bluuebunny/crossref_metadata_2025 huggingface dataset:
Differences in breast cancer outcomes amongst Black United States-born and Caribbean-born immigrants.
Authors: Barreto Coelho Priscila , Cerbon Danielle , Schlumbrecht Matthew , Parra Carlos , Hurley Judith , George Sophia
Published: May 2019

1088

Background: The Black population in the US constitutes of 4 million immigrants, with 50% from the Caribbean. It has been shown that breast cancer is responsible for 14%-30% of cancer deaths in the Caribbean; this is up to two times higher than the USA. Methods: Retrospective cohort of 1369 self-identified Black women with breast cancer. Data was obtained from Jackson Memorial Health Systems and University of Miami Health System Tumor Registry. Individual-level data from 1132 cases was used to estimate hazard rations (HRs) of women born in the Caribbean (CB) or in the USA (USB) using Cox proportional hazards regression analysis for overall survival. Median follow-up was 115 months (interquartile range, 91.9-138.1 months) per participant. Results: Data from 622 (54.9%) USB women and 507 (45%) CB women diagnosed with breast cancer between 2006-2017. 90% (n = 1232) of the cohort is of non-Hispanic ethnicity. Caribbean immigrants from Haiti (18.3%), Jamaica (6.5%), Bahamas (3.1%), Cuba and Dominica Republic (2.8% each), Trinidad and Tobago (1%) and other nationalities from the Organization of Eastern Caribbean States were included, mean age 55.7 [95% CI, 54.7-56.8]; USB mean age 57.6 [95% CI, 56.4-58.7] (P = 0.02). Compared to USB, CB had lower BMI at diagnosis 29.6 [95% CI, 28.9-30.3] versus 30.9 [95% CI, 30.1-31.7, P = 0.015]. Compared to CB patients, USB patients had more ER- [31.4% vs 39.1 %, P = 0.018] and triple negative breast cancers [19.6% vs 27.9%, P = 0.003]. Compared to USB patients, CB presented at more advanced stage, III and IV [44.2% vs 35.2%], p = 0.016. In spite of higher advanced stage at diagnoses, CB patients had a better breast cancer overall survival [HR = 0.75; 95%CI, 0.59-0.96; P = 0.024]. Black Hispanic patients had a better overall survival [HR = 0.51; 95%CI, 0.28-0.93; p = 0.028] compared to non-Hispanic Blacks. Compared to Hispanic Caribbean, non-Hispanic Caribbean had a worse overall survival [HR = 1.98; 95%CI, 1.00-3.94; P = 0.048]. The distribution of patients treated at the private cancer center and the safety net hospital were the same, differences in outcomes observed are due to intrinsic differences. Conclusions: This is the largest analysis to date of self-identified Black breast cancer patients in the context of nativity, race, ethnic identity and overall survival with clinico-pathologic characteristics. CB immigrants diagnosed with breast cancer have a better overall survival than US born Black patients. This finding suggests that within the African diaspora in the USA, additional factors beyond race contribute to the outcomes.
RUBY: A phase II study testing rucaparib in germline (g) BRCA wild-type patients presenting metastatic breast cancer (mBC) with homologous recombination deficiency (HRD).
Authors: Patsouris Anne , Tredan Olivier , Nenciu Daniel , Tran-Dien Alicia , Campion Loic , Goncalves Anthony , Arnedos Monica , Sablin Marie-Paule , Gouraud Wilfried , Jimenez Marta , Droin Nathalie , Bieche Ivan , Callens Celine , Loehr Andrea , Vicier Cecile , Andre Fabrice
Published: May 2019

1092

Background: PARP-inhibitors improve PFS in mBC patients (pts) harboring a gBRCA mutation (mut). However, unlike ovarian cancer, there is no evidence until now that this class of agents has efficacy in gBRCA wild-type (WT) pts. In RUBY, we evaluated rucaparib in gBRCA WT mBC pts, and whose tumor present with HRD as assessed by genome-wide Loss of Heterozygosity (LOH) score. Methods: 713 gBRCA WT women with HER2- mBC, initiating a first metastatic chemo, were screened for high (≥18%) genomic tumor LOH generated from a SNP array on metastatic sample. Eligible pts with a high LOH score or somatic (s) BRCA mut and ≥1 prior chemo regimen were proposed to enter RUBY and receive oral rucaparib 600 mg BID continuously in 28-day cycles until disease progression. The primary endpoint was clinical benefit rate (CBR), defined by complete (CR) and partial response (PR) or stable disease (SD) ≥16 weeks. We used a Simon’s two-stage design (p0=20%; p1=40%), responses in ≥4/17 pts were expected to move to second step, and ≥11/37 pts to be considered of clinical interest (α=10% and power of 90%). Whole genome sequencing (WGS) was performed retrospectively to further assess potential biomarkers of PARP inhibitor response. Results: Tumors from 221 (31%) pts were LOH high. 41 pts were enrolled, including 4 pts with sBRCA mut. Median prior metastatic chemo lines was 2 (1-5), 17 pts had TNBC at diagnosis. As of 14 Jan 2019, 16 pts were alive, 5 are still on treatment. The median number of cycles was 2 (1 -20), and 37/40 patients were evaluable for CBR. 5 pts (13.5%) demonstrated clinical benefit (1 CR [LOH high], 3 PR [2 LOH high, 1 sBRCA2] and 1 SD>31 weeks [sBRCA1]). 19 pts had grade 3-4 toxicities. 3 pts discontinued due to toxicity. 4/5 responders pts had their tumor profiled by WGS: preliminary analyses showed that 4 pts presented high large scale state transitions, and 3 presented a somatic biallelic loss of function in HR-related genes. The fifth responder harbored a mut on gPALB2 and sBRCA2 at inclusion. Conclusions: In this study, rucaparib demonstrates antitumor activity in a subset of gBRCA WT mBC pts whose tumor has high LOH. Final analyses of WGS will provide insights about HRD signatures and drivers alterations associated with response. Clinical trial information: NCT02505048.
Survival outcomes of premenopausal patients diagnosed with invasive lobular carcinoma.
Authors: Kim Hee Jeong , Kim Seon-Ok , Freedman Rachel A. , Partridge Ann H. , Metzger-Filho Otto
Published: May 2019

