Abstract: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate  〈  5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p   〈  0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

Abstract: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values  〈  5 × 10 –8 as genome-wide significant, and p-values  〈  1 × 10 –5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values  〈  1 × 10 5 . The strongest evidence was found for rs4674019 (p-value = 2.27 × 10 –7 ), which showed genome-wide significant interaction (p-value = 3.8 × 10 –8 ) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen–progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

Abstract: Cure rates for primary mediastinal large B-cell lymphoma (PMBCL) have improved with the integration of rituximab. However, the type of primary therapy and role of radiotherapy (RT) remains ill-defined. Herein, we evaluated the outcome of PMBCL primarily treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and the impact of an end-of-treatment (EOT) 18F-fluorodeoxyglucose positron emission tomography (PET) scan to guide consolidative RT. Patients ≥18 years of age with PMBCL treated with curative intent rituximab-chemotherapy were identified. Prior to 2005, patients were recommended to receive R-CHOP + RT (RT era). Beginning in 2005, EOT PET was used to guide RT and only those with a PET-positive scan received RT (PET era). In total, 159 patients were identified, 94% were treated with R-CHOP and 44% received RT (78% in RT era, 28% in PET era). The 5-year time to progression (TTP) and overall survival (OS) for the entire cohort were 80% and 89%, respectively, similar across treatment eras. Overall, 10% had refractory disease. In total, 113 patients had an EOT PET scan: 63% negative and 37% positive with a 5-year TTP of 90% vs 71% and 5-year OS of 97% vs 88%, respectively. For those with Deauville (D)-scored PET scans (n = 103), the 5-year TTP for PET-negative cases by Deauville criteria (D1-D3, DX) was 91%, with inferior outcomes for D5 vs D4 (5-year TTP 33% vs 87%, P = .0002). Outcomes for PMBCL treated with RCHOP are favorable and use of a PET-adapted approach reduces RT in the majority of patients. A small proportion have refractory disease and may benefit from an alternate treatment.

Abstract: Purpose Since its publication in 1998, the International Prognostic Score (IPS-7) has been widely adopted as a risk stratification tool in patients with advanced stage classical Hodgkin lymphoma (cHL).1 In this study, the 5-y freedom-from-progression (FFP) ranged from 42 to 84% and 5-y overall survival (OS) from 56 to 89%. This index has demonstrated utility in the modern era, but with a significantly narrowed prognostic range.2 Further, missing factors can be problematic, limiting utility in clinical practice. A novel prognostic score (IPS-3), comprised of three of the seven IPS-7 indicators (age ≥ 45, stage IV, hemoglobin 〈 105), was proposed with data derived from advanced stage cHL patients enrolled on the E2496 clinical trial comparing ABVD to Stanford V.3 This model was reported to outperform the IPS-7 in predicting 5-y FFP and OS. We aimed to validate the IPS-3 model in advanced stage cHL treated with ABVD or ABVD equivalent chemotherapy in British Columbia. Patients and Methods The BC Cancer Lymphoid Cancer database was used to identify all advanced stage cHL patients (stage 1/2 bulky, stage 2B, stage 3/4), age ≥ 16 years, diagnosed between January 1, 1980 and June 6, 2018, treated with curative intent ABVD or an ABVD-equivalent regimen with available information for all seven IPS variables. Kaplan-Meier method and Cox proportional hazard models were used to estimate survival rates, hazard ratios (HRs), and 95% CIs. FFP was defined as time from date of diagnosis to disease progression or relapse. Log-rank testing was used to compare the survival curves between groups. As previously described3, prognostic performance and predictive accuracy of IPS-7 and IPS-3 were evaluated using concordance probability estimates (CPEs) with a Cox proportional hazard model based on risk groups. Results 1191 patients were identified. Median age was 33 years (range 16 to 85), 30% were ≥45 years of age and 9% were 〉 65 years of age, 55% were male and 22% had a high risk IPS-7 (≥4). Patient characteristics were similar to the E2946 cohort used to create the IPS-3 (Table 1). Furthermore, estimates of 5-y FFP and 5-y OS in the risk groups were very similar to those in the original report3 (Table 2). In the BC IPS-7 patients, 5-y FFP ranged from 65% to 91% (p 〈 .001) and 5-y OS ranged from 68 to 99% (p 〈 .001) and the IPS-3 model predicted a 5-y FFP of 84% ±2 for a score of 0, 76% ±2 for a score of 1 (HR 1.5, 95% CI 1.2 to 2.1), 72% ±4 for a score of 2 (HR 1.9, 95% CI 1.4 to 2.7) and 68% ±7 for a score of 3 (HR 2.4, 95% CI 1.4 to 4.2) and corresponding values for 5-y OS were 95% ±1, 87% ±2 (HR 3.5, 95% CI 2.4 to 5.1), 80% ±3 (HR 5.1 95% CI 3.4 to 7.7) and 61% ±8 (HR 9.0 95% CI 5.2 to 15.8). Restricting the analysis to patients 65 years of age and younger in our cohort (N = 1080), values for 5-y FFP were similar to the full cohort, ranging from 67 to 84% for IPS-3 and 69 to 91% for IPS-7. Values were slightly improved for OS, ranging from 70 to 95% for IPS-3 and 76 to 99% for IPS-7. Both the IPS-7 and the IPS-3 scores were not effective for predicting 5-y FFP or OS when applied to patients older than 65 years of age (all P≥0.54, N=111). Predictive accuracy and discriminatory performance were evaluated by CPE with higher scores associated with greater accuracy. CPEs for OS were 0.63 (SE 0.014) and 0.66 (SE 0.014) for IPS-7 and IPS-3, respectively. This result may suggest a better concordance between the observed data and IPS-3; however, there was a reversal in performance when analyzing FFP, as the CPEs for FFP were 0.59 (SE 0.014) and 0.57 (SE 0.015) for IPS-7 and IPS-3 respectively. Conclusion This population-based study confirms that both IPS-3 and IPS-7 are prognostic in advanced stage cHL patients treated with ABVD. Unlike the original study evaluating the IPS-3, we did not find overwhelming evidence to suggest that the IPS-3 was more accurate for predicting prognosis than the IPS-7; however, given its simplicity and comparable performance to the IPS-7, IPS-3 may be more appealing for application in the clinical setting. References:Hasenclever D, et al: A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med, 1998Moccia AA et al: International Prognostic Score in advanced-stage Hodgkin's lymphoma: altered utility in the modern era. J Clin Oncol, 2012Diefenbach CS et al: Evaluation of the International Prognostic Score (IPS-7) and a Simpler Prognostic Score (IPS-3) for advanced Hodgkin lymphoma in the modern era. Br J Haematol, 2015 Disclosures Scott: Roche: Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding. Sehn:TG Therapeutics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria. Connors:NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Cephalon: Research Funding; Merck: Research Funding; Genentech: Research Funding; Takeda: Research Funding; Lilly: Research Funding; Roche Canada: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bristol Myers-Squibb: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Bayer Healthcare: Research Funding; F Hoffmann-La Roche: Research Funding.

