Susan M. Gerty

Common Breast Cancer Susceptibility Loci Are Associated with Triple-Negative Breast Cancer

Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six single-nucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer.

Obesity and the outcome of young breast cancer patients in the UK: the POSH study

BACKGROUND Obese breast cancer patients have a poorer prognosis than non-obese patients. We examined data from a large prospective cohort study to explore the associations of obesity with tumour pathology, treatment and outcome in young British breast cancer patients receiving modern oncological treatments. PATIENTS AND METHODS A total of 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 126 UK hospitals from 2001 to 2007. Height and weight were measured at registration. Tumour pathology and treatment details were collected. Follow-up data were collected at 6, 12 months, and annually. RESULTS A total of 2843 eligible patients (96.2%) had a body mass index (BMI) recorded: 1526 (53.7%) were under/healthy-weight (U/H, BMI <25 kg/m(2)), 784 (27.6%) were overweight (ov, BMI ≥25 to <30), and 533 (18.7%) were obese (ob, BMI ≥30). The median tumour size was significantly higher in obese and overweight patients than U/H patients (Ob 26 mm versus U/H 20 mm, P < 0.001; Ov 24 mm versus U/H 20 mm, P < 0.001). Obese and overweight patients had significantly more grade 3 tumours (63.9% versus 59.0%, P = 0.048; Ov 63.6% versus U/H 59.0% P = 0.034) and node-positive tumours (Ob 54.6% versus U/H 49.0%, P = 0.027; Ov 54.2% versus U/H 49%, P = 0.019) than U/H patients. Obese patients had more ER/PR/HER2-negative tumours than healthy-weight patients (25.0% versus 18.3%, P = 0.001). Eight-year overall survival (OS) and distant disease-free interval (DDFI) were significantly lower in obese patients than healthy-weight patients [OS: hazard ratio (HR) 1.65, P < 0.001; DDFI: HR 1.44, P < 0.001]. Multivariable analyses adjusting for tumour grade, size, nodal, and HER2 status indicated that obesity was a significant independent predictor of OS and DDFI in patients with ER-positive disease. CONCLUSIONS Young obese breast cancer patients present with adverse tumour characteristics. Despite adjustment for this, obesity still independently predicts DDFI and OS.BACKGROUND Obese breast cancer patients have a poorer prognosis than non-obese patients. We examined data from a large prospective cohort study to explore the associations of obesity with tumour pathology, treatment and outcome in young British breast cancer patients receiving modern oncological treatments. PATIENTS AND METHODS A total of 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 126 UK hospitals from 2001 to 2007. Height and weight were measured at registration. Tumour pathology and treatment details were collected. Follow-up data were collected at 6, 12 months, and annually. RESULTS A total of 2843 eligible patients (96.2%) had a body mass index (BMI) recorded: 1526 (53.7%) were under/healthy-weight (U/H, BMI <25 kg/m2), 784 (27.6%) were overweight (ov, BMI ≥25 to <30), and 533 (18.7%) were obese (ob, BMI ≥30). The median tumour size was significantly higher in obese and overweight patients than U/H patients (Ob 26mm versus U/H 20mm, P < 0.001; Ov 24mm versus U/H 20mm, P < 0.001). Obese and overweight patients had significantly more grade 3 tumours (63.9% versus 59.0%, P = 0.048; Ov 63.6% versus U/H 59.0% P = 0.034) and node-positive tumours (Ob 54.6% versus U/H 49.0%, P = 0.027; Ov 54.2% versus U/H 49%, P = 0.019) than U/H patients. Obese patients had more ER/PR/HER2-negative tumours than healthy-weight patients (25.0% versus 18.3%, P = 0.001). Eight-year overall survival (OS) and distant disease-free interval (DDFI) were significantly lower in obese patients than healthy-weight patients [OS: hazard ratio (HR) 1.65, P < 0.001; DDFI: HR 1.44, P < 0.001]. Multivariable analyses adjusting for tumour grade, size, nodal, and HER2 status indicated that obesity was a significant independent predictor of OS and DDFI in patients with ER-positive disease. CONCLUSIONS Young obese breast cancer patients present with adverse tumour characteristics. Despite adjustment for this, obesity still independently predicts DDFI and OS.