1093

Background: The survival outcomes of postmenopausal women with invasive lobular carcinoma (ILC) are similar to invasive ductal carcinoma (IDC) when treated with aromatase inhibitor, but inferior when treated with tamoxifen. We sought to investigate the survival outcomes of premenopausal ILC when compared to IDC using a population-based analysis. Methods: We used Surveillance, Epidemiology, and End Results data (SEER) between 1990 to 2015 to identify premenopausal patients (defined as < 50 years old), diagnosed with stage I to III IDC or ILC. Breast Cancer Specific Survival (BCSS) was assessed using log-rank test and piecewisecox models. Annual hazard of BCCS for hormone receptor positive (ER+) ILC and ER+ IDC were calculated from year 0 to 20 and defined as the proportion of patients with a BCSS event during a 1-year interval. Results: The study includes a total of 170,352 pts diagnosed with either IDC (n = 158,733) and ILC (n = 11,619). 71% of IDC and 95% of ILC pts were ER+. Median age was 44 years old and median follow up was 90 months(IQR 40-151 months). Survival analysis revealed a significant time-dependent effect of histology for BCSS (p < .0001). When compared to IDC, ILC pts had better BCSS in the first 10 years after diagnosis (HR 0.73, 95% CI 0.68-0.78), but worse BCSS outcome after year 10 (HR 1.80, 95% CI 1.59- 2.03). Similar results were observed when adjusting for ER status, histologic grade and stage on multivariate analysis. Among pts ≤ 35 years old(n = 371 ILC; 18086 IDC) survival analysis revealed a non-significant trend towards inferior outcome for ILC compared to IDC throughout the whole follow-up period (HR = 1.2 95% CI 0.96-1.52). Annual hazard of BCCS events showed a peak at year 5 for both IDC and ILC. In the subset of IDC, we noticed a decreasing hazard of BCSS from years 6 through 20. By contrast, in the subset of ILC, we observed higher frequencies of BCSS from years 6-20 when compared to IDC (p < 0.0001). Conclusions: In this population-based analysis, premenopausal ILC had worse BCSS estimates when compared to premenopausal IDC. This is explained by a higher incidence of late events in the subset of ILC when compared to IDC.
Patients with metastatic breast cancer enrolled in phase I clinical trials: Clinical outcomes and cohort trends.
Authors: Weiss Jennifer , Gao Dexiang , Elias Anthony D. , Borges Virginia F. , Kabos Peter , Davis S. Lindsey , Leong Stephen , Diamond Jennifer Robinson
Published: May 2019

1099

Background: Phase I clinical trials have traditionally enrolled patients with advanced solid tumors and many providers perceive the likelihood of clinical benefit as low. The purpose of this study was to evaluate clinical outcomes for patients with metastatic breast cancer enrolled on Phase I clinical trials and explore differences in outcomes for patients enrolled in all-comer versus breast cancer-specific cohorts. Methods: We performed a retrospective chart review of patients with metastatic breast cancer enrolled in Phase I clinical trials at the University of Colorado Cancer Center from 2012-2018. We included trials with Phase I and/or Phase Ib in the title. Studies or cohorts enrolling patients with ≥ 3 tumor types were considered all-comer and those with enrollment restricted to breast cancer or a breast cancer subtype were considered breast cancer-specific. Results: A total of 208 patients were enrolled in Phase I clinical trials, 168 in breast cancer-specific cohorts and 40 in all-comer trials. Patients on average were 56.9 years old (range 31-79), 98.6% (205/208) female, 1.4% (3/208) male, 57.2% ER+/Her2-, 30.1% ER-/Her2- and 11.1% Her2+. Patients received on average 2.1(range 0-10) prior lines of chemotherapy in the metastatic setting. Patients enrolled on Phase I clinical trials remained on study without progression on average for 138 days (CI 95%, 112.64 to 163.91). Patients enrolled on breast cancer-specific studies remained on study for 152 days (CI 95%, 120.66 to 182.56) compared to 82 days (CI 95%, 59.43 to 105.13) for those enrolled on all-comer trials, p< 0.05. Patients went off study for disease progression (83.17%), adverse events (7.69%), and other (9.14%), including withdrawal of consent. Conclusions: Patients with metastatic breast cancer previously treated with multiple lines of chemotherapy in the metastatic setting enrolled in Phase I clinical trials received clinical benefit from treatment that is favorable compared to historical controls of late-line chemotherapy. The majority of patients were treated on breast cancer-specific cohorts consistent with trends in Phase I trial design including more tumor specific cohorts.
Real-world outcomes of patients with advanced non-small cell lung cancer (aNSCLC) and autoimmune disease (AD) receiving immune checkpoint inhibitors (ICIs).
Authors: Khozin Sean , Walker Mark S. , Jun Monika , Chen Li , Stepanski Edward , Rubinstein Wendy S. , Komatsoulis George Anthony , Roberts Jeremy , Zhi Jizu , Miller Robert S. , Fukushima Ryan , Lau Denise , Hyde Brigham
Published: May 2019

