Exploring the Frequency of Homologous Recombination DNA Repair Dysfunction in Multiple Cancer Types

Our plain-English summary of Exploring the Frequency of Homologous Recombination DNA Repair Dysfunction in Multiple Cancer Types, by L. Gentles, B. Goranov, E. Matheson, et al (Cancers, 2019).

The study

• Authors: L. Gentles, B. Goranov, E. Matheson, A. Herriott, A. Kaufmann, S. Hall, A. Mukhopadhyay, Y. Drew, N.J. Curtin, R.L. O'Donnell
• Journal: Cancers
• Published: 2019;11(3)
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Dysfunctional homologous recombination DNA repair (HRR), frequently due to BRCA mutations, is a determinant of sensitivity to platinum chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi). In cultures of ovarian cancer cells, we have previously shown that HRR function, based upon RAD51 foci quantification, correlated with growth inhibition ex vivo induced by rucaparib (a PARPi) and 12-month survival following platinum chemotherapy. The aim of this study was to determine the feasibility of measuring HRR dysfunction (HRD) in other tumours, in order to estimate the frequency and hence wider potential of PARPi. A total of 24 cultures were established from ascites sampled from 27 patients with colorectal, upper gastrointestinal, pancreatic, hepatobiliary, breast, mesothelioma, and non-epithelial ovarian cancers; 8 were HRD. Cell growth following continuous exposure to 10 μM of rucaparib was lower in HRD cultures compared to HRR-competent (HRC) cultures. Overall survival in the 10 patients who received platinum-based therapy was marginally higher in the 3 with HRD ascites (median overall survival of 17 months, range 10 to 90) compared to the 7 patients with HRC ascites (nine months, range 1 to 55). HRR functional assessment in primary cultures, from several tumour types, revealed that a third are HRD, justifying the further exploration of PARPi therapy in a broader range of tumours.

In plain English

This laboratory feasibility study was done in Gateshead and Newcastle, UK. The authors grew cells from abdominal fluid (malignant ascites) of 27 patients with colorectal, upper gastrointestinal, pancreatic, hepatobiliary, breast, peritoneal mesothelioma and non-epithelial ovarian cancers; cultures grew from 26 samples. They tested whether a DNA repair pathway (homologous recombination repair) worked. The study did not examine asbestos exposure. Repair status was determined in 24 cultures; 8 (33%) were repair-deficient, including the single peritoneal mesothelioma culture. In 9 fresh cultures given rucaparib continuously, mean growth was 36.6% of untreated controls in deficient cultures and 90.4% in competent ones. In 9 thawed cultures exposed for 48 hours, growth did not differ significantly between deficient (42.3%) and competent (48.2%) cultures (p = 0.5556). Median overall survival was 11 months with deficient and 8 months with competent cultures (p = 0.9). Among 10 patients given platinum chemotherapy it was 17 versus nine months (p = 0.3). The mesothelioma patient was alive at 50 months. The authors concluded that about a third of these tumours were repair-deficient and that PARP inhibitors deserve exploration in them. They cautioned that the cohort was small and varied.

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: Laboratory (translational) feasibility study of primary cell cultures from patients' malignant ascites, with linked clinical survival data
• Who was studied: 27 consenting adult patients with malignant ascites from colorectal, upper gastrointestinal, pancreatic, hepatobiliary, breast, peritoneal mesothelioma and non-epithelial ovarian cancers, sampled at Queen Elizabeth Hospital, Gateshead and Freeman Hospital, Newcastle, UK. Cultures were established from 26 of the 27 samples, and 24 were analysed, including 1 primary peritoneal mesothelioma (epitheloid subtype). No study dates are given.
• Exposure: No asbestos or occupational exposure was studied. Cultured cells were exposed in the laboratory to the PARP inhibitor rucaparib: at 10 µM for the repair test, and for growth testing either continuously for 10 days or for 48 hours.
• Main results:
  • Primary cultures were established from 26 of 27 ascites samples
  • DNA repair (HRR) status was determined in 24 of 26 cultures
  • 8 of 24 cultures (33%) were repair-deficient (HRD): 2/8 colorectal, 1/3 upper GI, 2/5 pancreatic, 1/3 hepatobiliary, 1/2 breast, and 1/1 peritoneal mesothelioma
  • In 9 fresh cultures exposed continuously to 10 µM rucaparib, mean cell growth relative to untreated controls was 36.6% (plus or minus 8.8) in HRD cultures versus 90.4% (plus or minus 7.6) in repair-competent (HRC) cultures, p = 0.0238
  • In 9 thawed (re-established from frozen) cultures exposed to rucaparib for 48 hours, growth did not differ significantly between HRD (42.3%) and HRC (48.2%) cultures (p = 0.5556)
  • Median overall survival was 8 months (range 1 to 58) in patients with HRC cultures (n = 16) and 11 months (range 2 to 90) in patients with HRD cultures (n = 8), p = 0.9
  • Among the 10 patients treated with platinum therapy, median overall survival was nine months (range 4 to 55) with HRC cultures (n = 7) and 17 months (range 10 to 50) with HRD cultures (n = 3), p = 0.3
  • The one patient with peritoneal mesothelioma (culture PA022, HRD) had a good response to carboplatin and pemetrexed, with progression-free survival of 27 months, and was alive at last follow-up at 50 months
• The authors' conclusion: The authors concluded that around a third of tumours presenting with abdominal ascites were HRD, including types not generally associated with BRCA mutations. They considered PARP inhibitor therapy in these tumour types, including mesothelioma, worthy of exploration.
• Limitations the authors state:
  • The survival observations should be interpreted with caution because of the limited sample size and the heterogeneous cohort
  • The study included a relatively small number of samples and restricted tumour types
  • Cases differed in cancer stage, tumour origin, comorbidities and prior chemotherapy
  • The effect of freezing cultures on drug response is unknown, and more cultures would need to be analysed
  • Samples were collected at different points in treatment, and tumour biology may change over time and with treatment

Topics

Medical terms in this study, explained in our Lexicon: Chemotherapy, Ovarian Cancer, Ascites, Mesothelioma, Overall Survival, Median Overall Survival.

Related studies

• High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer — B. Bertelsen, I.V. Tuxen, et al. (2019)
• Assessing the function of homologous recombination DNA repair in malignant pleural effusion (MPE) samples — M.J. Patterson, R.E. Sutton, et al. (2014)
• Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro — S. Borchert, M. Wessolly, et al. (2019)
• The Association of BAP1 Loss-of-Function With the Defect in Homologous Recombination Repair and Sensitivity to PARP-Targeted Therapy — H. Yang, D. Xu, et al. (2020)
• Chrysotile asbestos fibers mediate homologous recombination in Rat2 lambda fibroblasts: implications for carcinogenesis — K. Lezon-Geyda, C.M. Jaime, et al. (1996)
• High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas — A.B. Bianchi, S.I. Mitsunaga, et al. (1995)

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