-pass resistance identified 51 variants, with KRAS (13.7%), PIK3CA (11.8%), PTEN (11.8%), NF2 (7.8%), AKT1 (5.9%), and NF1 (5.9%) being the most altered genes. Treatment was tailored for 45% of the patients with a resistance mechanism identified leading to an 11 months median extension of clinical benefit. A total of 341 biopsies were implanted in mice, successfully establishing 136 PDX models achieving a 39.9% success rate. PDX models are available for EGFR (n = 31), FGFR2/3 (n = 26), KRAS (n = 18), ALK (n = 16), BRAF (n = 6) and NTRK (n = 2) driven cancers. These models closely recapitulate the biology of the original tumors in term of molecular alterations and pharmacological status, and served as valuable models to validate overcoming treatment strategies.
Conclusion:
The MATCH-R study highlights the feasibility of on purpose image guided tumor biopsies and PDX establishment to characterize resistance mechanisms and guide personalized therapies to improve outcomes in pre-treated metastatic patients.
Insights
The MATCH-R study demonstrated that molecular profiling of tumor biopsies can identify resistance mechanisms in metastatic cancer patients. Tailored treatments based on these findings extended clinical benefit by a median of 11 months.
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- Understanding tumor resistance mechanisms is critical for advancing cancer therapies.
- The MATCH-R trial (NCT02517892) prospectively characterized resistance mechanisms using molecular analysis of tumor biopsies.
- This report details the genomic analysis from 2015-2022, focusing on targeted therapies.
Purpose of the Study:
- To characterize tumor resistance mechanisms through molecular analysis of fresh tumor biopsies.
- To identify targetable drivers and resistance alterations in metastatic cancer patients.
- To evaluate the feasibility of image-guided biopsies and patient-derived xenografts (PDX) for guiding personalized therapies.
Main Methods:
- Collected 1,120 biopsies from 857 resistant metastatic patients.
- Performed targeted next-generation sequencing (NGS), Whole Exome Sequencing, and RNA sequencing on tumor biopsies.
- Established patient-derived xenografts (PDX) from tumor fragments for further analysis and treatment validation.
Main Results:
- Identified molecular targetable drivers in 30.9% of patients, with EGFR, FGFR2/3, ALK, BRAF, and KRAS as common alterations.
- Among patients progressing on targeted therapy, 41.1% had no identified mechanism, 32.0% had on-target resistance, and 25.1% had bypass resistance.
- Tailored treatment for 45% of patients with identified resistance mechanisms led to an 11-month median extension of clinical benefit; 136 PDX models were successfully established.
Conclusions:
- Image-guided tumor biopsies are feasible for characterizing resistance mechanisms in pre-treated metastatic patients.
- PDX model establishment is effective for studying tumor biology and validating treatment strategies.
- Molecular profiling and subsequent personalized therapies can improve outcomes in metastatic cancer.
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