Ethnicity and outcome of young breast cancer patients in the United Kingdom: the POSH study.

Background:Black ethnic groups have a higher breast cancer mortality than Whites. American studies have identified variations in tumour biology and unequal health-care access as causative factors. We compared tumour pathology, treatment and outcomes in three ethnic groups in young breast cancer patients treated in the United Kingdom.Methods:Women aged ⩽40 years at breast cancer diagnosis were recruited to the POSH national cohort study (MREC: 00/06/69). Personal characteristics, tumour pathology and treatment data were collected at diagnosis. Follow-up data were collected annually. Overall survival (OS) and distant relapse-free survival (DRFS) were assessed using Kaplan–Meier curves, and multivariate analyses were performed using Cox regression.Results:Ethnicity data were available for 2915 patients including 2690 (91.0%) Whites, 118 (4.0%) Blacks and 87 (2.9%) Asians. Median tumour diameter at presentation was greater in Blacks than Whites (26.0 mm vs 22.0 mm, P=0.0103), and multifocal tumours were more frequent in both Blacks (43.4%) and Asians (37.0%) than Whites (28.9%). ER/PR/HER2-negative tumours were significantly more frequent in Blacks (26.1%) than Whites (18.6%, P=0.043). Use of chemotherapy was similarly high in all ethnic groups (89% B vs 88.6% W vs 89.7% A). A 5-year DRFS was significantly lower in Blacks than Asians (62.8% B vs 77.0% A, P=0.0473) or Whites (62.8 B% vs 77.0% W, P=0.0053) and a 5-year OS for Black patients, 71.1% (95% CI: 61.0–79.1%), was significantly lower than that of Whites (82.4%, 95% CI: 80.8–83.9%, W vs B: P=0.0160). In multivariate analysis, Black ethnicity had an effect on DRFS in oestrogen receptor (ER)-positive patients that is independent of body mass index, tumour size, grade or nodal status, HR: 1.60 (95% CI: 1.03–2.47, P=0.035).Conclusion:Despite equal access to health care, young Black women in the United Kingdom have a significantly poorer outcome than White patients. Black ethnicity is an independent risk factor for reduced DRFS particularly in ER-positive patients.

Family history and outcome of young patients with breast cancer in the UK (POSH study).

Young patients presenting to surgical clinics with breast cancer are usually aware of their family history and frequently believe that a positive family history may adversely affect their prognosis. Tumour pathology and outcomes were compared in young British patients with breast cancer with and without a family history of breast cancer.

A Genome Wide Meta-Analysis Study for Identification of Common Variation Associated with Breast Cancer Prognosis

Objective Genome wide association studies (GWAs) of breast cancer mortality have identified few potential associations. The concordance between these studies is unclear. In this study, we used a meta-analysis of two prognostic GWAs and a replication cohort to identify the strongest associations and to evaluate the loci suggested in previous studies. We attempt to identify those SNPs which could impact overall survival irrespective of the age of onset. Methods To facilitate the meta-analysis and to refine the association signals, SNPs were imputed using data from the 1000 genomes project. Cox-proportional hazard models were used to estimate hazard ratios (HR) in 536 patients from the POSH cohort (Prospective study of Outcomes in Sporadic versus Hereditary breast cancer) and 805 patients from the HEBCS cohort (Helsinki Breast Cancer Study). These hazard ratios were combined using a Mantel-Haenszel fixed effects meta-analysis and a p-value threshold of 5×10−8 was used to determine significance. Replication was performed in 1523 additional patients from the POSH study. Results Although no SNPs achieved genome wide significance, three SNPs have significant association in the replication cohort and combined p-values less than 5.6×10−6. These SNPs are; rs421379 which is 556 kb upstream of ARRDC3 (HR = 1.49, 95% confidence interval (CI) = 1.27–1.75, P = 1.1×10−6), rs12358475 which is between ECHDC3 and PROSER2 (HR = 0.75, CI = 0.67–0.85, P = 1.8×10−6), and rs1728400 which is between LINC00917 and FOXF1. Conclusions In a genome wide meta-analysis of two independent cohorts from UK and Finland, we identified potential associations at three distinct loci. Phenotypic heterogeneity and relatively small sample sizes may explain the lack of genome wide significant findings. However, the replication at three SNPs in the validation cohort shows promise for future studies in larger cohorts. We did not find strong evidence for concordance between the few associations highlighted by previous GWAs of breast cancer survival and this study.

