To BRCA or not to PALB

Mairead Mcnamara, A Lamarca, RA Hubner, JW Valle

Research output: Contribution to journalArticlepeer-review


To BRCA or Not to PALBTO THE EDITOR: Kaufman et al1 report interesting data from anonrandomized phase II multicenter study of an oral poly (ADPribose)polymerase (PARP) inhibitor, olaparib, monotherapy in aspectrum of germline BRCA1 and BRCA 2 (BRCA 1/2) –mutatedcancers (ovarian, breast, pancreatic, and prostate cancer). This articleby Kaufman et al adds to the growing body of evidence of the potentialfor PARP inhibitor inclusion in the therapeutic management of patientswith BRCA 1/2 mutations.2-5It is appreciated that the goal of phase II studies is to establisha signal of activity as a surrogate for a possible improvement inoverall survival. Kaufman et al1 selected tumor response rate accordingto RECIST version 1.1 as the primary end point of thestudy and although reduction in tumor bulk may potentially providesymptom relief, changes in tumor response rate do notalways translate to more clinically meaningful overall survivalbenefits.6 If an agent is active enough, demonstration of improvementin overall survival, even in heavily pretreated patients, shouldbe the mantra.A randomized phase II study may possibly have been moreenlightening as we know that patients with BRCA mutations mayrespond better to certain therapies and this would have allowed themagnitude of effect to be bench-marked. The Kaufman et al1 studyenrolled 298 patients quickly and there should not have been abarrier to recruitment. If standard comparators were not available,a best supportive care arm could have been considered.In addition, in the Kaufman et al1 study, patients were treatedcontinuously with oral olaparib 400 mg twice daily until disease progression.In the event of toxicity, dose reduction levels utilized were200 mg twice daily or 100 mg twice daily if required. These equate toreductions of 50% or 75% which are similar to targeted agent dosereduction in other disease groups.7 However, an initial dose reductionof 20% to 25% would be more usual in systemic chemotherapy studies.Given that 40.3% of 298 patients treated with olaparib experiencedadverse events leading to dose modification (interruption and/or reduction),one has to question if patients are receiving an adequate doseintensity following dose reduction and thus deriving maximal consequentgain, and if they are, would a lower initial dose of therapeuticagent produce equivalent value (with attenuated toxicity) as has beenseen in the treatment of other disease groups such as, for example,advanced melanoma?8Kaufman et al’s article1 is missing data on whether patients inthis study received treatment after olaparib. For example, patientswith a diagnosis of pancreatic cancer had a median progressionfreesurvival of 4.6 months and median overall-survival of 9.8months, therefore surviving 5.2 months beyond progression.Knowledge of the poststudy treatment would help to make sense ofthis survival data.The encouraging findings by Kaufman et al1 of response toolaparib across different tumor types associated with germlineBRCA 1/2 mutations causes one to ponder as to the potential of thistherapeutic in the management of those patients with a partner andlocalizer of BRCA2 (PALB2) mutation. Biallelic germline loss-offunctionmutations in PALB2 (FANCN) lead to development ofFanconi’s anemia, with monoallelic loss-of-function mutationsbeing associated with an increased risk of breast cancer and pancreaticcancer.9 Could PARP inhibitors have a role to play in thetreatment of PALB2-mutated cancers? A preclinical study has recentlyproduced cautiously optimistic results.10 Moreover, couldthe presence of an undiscovered PALB2 mutation in any way havecontributed to the increased hematologic adverse events describedby Kaufman et al?1The identification by Kaufman et al1 of response to olaparib inpatients with previously treated BRCA1/2-mutated advanced pancreaticcancer, with no apparent difference seen in those with or withoutprior platinum treatment, is exciting. The possibility of employing thisapproach in earlier lines of treatment also warrants exploration. Thispoor-prognosis disease group, which traditionally has derived littleadvantage from targeted agents, may somewhat tardily now enter therealm of patient-directed therapy.The question can then be posed as to whether widespread availabilityof multigene panels and whole-exome sequencing togetherwith germ-line testing for identification of inherited loss-of-functionmutations in BRCA1/2, and possibly PALB2, should enter routineclinical practice in prespecified patient subgroups, and if so, whatwould be the economic implications?Finally, Kaufman et al1 are to be congratulated on performingthis multi-institutional informative trial, and in so doing, producingthis thought-provoking data which should form the basis for potentiallypractice-changing endeavors.
Original languageEnglish
Pages (from-to)2581-2
Number of pages2578
JournalJ Clin Oncol
Issue number23
Publication statusPublished - 29 Jun 2015


  • Antineoplastic Agents/*therapeutic use
  • BRCA1 Protein/*genetics
  • BRCA2 Protein/*genetics
  • Female
  • *Germ-Line Mutation
  • Humans
  • Male
  • Neoplasms/*drug therapy/*genetics
  • Phthalazines/*therapeutic use
  • Piperazines/*therapeutic use


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