110

Background: Anecdotal and early evidence suggest ICIs are being used in patients with advanced malignancies and history of AD, despite such patients being typically excluded from traditional clinical trials. We compared the outcomes of patients with or without AD, all of whom had ICI treatment for aNSCLC. Methods: We conducted a retrospective, observational cohort study using de-identified, curated data in ASCO’s CancerLinQ. Patients with Stage III or IV NSCLC who received ≥1 dose of an ICI and had ≥2 visits from Jan 2011 to Nov 2018 were included. AD status prior to ICI treatment was identified using ICD-9/ICD-10 codes or AD medications (including steroids). Symphony claims data were linked via tokenization to build cohorts. Time to treatment discontinuation (TTD), time to next treatment (TTNT), real-world progression-free survival (rwPFS) and overall survival (OS) were compared across the two cohorts using the log-rank test. Cox Proportional Hazards Model was used to adjust for covariates. Adverse events (AEs) were compared using Chi-Square and Fisher’s Exact Test. Active AD was defined as evidence of autoimmune disease in the year prior to starting ICIs. Results: Among 2425 patients with aNSCLC treated with ICIs, AD was present in 22% (N=538). Median OS in all patients was 12.4 months (95% CI 11.3-13.5). TTD, TTNT, rwPFS and OS did not differ between the two cohorts (Table). There was no association between AD status and outcomes. There was no increased incidence of AEs in the AD group; however a sub-analysis among patients with active AD showed higher rates of select AEs including endocrine, GI and blood disorders. Conclusions: This analysis demonstrates that patients with evidence of AD prior to receiving ICI have similar outcomes compared to patients with no evidence of AD. Further research is needed to better understand the impact of active AD on the risk of AEs and patient outcomes. [Table: see text]
Risk of subsequent cancer diagnosis in patients treated with 3D conformal, intensity modulated, or proton beam radiation therapy.
Authors: Xiang Michael H. , Chang Daniel Tandel , Pollom Erqi L.
Published: May 2019

1503

Background: Approximately half of cancer patients receive radiation therapy (RT). Modern RT modalities (3D conformal [3DCRT], intensity modulated [IMRT], proton beam [PBRT]) have been theorized to pose different risks of second cancers, but the relationship between RT modality and subsequent cancers has been unclear due to their rarity. Methods: Pediatric and adult patients with a first cancer diagnosis who received 3DCRT, IMRT, or PBRT were identified in the National Cancer Database. To analyze a more uniform population, cases were required to be non-metastatic and have at least 2 years of follow-up time. Ten cancer types were included: head/neck, upper gastrointestinal (GI), lower GI, gynecological, lymphoma, non-small cell lung, prostate, breast, bone/soft tissue, and brain/central nervous system. Diagnosis of a subsequent cancer was determined using a variable denoting the sequence of malignant neoplasms over the lifetime of the patient. The risk of subsequent cancer diagnosis was modeled using multivariable logistic regression adjusting for age, follow-up time, cancer type, RT dose, chemotherapy, and other factors. Propensity score matching was additionally used to balance baseline characteristics. Results: In total, 430,866 patients were included (33.4% 3DCRT, 65.1% IMRT, 1.5% PBRT) with median follow-up of 5.0 years and total follow-up period of 2.35 million person-years. In the comparison of IMRT relative to 3DCRT, there was no difference in the risk of subsequent cancer diagnosis (adjusted odds ratio [OR] 1.01; 95% confidence interval [CI] 0.98-1.03; p = 0.62). In contrast, recipients of PBRT had significantly lower risk of subsequent cancer diagnosis relative to IMRT (adjusted OR 0.31; 95% CI 0.26-0.37; p < 0.0001). The benefit associated with PBRT persisted in sensitivity analyses that excluded patients with prostate cancer (71.6% of the PBRT cases), receipt of chemotherapy, and/or follow-up time less than 5 years. Conclusions: Risk of subsequent cancer diagnosis was similar between IMRT and 3DCRT and significantly lower for PBRT. PBRT may be preferred in situations where avoidance of second cancers is paramount, such as pediatrics and young adults.
Ten-fold increase in genetic testing in pancreatic and metastatic prostate cancer with implementation of point of care (POC) testing.
Authors: Symecko Heather , Mueller Rebecca , Spielman Kelsey , Batson Melissa , Pundock Stacy , Hamilton Jada G. , Robson Mark E. , Domchek Susan M.
Published: May 2019

1506

Background: Germline genetic testing (GT) for cancer susceptibility is recommended for pancreatic and advanced prostate cancer patients, due to potential implications for targeted therapies and risk assessment of family members. Traditional cancer GT programs may create barriers for certain patient populations. To more effectively integrate testing into standard oncology care POC GT was introduced in early 2018 in a joint protocol with Memorial Sloan Kettering Cancer Center. Here we report pre and post POC referral and testing numbers at the University of Pennsylvania. Methods: Patients with metastatic prostate or pancreatic cancer were ascertained through their GU/GI oncologist onto an IRB approved protocol and shown an educational video about GT by research staff who obtained informed consent and facilitated biospecimen collection. Genetic counselors returned results and provided post-test counseling by phone. To evaluate the impact of this model on the uptake of GT services, the number of patients who were referred to and proceeded with GT was compared before and after study initiation. Results: In 2017, 77 patients were referred to genetics of which 45 underwent genetic counseling and testing. Twenty-nine (38%) did not complete genetic counseling or testing, and 3 later underwent testing through the POC study. Since the study launched in 2018, 407 patients were referred and underwent testing through the study. This represents a ten-fold increase in patients who underwent GT. Conclusions: Comparing uptake of GT services before and after study initiation suggests that a POC model with abbreviated pre-test education and post-test genetic counseling by phone is a possible solution to barriers of traditional genetic counseling, increasing physician referrals and uptake of testing by patients. This approach allows for more timely access to genetic information that may impact treatment strategies and medical management of family members. Clinical trial information: pending. [Table: see text]
Characterization and clinical outcomes of mismatch repair deficient (dMMR) small bowel adenocarcinoma (SBA).
Authors: Latham Alicia , Reidy Diane Lauren , Segal Neil Howard , Yaeger Rona , Ganesh Karuna , Connell Louise Catherine , Kemeny Nancy E. , Shia Jinru , Hechtman Jaclyn Frances , Srinivasan Preethi , Patel Zalak , Tkachuk Kaitlyn , Berger Michael F. , Saltz Leonard B. , Cercek Andrea , Stadler Zsofia Kinga
Published: May 2019

