BRCAness Profile of Sporadic Ovarian Cancer Predicts Disease Recurrence

BACKGROUND:The consequences of defective homologous recombination (HR) are not understood in sporadic ovarian cancer, nor have the potential role of HR proteins other than BRCA1 and BRCA2 been clearly defined. However, it is clear that defects in HR and other DNA repair pathways are important to the effectiveness of current therapies. We hypothesize that a subset of sporadic ovarian carcinomas may harbor anomalies in HR pathways, and that a BRCAness profile (defects in HR or other DNA repair pathways) could influence response rate and survival after treatment with platinum drugs. Clinical availability of a BRCAness profile in patients and/or tumors should improve treatment outcomes. OBJECTIVE:To define the BRCAness profile of sporadic ovarian carcinoma and determine whether BRCA1, PARP, FANCD2, PTEN, H2AX, ATM, and P53 protein expression correlates with response to treatment, disease recurrence, and recurrence-free survival. MATERIALS AND METHODS:Protein microarray analysis of ovarian cancer tissue was used to determine protein expression levels for defined DNA repair proteins. Correlation with clinical and pathologic parameters in 186 patients with advanced stage III-IV and grade 3 ovarian cancer was analyzed using Chi square, Kaplan-Meier method, Cox proportional hazard model, and cumulative incidence function. RESULTS:High PARP, FANCD2 and BRCA1 expressions were significantly correlated with each other; however, elevated p53 expression was associated only with high PARP and FANCD2. Of all patients, 9% recurred within the first year. Among early recurring patients, 41% had high levels of PARP, FANCD2 and P53, compared to 19.5% of patients without early recurrence (p = 0.04). Women with high levels of PARP, FANCD2 and/or P53 had first year cumulative cancer incidence of 17% compared with 7% for the other groups (P = 0.03). CONCLUSIONS:Patients with concomitantly high levels of PARP, FANCD2 and P53 protein expression are at increased risk of early ovarian cancer recurrence and platinum resistance

Distribution of five mutually exclusive groups of P53, PARP and FANCD2.

<p>Distribution of five mutually exclusive groups of P53, PARP, and FANCD2. 37 patients (22%) were positive for all three of the proteins.</p

Patients' Baseline Characteristics.

<p>Patients' Baseline Characteristics.</p

The Associations of P53, BRCAness Profile and Residual Tumor with 3-year Recurrence-Free Survival.

<p>*Negative is defined as no or weak staining; positive is defined as moderate or strong staining.</p

Immunocytochemistry.

<p>Immunocytochemistry.</p

Associations of PARP and/or FANCD2 with P53.

<p>Association between PARP, FANCD2, and P53. Patients with positive PARP or positive FANCD2 were more likely to have positive P53. Patients positive for both PARP and FANCD2 were statistically more likely to stain positive for P53.</p

Kaplan-Meier Estimated 3-Year Recurrence-Free Survival Curves.

<p>Kaplan-Meier estimated 3-year recurrence-free survival curves. <b>A:</b> No difference in recurrence-free survival when each of the 5 mutually exclusive groups by expression of PARP, FANCD2, and P53 were examined independently. <b>B:</b> Patients positive for all three PARP, FANCD2, and P53 had lower recurrence-free survival compared to patients not positive for all three.</p

High Levels of PARP, FANCD2 and P53 on Risk of 3-Year Recurrence.

<p>*Adjusted for age, cancer status (grade, histology type and stage) at diagnosis and the presence of residual tumor at surgery.</p

Association between Early Recurrence and Positive P53, PARP, and FANCD2.

<p>Association between positive P53, PARP, and FANCD2 in patients with and without early recurrence. Patients with early recurrence at both 6 and 12 months after diagnosis were much more likely to have high levels of all 3 proteins (50% at 6 months and 41.2% at 12 months).</p