BRCA1/2 Reversion Mutations in Patients Treated with Poly ADP-Ribose Polymerase (PARP) Inhibitors or Platinum Agents

Our plain-English summary of BRCA1/2 Reversion Mutations in Patients Treated with Poly ADP-Ribose Polymerase (PARP) Inhibitors or Platinum Agents, by S. Darabi, D.R. Braxton, J. Xiu, et al (Medicina, 2022).

The study

• Authors: S. Darabi, D.R. Braxton, J. Xiu, B.A. Carneiro, J. Swensen, E.S. Antonarakis, S.V. Liu, R.R. McKay, D. Spetzler, W.S. El-Deiry, M.J. Demeure
• Journal: Medicina
• Published: 2022;58(12)
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Reversion mutations in BRCA1/2, resulting in restoration of the open reading frame, have been identified as a mechanism of resistance to platinum-based chemotherapy or PARP inhibition. We sought to explore the incidence of BRCA1/2 reversion mutations in different tumor types. Methods: We retrospectively analyzed molecular profiling results from primary and/or metastatic tumor samples submitted by multiple institutions. The samples underwent DNA and RNA sequencing at a CLIA/CAP-certified clinical lab. Reversion mutations were called only in patients whose available clinical records showed the use of PARP inhibitors or platinum agents prior to tumor profiling. Results: Reversion mutations were identified in 75 of 247,926 samples profiled across all tumor types. Among patients carrying pathogenic or likely pathogenic BRCA1/2 mutations, reversion mutations in BRCA1/2 genes were seen in ovarian cancer (OC) (30/3424), breast cancer (BC) (27/1460), endometrial cancer (4/564), pancreatic cancer (2/340), cholangiocarcinoma (2/178), prostate cancer (5/461), cervical cancer (1/117), cancer of unknown primary (1/244), bladder cancer (1/300), malignant pleural mesothelioma (1/10), and a neuroendocrine tumor of the prostate. We identified 22 reversion mutations in BRCA1 and 8 in BRCA2 in OC. In BC, we detected 6 reversion mutations in BRCA1 and 21 in BRCA2. We compared molecular profile results of 14 high-grade serous ovarian cancers (HGSOC) with reversion mutations against 87 control HGSOC with pathogenic BRCA1/2 mutations without reversion mutations. Tumors with reversion mutations trended to have had lower ER expression (25% vs. 64%, p = 0.024, q = 0.82) and higher KDM6A mutation rate (15% vs. 0, p = 0.016, q = 0.82). Conclusions: We present one of the largest datasets reporting reversion mutations in BRCA1/2 genes across various tumor types. These reversion mutations were rare; this may be because some patients may not have had repeat profiling post-treatment. Repeat tumor profiling at times of treatment resistance can help inform therapy selection in the refractory disease setting.

