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PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10−76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10−3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10−3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10−2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10−3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

Purpose Candidate predictive biomarkers for irinotecan and oxaliplatin were assessed in 1,628 patients in Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing (FOCUS), a large randomized trial of fluorouracil alone compared with fluorouracil and irinotecan and compared with fluorouracil and oxaliplatin in advanced colorectal cancer. Methods The candidate biomarkers were: tumor immunohistochemistry for MLH1/MSH2, p53, topoisomerase-1 (Topo1), excision repair cross-complementing gene 1 (ERCC1), O-6-methylguanine-DNA-methyltranserase (MGMT), and cyclooxygenase 2 (COX2); germline DNA polymorphisms in GSTP1, ABCB1, XRCC1, ERCC2, and UGT1A1. These were screened in more than 750 patients for interaction with benefit from irinotecan or oxaliplatin; two markers (Topo1 and MLH1/MSH2) met criteria to be taken forward for analysis in the full population. Primary end points were progression-free survival (PFS) and overall survival. Results One thousand three hundred thirteen patients (81%) were assessable for Topo1 immunohistochemistry (low, < 10%; moderate, 10% to 50%; or high, > 50% tumor nuclei). In patients with low Topo1, PFS was not improved by the addition of either irinotecan (hazard ratio [HR], 0.98; 95% CI, 0.78 to 1.22) or oxaliplatin (HR, 0.85; 95% CI, 0.68 to 1.07); conversely, patients with moderate/high Topo1 benefited from the addition of either drug (HR, 0.48 to 0.70 in all categories; interaction P = .005; overall, P = .001 for irinotecan; P = .05 for oxaliplatin). High Topo1 was associated with a major overall survival benefit with first-line combination chemotherapy (HR, 0.60; median benefit, 5.3 months); patients with moderate or low Topo1 did not benefit (HR, 0.92 and 1.09, respectively; interaction P = .005). MLH1/MSH2 did not show significant interaction with treatment, although the low rate of loss (4.4%) limits the power of the study for this biomarker. Conclusion Topo1 immunohistochemistry identified subpopulations that did or did not benefit from irinotecan, and possibly also from oxaliplatin. If verified independently, this information will contribute to the individualization of treatment for colorectal cancer.

10011 Background: We previously presented (ASCO 04 #9506) an exploratory analysis of 13 molecular markers in relation to clinical outcomes in 846 patients treated with fluorouracil (FU), or FU+irinotecan, or FU+oxaliplatin in a large UK-based randomized controlled trial (FOCUS - ASCO ’05 #3518). High TS IHC expression and tumor grade were highly significantly associated with reduced failure-free survival (FFS) in a multivariable model. We now present data from an independent validation set of 449 FOCUS patients and on the combined test and validation sets. Methods: Formalin-fixed, paraffin embedded blocks were retrieved from consenting patients and tissue microarrays made for IHC assessment. Factors assessed for the effect on FFS of first-line therapy were: liver metastases; ALP; grade; mucoid status; age; and IHC for dUTPase and TS. Log-rank univariate analyses and Cox Model multivariable analysis was performed. Results: Univariate analysis of the validation set failed to confirm evidence of the previously observed association between high TS expression and FFS (p=0.2); however high dUTPase IHC (p=0.01), ALP (p1000), TS IHC expression remained a highly significant predictor of FFS. Overall, our results cannot be taken to demonstrate a powerful and clinically useful influence of TS on treatment efficacy, but are consistent with a moderate effect. [Table: see text] No significant financial relationships to disclose.

10009 Background: We have assessed potential predictive markers of the efficacy of irinotecan and oxaliplatin in advanced CRC patients randomized to fluorouracil (FU), FU+irinotecan (Ir) or FU+oxaliplatin (Ox). Methods: Pathology specimens were retrieved from 1281 patient in the FOCUS trial (ASCO 05 #3518). Normal and tumor DNA were extracted and tissue microarrays were made for immunohistochemistry (IHC). The following factors were assessed for effect on failure-free survival (FFS) with first-line therapy: IHC for MLH1, MSH2, P53, Topo1, ERCC1, MGMT, and COX2; DNA polymorphisms in GSTP1 (105Val), ABCB1 (C3435T), XRCC1 (Q399R), ERCC2 (K751Q), and UGT1A1*28. Results: Among 823 patients assessable for Topo1 IHC, we observed highly significant heterogeneity (interaction) of treatment effect in relation to Topo1 staining intensity (p=0.008, see table). 489 patients (59%) had moderate or high Topo1 expression; these patients derived highly significant benefit from 1st-line chemotherapy with either Ir or Ox. In contrast, the 334 (41%) patients with low Topo1 IHC expression showed no evidence of benefit from the addition of either Ir or Ox compared with FU alone (HR 1 and 0.9 respectively). When patients receiving FU alone are considered separately, low Topo1 expression was associated with significantly better FFS (HR 0.7 (0.6–0.9)). The other 11 molecular markers showed no significant interactions with treatment received (p values for interaction all > 0.1). Conclusions: We have identified a subgroup of 41% patients (with low Topo1 expression) for whom treatment outcome with FU alone is superior, but who appear to gain no benefit from the addition of Ir or Ox. We believe this to be the first demonstration in a large randomized trial of a genuinely predictive molecular marker. If verified in an independent dataset, this information could be used to select patients who can be safely treated with FU alone, or together with alternative additional agents. [Table: see text] No significant financial relationships to disclose.

9506 Background: We have assessed potential prognostic and predictive markers of response to fluorouracil (FU) in advanced CRC patients randomized 4:1:1 to FU alone, FU+oxaliplatin, or FU+irinoteca...