1511

Background: SBA is a rare cancer known to be associated with Lynch syndrome (LS). The prevalence, tumor characteristics, and clinical course of SBAs in the setting of LS is not well understood. We sought to characterize SBA according to mismatch repair and germline mutation status, comparing clinical outcomes. Methods: A retrospective review of SBAs at a single institution identified 74 SBAs that were assessed for dMMR either via immunohistochemical staining (IHC) or microsatellite instability status (MSI) using NGS. Germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM) and when available, clinical records were reviewed. Results: Of 74 individuals with SBA, 28.4% (21/74) of tumors exhibited dMMR and/or high-frequency MSI (MSI-H). The overall prevalence of LS in SBA was 9.5% (7/74), with all LS patients having dMMR/MSI-H tumors. 33.3% (7/21) of dMMR/MSI-H SBA patients had LS. The distribution of germline mutations among LS patients was 57.1% (4/7) in MLH1, 28.6% (2/7) in MSH2, and 14.3% (1/7) in PMS2. One patient with an dMMR/MSI-H tumor was found to have a high-penetrance APC mutation, diagnostic of familial adenomatous polyposis (FAP). In the 38 patients with available clinical follow-up, median age of onset was similar in the dMMR/MSI-H vs the pMMR/MSS group (62 vs 57, p = 0.8). The prevalence of synchronous/metachronous cancers was 5.9% (1/17) in the pMMR/MSS group and 38% (8/21) in the dMMR/MSI-H group (p = 0.02), with 62.5% (5/8) of these in LS (p = 0.001; synchronous/metachronous in LS (5/7) vs. non-LS (4/31)). In the pMMR/MSS group, 58.8% (10/17) of patients presented with metastatic disease at diagnosis, compared to 19% (4/21) in the dMMR/MSI-H group (p = 0.01). In dMMR/MSI-H SBA patients with early-stage disease, 11.8% (2/17) recurred, compared to 71.4% (5/7) in the pMMR/MSS group (p = 0.009). Conclusions: This preliminary evaluation suggests that SBA exhibiting dMMR/MSI-H status is more closely associated with early-stage disease and lower recurrence rates, similar to prior observations in colon cancer. LS was found in 9.5% of all SBA and in 33.3% of dMMR/MSI-H tumors, suggesting that germline assessment for LS in SBA is warranted.
New onset diabetes as a predictive factor of focal lesions in the pancreas in a high-risk screening program.
Authors: Montiel Maria Fernanda , Quesada Pompeyo Rafael , Dunseith Margaret , Cazacu Irina , Luzuriaga Alexandra , Dong Wenli , Bannon Sarah A. , Mork Maureen E , Feng Lei , You Y. Nancy , Vilar Sanchez Eduardo , Arun Banu , Brown Powel , Kim Michael Paul , Katz Matthew H. G. , Maitra Anirban , Bhutani Manoop S. , McAllister Florencia
Published: May 2019

1512

Background: Genetic evolution studies have suggested the existence of a window of opportunity to improve clinical outcomes by intercepting pre-malignant lesions. This study reports the outcomes of Pancreatic Cancer (PC) surveillance in a high risk (HR) cohort followed at The University of Texas MD Anderson Cancer Center (MDA) between 2014 and 2018. Methods: The MDA PC High-Risk Clinic (MDA-PCHRC) performs surveillance based on risk stratification. This study reports 54 months of surveillance. The patients were stratified based on PC family history, personal history of other cancers, and germline mutations ( BRCA1/2, PALB2, STK11, CDKN2A, TP53) with high susceptibility to PC. Low risk patients were not offered surveillance while patients in the moderate or high-risk category were enrolled into a program which included annual screening with blood markers (CA 19-9, fasting glucose, HbA1C, amylase, and lipase) and magnetic resonance imaging/ cholangiopancreatography (MRI/MRCP). High risk patients also had a baseline endoscopic ultrasound (EUS). We evaluated the yield of premalignant lesions detection and our main goal was to detect predictive factors of focal pancreatic lesions and to validate our risk stratification strategy. Results: A total of 206 patients have been referred to our clinic during this time period. From this group, 126 (61%) patients completed at least one cycle of baseline surveillance, for the purposes of the analysis we only focus in the high risk (n=71) and moderate risk group (n=38). We have identified de novo pancreatic focal lesions in 22 patients, 20 from the high risk group (28%) and 2 from the moderate group (5%). Those lesions included 7 patients with simple cysts, 9 with side-branch IPMN, 3 with main duct IPMN, 1 with pseudocyst, 1 with mucinous cyst and 1 with a solid nodule (pancreatic neuroendocrine tumor). We compared demographic information (age, gender, and ethnicity) as well as family and personal medical history between patients with focal pancreatic lesions vs negative or diffuse findings. We found that new onset diabetes was significantly correlated with presence of focal pancreatic lesions 5 (22%) of patients with focal lesions versus patients without non focal lesion 2 (2%) ( P=0.003). Conclusions: Screening at the MDA-PCHRC detect pancreatic premalignant lesions in 20% of the patients in our cohort. We validated our risk stratification methodology and found that new-onset diabetes is predictive of pancreatic lesions, thus suggesting that this factor could be an important biomarker of focal lesions in a HR population.
Racial and ethnic differences in the results of multigene panel testing of inherited cancer predisposition genes in breast cancer patients.
Authors: Yadav Siddhartha , LaDuca Holly , Polley Eric , Shimelis Hermela , Niguidula Nancy , Hu Chunling , Lilyquist Jenna , Na Jie , Lee Kun , Gutierrez Stephanie , Yussuf Amal , Hart Steven , Tippin Davis Brigette , Chao Elizabeth , Pesaran Tina , Goldgar David , Dolinsky Jill S. , Couch Fergus
Published: May 2019