In plain English

This brief report did not study asbestos; it reported one mesothelioma tumor with a reversion mutation. The authors retrospectively reviewed genetic test results from 247,926 solid tumor samples from multiple institutions. They looked for BRCA1/2 reversion mutations, changes that restore a mutated BRCA gene's reading frame and have been identified as a way tumors resist platinum chemotherapy or PARP inhibitors. These mutations were called only when patients' records showed prior treatment with one of those drugs. Reversion mutations were found in 75 samples (32 BRCA1, 43 BRCA2), most often in ovarian cancer (30 of 3424 tumors with BRCA1/2 mutations) and breast cancer (27 of 1460). In malignant pleural mesothelioma, one was found among the 10 tumors with BRCA1/2 mutations (Table 1 lists 463 mesothelioma results). In high-grade serous ovarian cancer, tumors with reversion mutations trended toward lower ER expression and more KDM6A mutations. These differences were not significant after statistical adjustment. The authors concluded that these mutations were rare and that repeat tumor profiling at treatment resistance may help guide therapy. They noted they lacked detailed outcome data and matching primary tumor samples.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Brief report: retrospective analysis of molecular (DNA and RNA sequencing) tumor profiling data from one clinical laboratory database
• Who was studied: 247,926 solid tumor samples (primary or metastatic) profiled at a CLIA/CAP-certified laboratory (Caris Life Sciences). Reversion mutations were called only for patients whose submitted records showed prior platinum or PARP inhibitor treatment. A subgroup comparison covered 14 high-grade serous ovarian cancers with reversion mutations against 87 with BRCA1/2 mutations but no reversion mutations.
• Exposure: Prior treatment with platinum-based chemotherapy (e.g., cisplatin, carboplatin) or PARP inhibitors (e.g., rucaparib, olaparib). No asbestos or fiber exposure was studied.
• Main results:
  • Across all 247,926 tumors, reversion mutations were identified in 75 tumor samples: 32 in BRCA1 and 43 in BRCA2.
  • Among tumors with BRCA1/2 mutations, reversion mutations were found in 30 of 3424 ovarian cancers and 27 of 1460 breast cancers.
  • Ovarian cancer had more BRCA1 reversion mutations (22) than BRCA2 (8). Breast cancer had more BRCA2 reversion mutations (21) than BRCA1 (6).
  • One reversion mutation (in BRCA2, per Table 1) was found in malignant pleural mesothelioma. The denominator of 10 is the mesothelioma tumors with pathogenic BRCA1/2 mutations (2 BRCA1, 8 BRCA2), not all mesotheliomas; Table 1 lists 463 mesothelioma results in total. One reversion mutation was also found in bladder cancer, out of 300 bladder tumors with BRCA1/2 mutations.
  • Most BRCA1 reversion mutations were in exon 10 (18 out of 28), and most BRCA2 reversion mutations were in exon 11 (16 out of 26). The authors noted these exons are large, which may explain the clustering.
  • In high-grade serous ovarian cancer, tumors with reversion mutations (14) trended toward lower ER expression by immunohistochemistry than controls (87): 25% vs. 64%, p = 0.024, q = 0.82. The authors classed p less than 0.05 with q above 0.05 as a trending difference, not a statistically significant one.
  • The same high-grade serous ovarian cancers with reversion mutations had a trend toward a higher KDM6A mutation rate than controls: 15% vs. 0, p = 0.016, q = 0.82.
  • In high-grade serous ovarian cancer, TP53 mutations were gain-of-function in 7 of 14 (50%) in the reversion group vs. 19 of 84 (23%) in the control group (p = 0.048).
  • Detailed clinical history from insurance claims was available for only 29 patients with reversion mutations. Five of them were treated with carboplatin, olaparib, or both after the reversion mutations were detected.
• The authors' conclusion: The authors concluded that BRCA1/2 reversion mutations are rare events, but that repeat molecular tumor profiling when treatment stops working may help guide therapy choice.
• Limitations the authors state:
  • Because the data came from samples submitted as part of standard care, detailed outcome data were not available for all patients.
  • Primary tumors were not available for comparison with samples taken at resistance. It is therefore unclear whether reversion mutations were present at diagnosis or acquired later.
  • The low number of reversion mutations may reflect that some patients were not profiled again after treatment.

Topics

Medical terms in this study, explained in our Lexicon: Chemotherapy, Molecular Profiling, Ovarian Cancer, Pleural Mesothelioma.

Related studies

• Repositioning PARP inhibitors in the treatment of thoracic malignancies — F. Passiglia, M.L. Reale, et al. (2021)
• BAP1-Altered Malignant Pleural Mesothelioma: Outcomes With Chemotherapy, Immune Check-Point Inhibitors and Poly(ADP-Ribose) Polymerase Inhibitors — E. Dudnik, J. Bar, et al. (2021)
• Modulation of cell and DNA damage by poly(ADP)ribose polymerase in lung cells exposed to H(2)O(2) or asbestos fibres — T. Ollikainen, A. Puhakka, et al. (2000)
• Asbestos exposure affects poly(ADP-ribose) polymerase-1 activity: role in asbestos-induced carcinogenesis — M. Tomasetti, M. Amati, et al. (2011)
• Synthesis of poly(ADP-ribose) in asbestos treated rat pleural mesothelial cells in culture — H.Y. Dong, A. Buard, et al. (1995)
• Cigarette smoke and asbestos activate poly-ADP-ribose polymerase in alveolar epithelial cells — D.W. Kamp, M. Srinivasan, et al. (2001)

Browse more research in Medicina, or return to medical research.