Abstract: e21074 Background: The prognosis of patients (pts) with stage III cutaneous melanoma is typically estimated at the time of diagnosis. Recent studies in other malignancies have reported the utility of estimating outcome using a conditional survival approach. Herein, we evaluated the risk of melanoma relapse at event-free survival (EFS) time points in pts with stage III cutaneous melanoma in British Columbia (BC). Methods: The Cancer Surveillance & Outcomes Database and Co Path Database were screened to identify pts diagnosed between 1998 and 2013 in BC with completely resected stage III cutaneous melanoma. A competing risk model was used to estimate 5-year (y) risk of recurrence at pre-specified EFS time points, with non-melanoma related deaths considered competing risks. Results: In total, 513 patients were identified: 329 males (64%); median age at diagnosis 58 y (16-99); median follow-up 5.6 y (0.2-17.5) for living pts. In total, 330 pts (64%) had a melanoma recurrence and most were distant metastases (n=194, 59% v regional n=79, 24% v local n= 57, 17%). The median time to first recurrence of any type was 11.6 months. The 5-y risk of any relapse was 63.8% at EFS 0, which decreased to 11.4% by EFS 5 y (Table 1). Full staging information was available for 423 pts (83%); the risk of relapse was lower for stage IIIA compared to IIIB and IIIC at EFS 0 (48%, 68% and 77%, respectively, p 〈 0.001). By EFS 2 y, there was no difference between the groups; however, the 5-y risk of relapse was still moderate (IIIA 40%, IIIB 41%, IIIC 36%, p=0.46). Conclusions: While the risk of melanoma relapse decreases over time, it remains moderate up until 5 y, with distant recurrence as the most frequent event. This data can help inform surveillance guidelines and serves as a benchmark to compare the impact of novel therapies in the adjuvant setting. [Table: see text]

Abstract: A novel prognostic score (IPS‐3), comprised of only three of the seven IPS‐7 indicators (age ≥45, stage IV, haemoglobin 〈 105 g/l), was recently proposed as a simplified model for advanced‐stage classic Hodgkin lymphoma (cHL). We aimed to validate this model in advanced‐stage cHL patients treated with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) in British Columbia. The estimated five‐year freedom from progression (FFP) for scores of 0, 1, 2 and 3 were very similar to the original report at 84%, 76%, 72% and 68% respectively. The IPS‐3 score is highly reproducible in this independent dataset and its simplicity makes it appealing for everyday clinical practice.