1514

Background: The prevalence of germline mutations in non-white patients with breast cancer and the germline genetic drivers of breast cancer risk in non-white populations are largely unknown. Methods: The study population included 77,900 women with breast cancer (Non-Hispanic white: 57,003; Black: 6,722; Asian: 4,183; Hispanic: 5,194; Ashkenazi-Jewish: 4,798) who underwent germline multigene panel testing of cancer predisposition genes from March 2012 to December 2016. The prevalence of predisposition gene mutations in racial and ethnic populations relative to non-Hispanic Whites was assessed while accounting for age at diagnosis of breast cancer, family history of breast and ovarian cancer, and estrogen receptor status of breast tumors. Associations between mutations in each gene and breast cancer risk were evaluated using reference controls. Results: The overall frequency of pathogenic mutations in known breast cancer predisposition genes was 9.1% for non-Hispanic Whites, 9.8% for African Americans, 10.2% for Hispanics, 7.6% for Ashkenazi-Jewish, and 7.5% for Asians. BRCA1 mutations were enriched (p < 0.05) and CHEK2 mutations were under-represented in all racial and ethnic populations relative to non-Hispanic Whites. BRCA2 and BARD1 mutations were enriched in African Americans and Hispanics relative to non-Hispanic Whites, whereas PALB2 and RAD51C mutations were enriched in Hispanics. Among genes with mutation counts large enough for assessment, mutations in BARD1, BRCA1, BRCA2, PALB2 and TP53 were significantly associated with clinically relevant increased risks (odds ratio (OR) > 2) of breast cancer across all ethnicities and races. Rates of variants of uncertain significance were highest among Asians (29%), followed by blacks (27%), Hispanics (21%), non-Hispanic whites (16%) and Ashkenazi-Jews (14%). Conclusions: While there is some similarity across ethnic groups, substantial heterogeneity exists in the prevalence of mutations in breast cancer predisposition genes across major racial and ethnic groups in the US population. These findings contribute to our understanding of breast cancer risk and have significant implications for genetic testing, screening, and management of patients with an inherited predisposition to breast cancer, with a need for continued analysis with increased cohort size in ethnic minority groups.
Germline mutations and onset of lung adenocarcinoma in smokers and nonsmokers.
Authors: Reckamp Karen L. , Slavin Thomas Paul , Gray Stacy W. , Behrendt Carolyn E. , Castillo Danielle , Koczywas Marianna , Cristea Mihaela C. , Babski Kirsten , Stearns Donna , Marcum Catherine A , Rodriguez Yeny , Hass Amie , Vecchio Mary , Mora Alferez Analí Pamela , Cervantes Aleck , Sand Sharon , Mach Stephanie L , Tsou Terrence , Salgia Ravi , Weitzel Jeffrey N.
Published: May 2019

1518

Background: Eligibility for lung cancer screening is based largely on pack-years of smoking, missing many cases. To propose additional groups for screening, this observational study evaluated whether germline mutations associated with cancer risk accelerate onset of lung adenocarcinoma (LA) in ever- and never-smokers. Methods: Patients with LA and family history of cancer were recruited from our oncology clinic and the Clinical Cancer Genomics Community Research Network. With consent, blood samples were screened by large multi-gene panel for 4 categories of germline mutation [lung cancer-associated genes ( TP53, EGFR); BRCA2; other genes in Fanconi anemia (FA) pathway; other DNA repair genes]. Accelerated failure-time models of age at LA diagnosis, adjusted for sex, ethnicity, and packs per day, were constructed for never-smokers and ever-smokers. Statistical significance, at p<0.05 limited the False Discovery Rate to 5% across 8 hypotheses. Results: In never-smokers with LA (n=104), mutated BRCA2, TP53 or EGFR were associated with younger age at diagnosis, while mutation in other FA or DNA repair gene was not. In ever-smokers with LA (n=65), mutated BRCA2 and other FA gene were associated with younger age at diagnosis, while other mutation categories were not (Table). Conclusions: Regardless of smoking history, BRCA2 mutation carriers experience accelerated onset of LA, as do never-smokers carrying TP53 or EGFR mutation and ever-smokers with mutation in FA gene other than BRCA2. With the exception of TP53 carriers (who merit whole body MRI), lung cancer screening with low-dose computed tomography, starting earlier in adulthood than usual, may be warranted for individuals with germline mutations in these genes. Age at Diagnosis of Lung Adenocarcinoma, by Germline Mutation and Smoking History, Adjusted for Sex, Ethnicity, and Packs per Day. [Table: see text]
Prevalence and clinical implications of mismatch repair (MMR) deficiency in unselected non-serous epithelial ovarian cancer (EOC) patients (pts).
Authors: Scaranti Mariana , Murali Krithika , Orbegoso Cecilia , Vroobel Katherine , Banerjee Susana N. , Gore Martin Eric , Attygalle Ayoma , George Angela
Published: May 2019

