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Increased chemotherapy-induced ovarian reserve loss in women with germline BRCA mutations due to oocyte deoxyribonucleic acid double strand break repair deficiency

      Objective

      To assess whether woman who have BRCA mutations (WBM) experience more declines in ovarian reserve after chemotherapy treatment, as it induces oocyte death by deoxyribonucleic acid (DNA) damage, and BRCA mutations result in DNA damage repair deficiency.

      Design

      Longitudinal cohort study.

      Setting

      Academic centers.

      Patient(s)

      The 108 evaluable women with breast cancer were stratified into those never tested (negative family history; n = 35) and those negative (n = 59) or positive (n = 14) for a pathogenic BRCA mutation.

      Intervention(s)

      Sera were longitudinally obtained before and 12–24 months after chemotherapy treatment, assayed for antimüllerian hormone (AMH), and adjusted for age at sample collection.

      Main Outcome Measure(s)

      Ovarian recovery, defined as the geometric mean of the after chemotherapy age-adjusted AMH levels compared with baseline levels.

      Result(s)

      Compared with the controls, the before chemotherapy treatment AMH levels were 24% and 34% lower in those negative or positive for BRCA mutations, consistent with accelerated ovarian aging in WBM. The WBM had a threefold difference in AMH recovery after chemotherapy treatment (1.6%), when compared with BRCA negative (3.7%) and untested/low risk controls (5.2%). Limiting the analysis to the most common regimen, doxorubicin and cyclophosphamide followed by paclitaxel, showed similar results. These findings were mechanistically confirmed in an in vitro mouse oocyte BRCA knockdown bioassay, which showed that BRCA deficiency results in increased oocyte susceptibility to doxorubicin.

      Conclusion(s)

      Women who have pathogenic BRCA mutations are more likely to lose ovarian reserve after chemotherapy treatment, suggesting an emphasis on fertility preservation. Furthermore, our findings generate the hypothesis that DNA repair deficiency is a shared mechanism between aging, infertility, and cancer.

      Clinical Trial Registration Number

      NCT00823654.
      Pérdida de reserva ovárica inducida por la quimioterapia incrementada en mujeres con mutaciones de la línea germinal BRCA debido a deficiencia en la reparación del ácido desoxirribonucleico de doble cadena en el ovocito

      Objetivo

      Evaluar si las mujeres con mutaciones BRCA (WBM) experimentan una mayor disminución en la reserva ovárica después de tratamiento con quimioterapia, debido a que este provoca la muerte ovocitaria debido a daño del ácido desoxirribonucleico (DNA), y las mutaciones BRCA resultan en deficiencia en la reparación de daños en el DNA.

      Diseño

      Estudio longitudinal de cohorte.

      Ubicación

      Centros académicos.

      Paciente(s)

      Las 108 mujeres con cáncer de mama evaluables fueron estratificadas en aquellas que nunca habían sido testadas para mutación BRCA patogénica (historia familiar negativa; (n=35) y aquellas negativas (n=59) o positivas (n=14).

      Intervención(es)

      Se obtuvo suero longitudinalmente antes y 12-24 meses después de tratamiento con quimioterapia, utilizado para medir hormona antimülleriana (AMH), y ajustado para la edad en el momento de la obtención de la muestra.

      Principales Medidas de Resultados

      Recuperación ovárica, definida como la media geométrica de los niveles de AMH ajustados a la edad después de la quimioterapia comparados con los basales.

      Resultado(s)

      En comparación con los controles, los niveles de AMH antes del tratamiento de quimioterapia fueron 24% y 34% más bajos en aquellos negativos o positivos para mutaciones BRCA, consistente con el envejecimiento ovárico acelerado en WBM. El WBM tuvo una diferencia del triple en la recuperación de AMH después del tratamiento de quimioterapia (1.6%), en comparación con los controles BRCA negativos (3.7%) y no testados/ bajo riesgo (5.2%). Al limitar el análisis al régimen más común, doxorubicina y ciclofosfamida seguido de paclitaxel, se observaron resultados similares. Estos hallazgos se confirmaron mecánicamente en un bioensayo de eliminación de BRCA de ovocitos de ratón in vitro, que mostró que la deficiencia de BRCA resulta en un aumento de la susceptibilidad de los ovocitos a la doxorubicina.

      Conclusión(es)

      Las mujeres que tienen mutaciones BRCA patogénicas tienen más probabilidades de perder reserva ovárica después del tratamiento de quimioterapia, sugiriendo un énfasis en la preservación de la fertilidad. Además, nuestros hallazgos generan la hipótesis de que la deficiencia de reparación del ADN es un mecanismo compartido entre envejecimiento, infertilidad y cáncer.

      Key Words

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