An evaluation of the prognostic model PREDICT using the POSH cohort of women aged ⩽40 years at breast cancer diagnosis

Background:Breast cancer is the most common cancer in younger women (aged ⩽40 years) in the United Kingdom. PREDICT (http://www.predict.nhs.uk) is an online prognostic tool developed to help determine the best available treatment and outcome for early breast cancer. This study was conducted to establish how well PREDICT performs in estimating survival in a large cohort of younger women recruited to the UK POSH study.Methods:The POSH cohort includes data from 3000 women aged ⩽40 years at breast cancer diagnosis. Study end points were overall and breast cancer-specific survival at 5, 8, and 10 years. Evaluation of PREDICT included model discrimination and comparison of the number of predicted versus observed events.Results:PREDICT provided accurate long-term (8- and 10-year) survival estimates for younger women. Five-year estimates were less accurate, with the tool overestimating survival by 25% overall, and by 56% for patients with oestrogen receptor (ER)-positive tumours. PREDICT underestimated survival at 5 years among patients with ER-negative tumours.Conclusions:PREDICT is a useful tool for providing reliable long-term (10-year) survival estimates for younger patients. However, for more accurate short-term estimates, the model requires further calibration using more data from young onset cases. Short-term prediction may be most relevant for the increasing number of women considering risk-reducing bilateral mastectomy.

Genetic testing in a cohort of young patients with HER2-amplified breast cancer

BACKGROUND Young age at diagnosis for breast cancer raises the question of genetic susceptibility. We explored breast cancer susceptibility genes testing on ≤40-year-old patients with HER2-amplified invasive breast cancer. PATIENTS AND METHODS Patients were selected from a large UK cohort study. The inclusion criterion was age ≤40 at diagnosis with confirmed HER2-amplified breast cancer. The probability of finding a BRCA gene mutation was calculated based on family history. Genetic testing used was either clinical testing for BRCA1 and BRCA2, with a subset also tested for TP53 mutations, or research-based testing using a typical panel comprising 17 breast cancer susceptibility genes (CSGs) including BRCA1, BRCA2 and TP53. RESULTS Of the 591 eligible patients, clinical testing results were available for 133 cases and an additional 263 cases had panel testing results. BRCA testing across 396 cases found 8 BRCA2 (2%) and 6 BRCA1 (2%) pathogenic mutations. Of the 304 patients tested for TP53 mutations, overall 9 (3%) had deleterious TP53 mutations. Of the 396 patients, 101 (26%) met clinical criteria for BRCA testing (≥10% probability), among whom 11% had pathogenic BRCA mutations (6 BRCA2, 5 BRCA1). Where the probability was calculated to be <10%, only 4 of 295 (1%) patients had BRCA mutations. Among the 59 patients who had TP53 testing meeting the 10% threshold, 7 had mutations (12%). Likely functionally deleterious mutations in 14 lower penetrance CSGs were present in 12 of 263 (5%) panel-tested patients. CONCLUSION Patients aged <41 at diagnosis with HER2+ breast cancer and no family history of breast cancer can be reassured that they have a low chance of being a high-risk gene carrier. If there is a strong family history, not only BRCA but also TP53 gene testing should be considered. The clinical utility of testing lower penetrance CSGs remains unclear.