1521

Background: It has previously been reported that 6-7% of clear cell (CC) and endometrioid (E) ovarian cancers are MMR deficient (MMRd). The prevalence of MMRd in other histological subtypes and correlation with germline (g) MMR (Lynch Syndrome) mutations in unselected non-serous EOC pts is less clear. MMRd in solid tumors has been associated with enhanced response to immunotherapy, hence knowledge of MMR status has therapeutic and familial implications. We aimed to study the prevalence and implications of MMRd and gMMRd in unselected pts with non-serous EOC. Methods: Routine immunohistochemistry (IHC) was performed for the MMR proteins MLH1, MSH2, MSH6 and PMS2 in all non-serous EOC pts from June 2016; retrospective MMR IHC testing in pts in follow-up was performed. Pts with MMRd tumors were referred for gMMR testing. Results: We analyzed 66 unselected pts with non-serous EOC. Median age was 56.4 years (yrs). The majority had E ovarian cancer (54.5%) followed by CC (25.8%), mixed histology (12.1%), mucinous (4.5%) and mullerian (3%) subtypes. Endometriosis was noted in 45.5% of pts, and 75% were FIGO stage I and II at diagnosis. Seventeen pts (25.8%) had concurrent endometrial cancer, all Grade I. On IHC, 15.2% were MMRd: 5 E, 2 CC, 2 mixed and 1 mullerian-type. Of these, 3 pts (30%) had gMMR mutation, 2/3 did not meet the Revised Bethesda criteria for testing. A lower average body mass index (Kg/m2) was noted in MMRd 25.9 versus 30.1 in MMR proficient (MMRp). Median age at diagnosis was 53.5 yrs in the MMRd and 57.7 yrs in MMRp. A higher frequency of concurrent endometrial cancer was observed on the MMRd group (60%) versus (20%) on MMRp (p = 0.007). No statistically significant difference in overall survival or disease-free survival was observed between the MMRd and MMRp population. Conclusions: Our study has shown a higher prevalence of somatic MMRd in non-serous EOC (15.2%) than in previously published literature with a significant proportion found to carry gMMR mutations (4.5%). These interim findings support the role of universal MMR IHC testing in non-serous EOC regardless of family history. [Table: see text]
Characterization of Lynch syndrome (LS) associated cancers in patients with immune dysfunction.
Authors: Bari Shahla , Wang Xia , Ajose Taiwo , Muzaffar Jameel
Published: May 2019

1532

Background: LS is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2. Inappropriate immune responses as seen in chronic inflammatory conditions as well as immunodeficiency states confer increased risk of developing cancer. This aim of this study was to evaluate the effect of immune dysfunction on the characteristics of LS associated cancers. Methods: This was a retrospective analysis of LS patients and carriers at two institutions listed above. We evaluated mutational profiles, immune status, age of onset of first and subsequent cancers in this cohort. Results: 106 patients with mutations consistent with LS were included. 72 patients had at least one cancer while 34 were carriers. 44% patients were Caucasian female, 18% white males, 14% African American males, 11% African American females and 10% Hispanic females. Colon cancer (CRC) was the most common cancer (44%) and PMS2 was the most common mutation, noted in 35 patients (33%). Of the 72 patients with LS associated cancer, 18 patients were either immunosuppressed or had an autoimmune condition. Of the 10 patients who had an autoimmune condition ,7 had multiple cancers. Of the 9 patients who were immunosuppressed, 5 had multiple cancers. Out of a total of 18 out of 72 patients who had multiple cancers, 12 (66%) had either an autoimmune condition or were immunosuppressed. CRC was the index cancer in 42% and breast in 33% of patients with multiple cancers. Patients with MSH2 were most likely to have an immune related condition (32%) and accounted for 41% of patients with multiple cancers. The median age of first cancer in this group was 46 years while it was 48.5 years in the population without immune dysfunction (p = 0.2). There was a high prevalence of breast cancer (24%) as a LS associated cancer in our study population. 66% of the patients with PMS2 mutation had breast cancer with a median age of onset of 48 years (62 years for sporadic cancer). Conclusions: Our study is the first to look at the effect of immune dysfunction in LS patients. Immune dysfunction was associated with a higher rate of multiple cancers and was more commonly associated with the MSH2 mutation. It also highlights importance of aggressive screening for breast cancer in LS patients (especially with PMS2 mutation).
Risk of colon adenoma in patients with breast cancer.
Authors: Wang Yinghong , Abu-Sbeih Hamzah , Ali Faisal , Ge Phillip S. , Barcenas Carlos Hernando , Lum Phillip , Qiao Wei , Bresalier Robert , Bhutani Manoop S. , Gottumukkala Raju S.
Published: May 2019