Abstract: Introduction Many pts with advanced (adv) stage follicular lymphoma (FL) present with low burden asymptomatic disease and are suitable for observation. Previous studies have shown that rituximab can delay the need for definitive therapy in these pts (Ardeshna et al, Lancet Oncol 2014), and that rituximab maintenance does not offer a long-term advantage (Kahl et al, JCO 2014). Based on early results of these trials, BC Cancer endorsed the use of rituximab monotherapy (R-mono), administered as 4 weekly doses for pts with newly diagnosed asymptomatic adv stage FL in British Columbia in 2011. The aim of this study was to assess the benefit of R-mono and to compare outcomes to pts undergoing observation (OBSE) prior to the introduction of R-mono (OBSE-1) or since the availability of R-mono (OBSE-2). Methods The BC Cancer Lymphoid Cancer and Provincial Pharmacy Databases were used to identify all pts & gt;16 y of age with newly diagnosed, adv stage (extensive stage 2-4), asymptomatic (low tumour burden), grades 1-3a FL betw Jan 2011-Aug 2019, who were treated with R-mono. Results were compared with two OBSE cohorts with similar clinical inclusion criteria; a historical cohort (OBSE-1) diagnosed Jan 2004-Dec 2010 and a current-era cohort (OBSE-2) diagnosed Jan 2011-Aug 2019. Use of R-mono was at the discretion of the treating physician and reflected patient preference. The primary endpoint was time-to-new treatment (TTNT), measured from date of diagnosis to start of any therapy following R-mono or OBSE (systemic, radiotherapy or splenectomy); pts who did not need new treatment were censored at last follow-up. Clinical factors were compared using chi-square tests, ANOVA, and Kruskal-Wallis tests. Kaplan-Meier curves were used to generate survival estimates and differences between cohorts were examined using a log-rank test. Multivariable cox proportional hazard models were used to estimate hazard ratios for each cohort adjusting for relevant clinical factors, including the FLIPI group. Results In total, 843 pts were identified; R-mono (n=301), OBSE-1 (n=302), OBSE-2 (n=240). Median f/up was longer for OBSE-1 (12.1y, range 0.2-16.2), compared with R-mono (4.5y, 0.1-8.8) and OBSE-2 (4.3y, 0.4-9.3). Median time from diagnosis to R-mono was 0.21y (range, 0.05-1.06). Clinical characteristics were largely comparable betw the historical (OBSE-1) and current-era cohorts (R-mono + OBSE-2). However, in the current era, pts receiving R-mono were slightly younger and more likely to have stage 3/4 disease than OBSE-2 pts, indicating a possible selection bias in the use of R-mono (Table). Of the 301 pts receiving R-mono, 298 were evaluable for response, with 210 (70%) achieving CR(u), 70 (23%) PR, and 18 with non-response (2 stable disease, 16 progression, 6%). 10/18 R-mono non-responders developed transformed disease, with significantly poorer OS than responders (p & lt;0.001) (Fig. 1). However, time-to-transformation was not significantly different betw the R-mono, OBSE-1 and OBSE-2 cohorts (p=0.40). Overall, TTNT was significantly improved in the R-mono cohort (p & lt;0.001), with 3y and 5y TTNT estimates as follows: 3y TTNT R-mono 73% (95% CI 67-79), OBSE-1 52% (47-58), OBSE-2 57% (51-65); 5y TTNT R-mono 61% (54-68), OBSE-1 40% (35-46), OBSE-2 44% (37-52) (Fig. 2a). Median TTNT was 6.4y, 3.3y and 3.6y in R-mono, OBSE-1 and OBSE-2, respectively. Hemoglobin & lt;120 (p=0.037), number of nodal sites & gt;4 (p & lt;0.0001), and high-risk FLIPI (p & lt; 0.001) were associated with a shorter TTNT. On multivariate analysis controlling for relevant clinical factors and FLIPI, R-mono remained an independent predictor for TTNT (HR 0.53, 95% CI 0.41-0.69, p & lt;0.001). With available f/up, OS was not statistically different (p=0.32). 5y OS was 86% (95% CI 81-91), 81% (76-85) and 80% (74-86) in R-mono, OBSE-1 and OBSE-2, respectively (Fig. 2b). Conclusions This is the largest study to date evaluating the benefit of R-mono in pts with newly diagnosed adv stage asymptomatic FL. The use of R-mono administered over 1 month delayed the median time to start of new treatment by approximately 3 years. Non-responders to R-mono had a high rate of transformation and poor OS, and may represent pts with high-risk biology. While the overall rate of transformation and OS were not altered, pts receiving R-mono were approximately 50% less likely to require definitive therapy at 5-years, enabling some pts to avoid treatment toxicity and providing time for novel therapies to emerge. Disclosures Perry: Seattle Genetics: Honoraria. Villa:Seattle Genetics: Consultancy, Honoraria; Purdue Pharma: Consultancy, Honoraria; Nano String: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria; AZ: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Sandoz Canada: Consultancy, Honoraria; Immunovaccine: Consultancy, Honoraria. Gerrie:Sandoz: Consultancy; Roche: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Astrazeneca: Consultancy, Research Funding. Scott:Abbvie: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding. Savage:Abbvie: Consultancy, Honoraria; Verastem: Honoraria; Takeda: Honoraria; Servier: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sehn:AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Chugai: Consultancy, Honoraria; Verastem Oncology: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria.