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Mutations in DNA Damage Repair Predict Benefit With Platinum Agents in Pancreatic Cancer


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Patients with advanced pancreatic cancer who have homologous repair damage response mutations may derive considerable benefit from treatment with platinum agents, according to an analysis of patients in the Know Your Tumor Program presented by Michael Pishvaian, MD, PhD, of Georgetown University, at the 2019 Gastrointestinal Cancers Symposium.1

DNA damage response mutations are fairly common in pancreatic cancer, with rates of up to 25% reported from multiple data sets. Most of these mutations are genes related to homologous recombination, most notably BRCA1/2. In the Know Your Tumor data set, as well as other databases, approximately 17% of patients have homologous recombination DNA damage response mutations including in BRCA,ATM, PALB2, ATRX, and RAD51.


We found that homologous recombination DNA damage response mutations are not prognostically favorable in platinum-naive pancreatic adenocarcinoma.
— Michael Pishvaian, MD, PhD

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Compared with a median overall survival of around 8 to 11 months for patients with advanced pancreatic cancer overall, there is growing evidence that patients harboring homologous recombination DNA damage response mutations live longer when treated with platinum-based therapy (and ideally inhibitors of poly [ADP–ribose] polymerase [PARP]), Dr. Pishvaian said. In a study by Golan et al, in BRCA-mutated patients treated with platinum-based therapy, the median overall survival was 22 months compared with 9 months without platinum therapy.2

“A growing body of evidence suggests that PARP-inhibitor based therapy can also help this patient population,” commented Dr. Pishvaian. For example, in studies of patients with BRCA--mutated tumors:

  • Kaufman and colleagues reported 5 responses (1 complete and 4 partial) among 23 patients treated with olaparib.3
  • O’Reilly and colleagues reported 7 responses (1 complete and 6 partial) among 9 patients treated with gemcitabine/cisplatin plus veliparib.4
  • Shroff and colleagues reported 4 responses (2 complete and 2 partial) among 19 patients treated with rucaparib.5

“This does seem to be a promising approach; however, the lingering question is whether the patients with homologous repair damage response mutations actually have a better prognosis, irrespective of treatment,” continued Dr. Pishvaian. “In other words, is there some underlying biology to the homologous recombination DNA damage response mutation that confers a better outcome, a slower growth rate, and improved median overall survival?”

Helping to answer this question is the Know Your Tumor program, which is a collaboration between the Pancreatic Cancer Action Network and Perthera. Patients are referred from across the United States, consent to a registry protocol, undergo broad-based molecular profiling (including next-generation sequencing of cancer-related exomes), and are then followed for outcomes.

Study Details

In a study based on 822 patients from the Know Your Tumor program, Dr. Pishvaian and his co-investigators categorized patients into various subgroups: resected vs advanced; homologous recombination DNA damage response–mutated (defined by a certain gene profile) vs homologous recombination DNA damage response–proficient; and platinum-treated (at any point) vs platinum-naive. Consistent with prior reports, approximately 17% had homologous recombination DNA damage response mutations, and about 70% had received a platinum.

The analysis of patients who had not received a platinum agent showed outcomes for patients with homologous recombination DNA damage response mutations that were no better than those without these mutations. “We found that homologous recombination DNA damage response mutations are not prognostically favorable in platinum-naive pancreatic adenocarcinoma,” Dr. Pishvaian said. In platinum-naive resected patients, the median overall survival was 1.8 years in the mutated patients vs 3.75 years in the patients without mutations; in patients with platinum-naive advanced disease, the median survival was 0.76 years and 1.2 years, respectively.

Platinum Therapy for Pancreatic Cancer

  • The Know Your Tumor program is evaluating the mutational landscape of pancreatic cancer.
  • Homologous recombination DNA damage response mutations do not confer a more favorable outcome vs homologous recombination DNA damage response–proficient disease.
  • In patients who have homologous recombination DNA damage response mutations and receive platinum therapy, however—especially those with advanced disease—survival is significantly better than for those without these mutations.

By contrast, treatment with a platinum seemed to be associated with a survival benefit in the patients with homologous recombination DNA damage response mutations. In the resected patients who had received a platinum, the median survival improved from 3.0 years in those without these mutations to 4.35 years in patients with these mutations (although this was not statistically significant, P = .1); in platinum-treated patients with advanced disease, survival improved from 1.45 to 2.37 years, respectively, which was statistically significant (P < .0001).

“In platinum-treated resected patients, this difference was not statistically significant, but there was a separation of the curves. But in patients with platinum-treated advanced disease, there was clearly a statistically significant improvement,” Dr. Pishvaian noted.

“In the absence of platinum treatment, there is no overall survival difference observed in those with homologous recombination DNA damage response mutations vs those without these mutations, and there is no prognostic value to homologous recombination DNA damage response deficiency,” Dr. Pishvaian said. “However, critically, in this patient population, homologous recombination DNA damage response mutations do confer improved overall survival when these patients are treated with platinum-based therapy.”

“This is important, because we know that about 50% of patients in the advanced setting receive first-line therapy with a platinum and [only] 50% of them will ever receive second-line therapy. Altogether, about 75% of patients with homologous recombination DNA damage response mutations never receive optimal platinum-based therapy,” he said.

Treatment could be improved by greater use of molecular testing, suggested Dr. Pishvaian. “This should at least be considered for all patients with pancreatic cancer.” 

DISCLOSURE: Dr. Pishvaian has served as a consultant or advisor for or received honoraria from Caris Life Sciences, Celgene, Merrimack, Sirtex Medical, Armo BioSciences, AstraZeneca/MedImmune, Ignyta, Perthera, Rafael Pharmaceuticals, and RenovoRx; owns stock in Perthera; and has received institutional research funding from Armo BioSciences, Bavarian Nordic, Bayer, Bristol-Myers Squibb, Calithera Bioscience, Celgene, Celldex Therapeutics, Curegenic, FibroGen, Genentech, Gilead Sciences, GlaxoSmithKline, Halozyme, and Karyopharm.

REFERENCES

1. Pishvaian MJ, Blais EM, Brody JR, et al: Outcomes in pancreatic adenocarcinoma patients with genetic alterations in DNA damage response pathways: Results from the Know Your Tumor Program. 2019 Gastrointestinal Cancers Symposium. Abstract 191. Presented January 18, 2019.

2. Golan T, Kanji ZS, Epelbaum R, et al: Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer 111:1132-1138, 2014.

3. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al: Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 33:244-250, 2015.

4. O’Reilly EM, Lee JW, Lowery MA, et al: Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma. Cancer 124:1374-1382, 2018.

5. Shroff RT, Hendifar A, McWilliams RR, et al: Rucaparib monotherapy in patients with pancreatic cancer and a known deleterious BRCA mutation. JCO Precis Oncol 2018, 2018.


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