Does BRCA status affect outcome in young breast cancer patients? Results from the prospective study of outcomes in sporadic and hereditary breast cancer (POSH)

Background Germline mutations in BRCA1/2 account for ∼3% of breast cancer cases but >10% of young patients who present with triple negative (TN) breast cancer. Young age at diagnosis is also associated with an increased risk of recurrence and inferior survival compared to older patients. Numerous publications describe an increased incidence of adverse biological features in tumours from young breast cancer patients; however it is unclear whether these fully explain the poor outcome. The effect of carrying a BRCA1/2 mutation on the prognosis of breast cancer remains controversial with retrospective studies reporting better, similar and worse outcomes for mutation carriers compared to patients with sporadic tumours. BRCA carriers could feasibly have enhanced or reduced sensitivity to certain chemotherapeutics; however retrospective studies are problematic due to missing data and biased ascertainment. POSH is multicentre prospective observational cohort study designed to investigate factors which affect prognosis in young breast cancer patients (Copson et al, JNCI, 2013). Here we report the pathology, treatment and outcome of patients with TN tumours as a preliminary analysis to determine the impact of a germline BRCA1 mutation on survival. The whole cohort analysis including BRCA1 and BRCA2 is in progress. Methods 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 127 UK oncology centres between 2000 and 2008. Patient characteristics, family history, risk factors, tumour pathology and treatment information, and blood DNA were collected at recruitment. Follow-up data were collected at 6 and 12 months, then annually. Summary statistics were used to describe patients by BRCA1 status. Kaplan-Meier estimates were used to describe univariate survival data. Results BRCA1 status is currently available for 542 patients with TN tumours. Pathogenic BRCA1 mutations were identified in 122 patients (BRCA1+); 420 had no BRCA1 mutation (BRCA1-). BRCA1+ were younger than BRCA1- (median age 34 vs 36 years, p Median follow-up was 7.3 years. Overall survival of patients with stage 1-3 disease treated with anthracycline +/- taxane neoadjuvant chemotherapy (n=538; 151 deaths) was better for BRCA1+ vs BRCA1- (79.1% vs 73.6% at 5-yrs; HR[95%CI]=0.84[0.57,1.25],p=0.388). Distant disease-free survival (DDFS) was also higher for BRCA1+ (5-yr DDFS 76.1% vs 71.5%; HR[CI]=0.92[0.63,1.35], p=0.682). Moreover, survival after first distant relapse was better for BRCA1+ patients (41.9% vs 36.8% at 1-yr; HR[CI]=0.78[0.51,1.18], p=0.233). Conclusions Our prospective data show better survival in young BRCA1+ patients with early TN breast cancer treated with anthracycline/-taxane chemotherapy than BRCA1- patients. However, the difference between the groups was not significant in this partial sample. Results for the whole cohort will be available by the time of the meeting. Citation Format: Eccles DM, Copson ER, Maishman T, Tapper W, Cutress R, Gerty S, Stanton L, Altman DG, Durcan L, Simmonds P, Decker B, Allen J, Luccarini C, Easton D, Dunning A, POSH Steering Group and Collaborators. Does BRCA status affect outcome in young breast cancer patients? Results from the prospective study of outcomes in sporadic and hereditary breast cancer (POSH) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-03.

Abstract PD6-02: Local recurrence in young women with invasive breast cancer; the prospective study of outcomes in sporadic and hereditary breast cancer (POSH)

