Abstract Clinicians have traditionally used clinicopathological (CP) factors to determine locoregional recurrence (LR) risk of breast cancer and have generated the IBTR! nomogram to predict the risk of ipsilateral breast tumor recurrence (IBTR). The 21-gene recurrence score (RS) assay was recently correlated with LR in retrospective studies. The objective of this study was to examine the relationship between the RS and IBTR!. CP characteristics of 308 consecutive patients who underwent RS testing at our institution were examined. IBTR! was used to estimate the risk of 10-year IBTR. Descriptive statistics were used to compare the RS with the estimated IBTR!. Given a low event rate in this cohort, actual IBTR rates were not reported. Most patients had stage I/II (98%) and grade I/II (77%) disease. Median age was 54 years (range, 30–78). Median IBTR! without radiation therapy was 10% (mean, 12% [range, 4-43%]). RS was low (<18), intermediate (18–30), and high (>30) in 52% (n = 160), 40% (n = 123), and 8% (n = 25) patients. Overall, IBTR! did not correlate with RS ( P = .77). We saw no correlation between RS and IBTR! in patients with less than ( P = .32) or greater than ( P = .48) a 10% risk of IBTR. Interestingly, Ki-67 expression correlated with both IBTR! ( P = .019) and the RS ( P = .002). Further study is warranted to determine if the RS can provide complementary biological information to CP factors in estimating the risk of LR. Prospective studies evaluating this association may potentially allow for individualized treatment decisions.
5512 Background: Screening for Lynch Syndrome (LS) in endometrial cancer (EC) has traditionally been based on early age at diagnosis and family history. Universal tumor testing has been proposed given poor sensitivity of referral criteria and low referral rates. While immunohistochemistry (IHC) is cost effective and widely available, no prospective evaluation of concordance between screening strategies has been completed in EC to define the optimal approach. Our objective was to perform a prospective, population-based evaluation of universal tumor testing in EC to evaluate concordance between microsatellite instability (MSI) and IHC. Methods: MSI and IHC for expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2) were performed prospectively on all EC undergoing surgical staging from August 2012 to August 2013 (n=184). PCR-based MLH1 methylation analysis was performed on tumors with IHC loss of MLH1. Results: Forty-five tumors (24.9%) were MSI-H and 50 tumors (27.2%) had loss of ≥1 MMR protein on IHC. Overall concordance between MSI analysis and IHC was 93.9% (CI 89.4 – 96.9); however, 11 patients (6.1%) had discordant tumor studies. One of 45 MSI-H tumors (2.2%) had intact IHC for all 4 proteins and demonstrated MLH1 methylation. Five of 50 tumors (10.0%) with loss of ≥1 MMR protein on IHC were MS-stable (MSS). Three of these 5 tumors had heterogeneous loss of MLH1 and PMS2 and 1 tumor had complete loss of expression of MLH1 and PMS2. All 4 tumors had MLH1 methylation and presumed sporadic. One MSS tumor had isolated MSH6 loss and a confirmed germline mutation in MSH6. Five tumors (2.8%) were MSI-L, 4 of which had intact IHC. Of these 4, 2 had no germline mutation detected in MSH6, 1 had a variant of unknown significance (VUS) in MSH6, and one did not undergo germline testing. One MSI-L tumor had loss of MLH1 and PMS2, with MLH1 methylation. Conclusions: Overall concordance between MSI and IHC was high in this prospective EC population. However, 6.1% of patients had discordant tumor studies and 2 of 5 patients without MLH1 methylation had a confirmed germline mutation or VUS. Heterogeneous loss of expression on IHC and MSI-L tumors present clinical caveats that are not well defined in EC and warrant further evaluation.
254 Background: The addition of bevacizumab to capecitabine-based chemoradiotherapy (CRT) for LAPC has been shown to be safe. The aim of this study was to determine the safety, tolerability and maximum tolerated dose (MTD) of the addition of erlotinib to this treatment regimen. Methods: Seventeen patients with CT-staged biopsy-proven non-metastatic unresectable LAPC were enrolled between March 2008 and October 2010. Prior chemotherapy was permitted. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose was escalated using a continual reassessment method. Two patients each were enrolled at dose levels (DLs) 1-4 and 9 patients at DL 5. Bevacizumab was escalated from 5mg/Kg every two weeks (DLs 1-4) to 10mg/Kg (DL 5); erlotinib from 100 mg/day (DLs 1-2) to 150 mg/day (DLs 3-5); and capecitabine from 400mg/m 2 twice daily on days of radiation (DL 1) to 600mg/m 2 (DLs 2-3) to 825 mg/m 2 (DLs 4-5). Reassessment for potential resection was performed 6-8 weeks later. Results: With a median follow-up of 10 months (range 3-23), no grade 3 toxicities were observed in DLs 1-4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrheas and 1 rash). No grade 4 or 5 toxicities were seen. DL 4, with a posterior probability of 0.122 of dose limiting toxicity, was selected as the MTD. Median survival was 19.4 months and time to distant progression was 9.8 months. Patients treated at DLs 4 and 5 had a median survival of 24 months. Of 5 patients who underwent margin-negative resections, 4 were originally deemed unresectable and 1 was borderline; 4 were treated at DLs 4 or 5 (36% of patients treated at these DLs); 3 patients had excellent pathological responses (complete response, 5% viable tumor, and 20% viable tumor) at pancreatectomy and are alive at 13, 21 and 22 months respectively with no local or distant failures. Conclusions: The combination of erlotinib, bevacizumab and capecitabine with radiotherapy for LAPC is safe and tolerable. Both the promising survival and the high rate of resectability at the higher dose levels suggest that this strategy of dual inhibition of growth factor receptor pathways during CRT warrants continued evaluation.
Thyroid cancer predominately affects women, carries a worse prognosis in older age, and may have higher mortality in men. Superimposed on these observations is the fact that most women have attained menopause by age 55 yr.The objective of the study was to determine whether men contribute disproportionately to papillary thyroid cancer (PTC) mortality or whether menopause affects PTC prognosis.Gender-specific mortality was normalized using age-matched subjects from the U.S. population. Multivariate Cox proportional hazard regression models incorporating gender, age, and National Thyroid Cancer Treatment Cooperative Study Group stage were used to model disease-specific survival (DSS).Patients were followed in a prospective registry.The relationships between gender, age, and PTC outcomes were analyzed.The unadjusted hazard ratio (HR) for DSS for women was 0.40 [confidence interval (CI) 0.24-0.65]. This female advantage diminished when DSS was adjusted for age at diagnosis and stage with a HR encompassing unity (HR 0.72, CI 0.44-1.19). Additional multivariate models of DSS considering gender, disease stage, and various age groupings showed that the DSS for women diagnosed at under 55 yr was improved over men (HR 0.33, CI 0.13-0.81). However, the HR for DSS increased to become similar to men for women diagnosed at 55-69 yr (HR 1.01, CI 0.42-2.37) and at 70 yr or greater (HR 1.17, CI 0.48-2.85).Although the overall outcome of women with PTC is similar to men, subgroup analysis showed that this composite outcome is composed of two periods with different outcomes. The first period is a period with better outcomes for women than men when the diagnosis occurs at younger than 55 yr; the second is a period with similar outcomes for both women and men diagnosed at ages greater than 55 yr. These data raise the question of whether an older age cutoff would improve current staging systems. We hypothesize that older age modifies the effect of gender on outcomes due to menopause-associated hormonal alterations.
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