1541

Background: In our clinical practice at a tertiary cancer center, we have observed increased adenoma detection rate (ADR) in patients with breast cancer. Here, we describe ADR in patients with breast cancer to define the appropriate timing to initiate colonoscopy screening in these patients. Methods: We conducted a retrospective study of patients with breast cancer who underwent a colonoscopy after their diagnosis of breast cancer between 2000 and 2017. A control group ( n = 3295) comprised patients without any type of cancer who underwent their first screening colonoscopy between 2008 and 2017 was used in the logistic regression. Results: Of the 62,820 patients who had a diagnosis of breast cancer, 3304 were included. The mean age was 59 years. Regarding ADR, 1803 patients (55%) had adenomas. High-grade dysplasia was evident in 28% of polyps and invasive adenocarcinoma in 172 (5%). The median time from breast cancer diagnosis to adenoma detection was 3 years (IQR 1-6). The ADR was 21% in patients younger than 40 years ( n=63), 39% in patients between 40 and 50 years ( n=314), 54% in patients between 50 and 60 years ( n=1420), and 60% in patients older than 60 years ( n=1507). ADR in patients younger than 50 years of age who do not have a family history of colorectal cancer or a body mass index (BMI) higher than 30 kg/m2 was 26%. A subsequent colonoscopy was performed in 831 patients who had colonic adenoma in the initial colonoscopy. The ADR was 40% in patients who had a repeat colonoscopy within 3 years, 50% within 3-5 years, and 53% > 5 years. Multivariate logistic regression analyses revealed an increased risk of colon adenoma with older age, male sex, higher BMI, and personal history of breast cancer ( P<0.05). Conclusions: In patients with breast cancer, ADR was higher than that of patients without history of cancer. Notably, breast cancer was an independent risk factor for colon adenoma. In patients who are younger than 40 years of age, screening colonoscopy should be considered within five years of breast cancer diagnosis. Multivariate logistic regression: risk factors of adenoma. [Table: see text]
Contralateral breast cancer risk according to first breast cancer characteristics among United States women from 1992 to 2015.
Authors: Ramin Cody , Withrow Diana , Davis Lynn Brittny , Gierach Gretchen , Berrington de González Amy
Published: May 2019

1549

Background: After recent advances in breast cancer treatment and increasing uptake of contralateral prophylactic mastectomies, estimates of contralateral breast cancer (CBC) risk by year of diagnosis and other patient characteristics are needed to help inform decision making. Methods: We estimated CBC risk in 399,032 1-year survivors of a first primary breast cancer (stage I-III) in the US Surveillance, Epidemiology, and End Results Database (1992-2015). CBC was defined as an invasive second breast cancer diagnosed in the opposite breast 12+ months after the first breast cancer diagnosis. We estimated standardized incidence ratios (SIRs) and 5-year cumulative incidence of CBC by calendar period, age, breast cancer subtype, and receipt of hormonal therapy for the initial breast cancer. SIRs were calculated as the observed number of CBCs among survivors compared to the expected number of first breast cancers in the general population. Cumulative incidence was estimated in women without contralateral prophylactic mastectomies and accounted for competing risks. Results: Among 399,032 breast cancer survivors, 11,365 cases of CBC were diagnosed through 2015. Risk of CBC was elevated over the entire study period (SIR = 2.23, 95% CI = 2.19-2.27). SIRs for CBC declined over calendar period and this decreasing trend was observed irrespective of age, estrogen receptor (ER) status, and hormonal therapy. Survivors had an overall 5-year cumulative incidence of CBC of 1.49% (95% CI = 1.44%-1.54%), which decreased over time to 1.31% (95% CI = 1.23%-1.41%) in 2008-2014. For recent diagnoses, the 5-year cumulative incidence of CBC was higher after ER-negative (1.80%, 95% CI = 1.55%-2.07%) and triple negative tumors (1.98%, 95% CI = 1.52%-2.55%), and lowest for women who received hormonal therapy (1.01%, 95% CI = 0.90%-1.13%). Conclusions: Although CBC risk is declining in the US from 1992-2015, survivors have approximately twice the risk of an incident breast cancer (in the contralateral breast) compared to the general population. The 5-year cumulative risk of CBC is highest after ER-negative/triple negative tumors highlighting the need for medical surveillance and targeted interventions among these patients.
Predicting future cancer incidence by age and gender.
Authors: Garner Wesley B. , Smith Benjamin D. , Shabason Jacob Ezra , Williams Grant Richard , Martin Michelle Y. , Ballo Matthew T. , VanderWalde Noam Avraham
Published: May 2019

1559

Background: Cancer remains a substantial and unique burden on society. While the impact of changing demographics on cancer incidence has previously been characterized (Smith et al, JCO, 2009), this has not been done with updated population data. Our objective was to update projections on the number of new cancer diagnoses in the United States by age and gender through 2040. Methods: Population-based cancer incidence data were obtained using SEER 18 delay-adjusted data. Population estimates were made by age, race, and gender using the 2010 US Census data population projections to calculate future cancer incidence rates. Trends in age- adjusted incidence rates for 23 cancer types were calculated as previously described (Edwards et al, Cancer, 2014). Results: From 2020 to 2040 the projected total cancer incidence will increase by almost 30% from 1.86 million to 2.4 million. This increase is due to the projected increase in population growth, particularly in older individuals. The population of older adults will represent a growing proportion of total cancer diagnoses. Specifically, patients ≥65 years old will make up 69% of all new cancer diagnoses, while 13% of new diagnoses will be in patients ≥85 years old by 2040 (see Table). Cancer diagnoses in females are projected to rise 27%, while male cancer diagnoses are projected to increase by 32% from 2020 to 2040. The incidence rates for lung, colorectal, and prostate cancer are expected to decline, while those for thyroid, liver, melanoma and myeloma are expected to increase. Conclusions: The landscape of cancer care will continue to change over the next several decades. The burden of disease will remain substantial and will continue to disproportionately affect older adults. The growing proportion of older cancer patients and changes in site-specific cancer incidence rates remain of particular interest. These projections should help guide future health policy and research priorities. [Table: see text]
Risk of anxiety and depression in breast cancer survivors compared to women who have never had cancer: A population-based cohort study in the United Kingdom.
Authors: Carreira Helena , Williams Rachael , Funston Garth , Stanway Susannah Jane , Bhaskaran Krishnan
Published: May 2019