Aim To evaluate the surgical and clinical factors affecting local recurrence and other outcomes in young breast cancer patients using the POSH study. Background POSH (MREC:00/06/69) is a prospective cohort study of 3024 women aged 18-40 with breast cancer. Randomized controlled trials suggest equivalent survival between mastectomy and breast conserving surgery (BCS); however, very few young patients were included in these analyses. Emerging data also suggests a possible survival advantage for mastectomy in gene mutation carriers, and young age may be a predictor of higher rates of local recurrence. Methods Summary statistics were used to describe the cohort by surgical type (mastectomy or BCS). Study endpoints were in-breast ipsilateral local-recurrence interval, distant disease-free interval and overall survival. Cumulative hazard and Kaplan-Meier plots were used to describe survival data. Univariable and multivariable analyses were carried out using Cox proportional hazards models and flexible parametric survival (FPS) models (for any models with time-varying covariates). Results Of 2882 patients analysed, 1464 underwent mastectomy, 1395 BCS; and 23 had lymph node surgery only. Patients undergoing mastectomy had significantly larger tumours and higher proportions of positive Family History, positive estrogen receptor (ER+), progesterone receptor (PR+) and/or human epidermal growth factor 2 (HER2+) tumours. Local events only accounted for 15% of recurrences. Local recurrence varied over time by surgical type; local recurrence rate was similar at 18 months but higher for BCS compared to mastectomy at 5- and 10-years (18-months: 1.0% vs 1.0%, FPS-HR[95%CI]=1.43[0.89,2.32], p=0.348; 5-years: 5.3% vs 2.6%, FPS-HR[CI]=3.39[2.03,5.66], p Conclusions In the short term, there is no difference in local recurrence between BCS and mastectomy in young women. Longer term, local recurrence is higher in BCS, but there is no difference in survival between surgical groups after adjusting for known prognostic factors. Surgical extent appears to be less important for distant relapse or death from breast cancer than completeness of excision or, where appropriate, chest-wall radiotherapy. Acknowledgements Data collection/analysis funded by CRUK (grants:A7572,A11699,C1275/A15956). Sponsored by UHS NHS Foundation Trust. Citation Format: Maishman T, Cutress RI, Hernandez A, Gerty S, Copson ER, Durcan L, Eccles DM. Local recurrence in young women with invasive breast cancer; the prospective study of outcomes in sporadic and hereditary breast cancer (POSH) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD6-02.

A Novel Tumour-Based Test To Identify Breast Cancer Due to BRCA1 and BRCA2 Mutations.

Background: Family history and young onset are the usual indicators of an underlying genetic predisposition to breast cancer development. BRCA1 associated breast tumours are more likely to be ER negative and express “basal” markers, however most patients with ER negative/ basal marker positive breast cancers (especially young onset) do not have inherited BRCA1 mutations. BRCA1 and BRCA2 gene carriers may have novel treatment options available and may need to consider future cancer prevention strategies. Genetic counselling and germline mutation analysis remains a relatively expensive option that is not appropriate for most breast cancer patients.Aim: To design a sensitive and specific pathology based predictor that would improve identification of BRCA1 and 2 gene carriers.Method: We assembled a training panel of breast cancer tumour blocks from 67 BRCA1, 71 BRCA2 associated and 105 sporadic young onset cases (≤ 40 years at diagnosis). All gene carriers were diagnosed before 50 years and were matched to sporadic cases for ER status. Tissue micro arrays (TMAs) were assembled and subjected to immunohistochemical analysis with a panel of 18 antibodies. DNA was extracted from micro dissected tumour tissue and matched patient lymphocytes and subjected to high resolution tiling path microarray-based Comparative Genomic Hybridisation (aCGH). Using robust statistical approaches, regions significantly differentially lost, gained or amplified in BRCA1, BRCA2 and controls were identified. Probes for chromogenic in situ hybridisation (CISH) for amplified regions were generated.Results: Two differentially amplified clones in BRCA1 cases designated P1 at 3q25.31 and P2 at 3q25.2 and one in BRCA2 cases, P3 at 20q13.13, were identified and amplifications validated in the training set using CISH. Logistic regression analysis of the panel comprising CISH and IHC markers was used to develop the best predictor. The best predictor for BRCA1 gene carriers was a combination of P1, ER and HER2. This combination outperformed all combinations of immunohistochemical markers, including ER and basal markers; the Positive Predictive Value (PPV) was 87.5% and NPV 92% giving a Receiver Operator Characteristic (ROC) curve with an AUC of 0.92 (CI 0.88-0.97). The BRCA2 signature panel is currently being evaluated. These BRCA1 and BRCA2 predictor panels are being validated in a new set of TMAs comprising 223 tumours from the POSH study 1 .Conclusion: This tumour based predictor for BRCA1 and BRCA2 carriers may prove useful to identify gene carriers at low a priori chance of having a mutation, to direct BRCA1/2 targeted treatment approaches and to identify familial non BRCA1/2 cases that may be suitable for new gene discovery studies.1. Eccles D et al. BMC Cancer 2007; 7(1):160. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5032.