A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer.
OBJECTIVE
To assess the prevalence of defective homologous recombination (HR)-based DNA repair in sporadic primary breast cancers, examine the clincopathologic features that correlate with defective HR and the relationship with neoadjuvant chemotherapy response.


METHODS
We examined a cohort of 68 patients with sporadic primary breast cancer who received neoadjuvant anthracylcine-based chemotherapy, with core biopsies taken 24 hours after the first cycle of chemotherapy. We assessed RAD51 focus formation, a marker of HR competence, by immunofluorescence in postchemotherapy biopsies along with geminin as a marker of proliferative cells. We assessed the RAD51 score as the proportion of proliferative cells with RAD51 foci.


RESULTS
A low RAD51 score was present in 26% of cases (15/57, 95% CI: 15%-40%). Low RAD51 score correlated with high histologic grade (P = 0.031) and high baseline Ki67 (P = 0.005). Low RAD51 score was more frequent in triple-negative breast cancers than in ER- and/or HER2-positive breast cancer (67% vs. 19% respectively; P = 0.0036). Low RAD51 score was strongly predictive of pathologic complete response (pathCR) to chemotherapy, with 33% low RAD51 score cancers achieving pathCR compared with 3% of other cancers (P = 0.011).


CONCLUSIONS
Our results suggest that defective HR, as indicated by low RAD51 score, may be one of the factors that underlie sensitivity to anthracycline-based chemotherapy. Defective HR is frequent in triple-negative breast cancer, but it is also present in a subset of other subtypes, identifying breast cancers that may benefit from therapies that target defective HR such as PARP inhibitors.
Graeser
Monika
M
The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Academic Department of Biochemistry, and Breast Unit, Royal Marsden Hospital, London, United Kingdom.
McCarthy
Afshan
A
Lord
Christopher J
CJ
Savage
Kay
K
Hills
Margaret
M
Salter
Janine
J
Orr
Nicholas
N
Parton
Marina
M
Smith
Ian E
IE
Reis-Filho
Jorge S
JS
Dowsett
Mitch
M
Ashworth
Alan
A
Turner
Nicholas C
NC
D000328:Adult; D000368:Aged; D000818:Animals; D018943:Anthracyclines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D001706:Biopsy; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011379:Prognosis; D051135:Rad51 Recombinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous
D018943:Anthracyclines; D054316:Biomarkers, Pharmacological; D051135:Rad51 Recombinase
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