1564

Background: Breast cancer survivors are the largest group of cancer survivors in the United Kingdom (UK). Having had a breast cancer diagnosis may adversely affect the patient’s mental health. We aimed to estimate the long-term risk of anxiety and depression in women with history of breast cancer compared to those who have never had cancer. Methods: We conducted a matched population-based cohort study, using data from the Clinical Practice Research Datalink (CPRD) GOLD primary care database. The exposed cohort included all adult women diagnosed with breast cancer between 1987 and 2018; the unexposed group included women with no cancer history, matched to exposed women in a 4:1 ratio on primary care practice and age. Cox regression models stratified on matched set were used to estimate hazard ratios of the association between breast cancer survivorship and anxiety and depression. Results: 59,972 women (mean 62 years; standard deviation (SD) 14.0) had history of breast cancer. The median follow-up time was 3.0 years (SD 4.4), which amounted to 256,186 person-years under observation. The comparison group included 240,387 women followed up over 3.5 years (SD 4.5) (1,163,819 person-years). The incidence of anxiety in breast cancer survivors was 0.08 (95% confidence interval (95%) 0.07-0.08) per 1000 person-years, and the incidence of depression was 70 (95%CI 68-71) per 1000 person-years. The risks of both depression and anxiety were raised in breast cancer survivors compared with controls, and this appeared to be driven by the first 3 years following diagnosis (Table). Conclusions: Breast cancer survivors in the UK had significantly higher risk anxiety and depression diagnosed in primary care for three years following diagnosis than women who never had cancer. Risk of anxiety and depression in breast cancer survivors compared to women who did not have cancer by time since diagnosis. [Table: see text]
Risk of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) in a cohort of 3,546 women prospectively followed after receiving textured breast implants.
Authors: Ghione Paola , Cordeiro Peter G. , Ni Ai , Hu Qunying , Ganesan Nivetha , Galasso Natasha , Dogan Ahmet , Horwitz Steven M.
Published: May 2019

1565

Background: Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare subtype of T-cell lymphoma, developing in in the fluid or capsule surrounding breast implants, primarily or exclusively in those with textured surfaces. Several prior series have estimated the risk of BIA- ALCL at 1/6920 - 1/3800 women in retrospectively defined cohorts (from diagnosed cases within national or pathology databases), approximating the population at risk from sales records or other estimates (Sirinvasa 2017; Loch-Wilkinson 2017; de Boer 2018). Methods: A prospective cohort study was conducted in the population that underwent breast reconstruction by a single surgeon at Memorial Sloan Kettering Cancer Center (MSKCC) from April 1993 to December 2017. Patients had long-term follow-up, and events related to implants were prospectively recorded. We identified all cases of BIA-ALCL by cross-checking data from internal clinical records, pathology records, and outside reports. Incidence rate per person-years and cumulative incidence when accounting for competing risk were calculated. 134 women who received smooth-surface implants were excluded from the analysis, since these implants have not been associated with BIA-ALCL. Results: From 1993 to 2017, 3546 patients underwent 6023 breast reconstructions using textured surface implants. All reconstructions were performed by a single surgeon (PGC) on patients enrolled in this study. To identify BIA-ALCL occurrence, clinical and pathological data were assessed from a prospective database. Median follow-up was 7 years (range, 3 days - 24.7 years). Eight women developed ALCL after a median exposure of 11.2 years (range, 8.3-15.8 years). Overall risk of BIA-ALCL in this cohort was 0.294 cases per 1000 person-years (1/443 women). Conclusions: This study, evaluating the risk of women with textured breast implants from a prospective database with long-term follow-up, demonstrated that the incidence rate of BIA-ALCL may be higher than previously reported. These results can help inform implant choice for women undergoing breast reconstruction.
Factors associated with breast cancer mortality-per-incident case in low-to-middle income countries (LMICs).
Authors: Chagpar Anees B. , Coccia Mario
Published: May 2019

1566

Background: Reducing breast cancer mortality is a key healthcare challenge worldwide. We sought to determine the impact of macro-socioeconomic factors on breast cancer age-standardized incidence (ASI) and mortality-per-incident case (MPI) in LMICs. Methods: Data regarding breast cancer ASI and mortality in 78 LMICs were obtained from IARC/WHO. MPI was defined as the age standardized mortality divided by the ASI. Country-level socioeconomic data were obtained from World Bank, UN Development Project, and WHO data sources. Results: In 2018, the median ASI for breast cancer was 26.5 (range; 5-67.3) per 100,000 population in LMICs, with a median MPI of 50.6% (range 27-70%). ASI and MPI were inversely correlated (Spearman rho = -0.236, p = 0.044). Factors associated with ASI and MPI are shown in the table below. We found no factor could discriminate between the highest and lowest quartile in terms of ASI. However, all (except health expenditure as a % of GDP) were significantly different between the highest and lowest quartile in terms of MPI. Conclusions: Results suggest considerable variation in terms of breast cancer MPI within LMICs. Improved rates are seen with increasing GDP, literacy, contraceptive use, and provision of doctors and mammography, but overall % GDP expended on public health does not seem to significantly influence breast cancer MPI. [Table: see text]