The Expression of CD44s in Squamous cell carcinoma of the oral tongue and association with clinicopathological factors and survival outcomes

Master'sMASTER OF SCIENC

Germline breast cancer susceptibility genes, tumor characteristics, and survival.

BACKGROUND: Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent. METHODS: Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease. RESULTS: PTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35-5.17], moderately vs well-differentiated 2.33 [1.56-3.49]), as well as luminal B [HER-] and triple-negative subtypes (vs luminal A 2.15 [1.58-2.92] and 2.85 [2.17-3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2-] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16-2.28]). CONCLUSIONS: PTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions

Polygenic risk scores for prediction of breast cancer risk in Asian populations.

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry

European polygenic risk score for prediction of breast cancer shows similar performance in Asian women

Abstract: Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia

Immediate breast reconstruction following nipple-sparing mastectomy in an Asian population: Aesthetic outcomes and mitigating nipple-areolar complex necrosis

Background Nipple-sparing mastectomies (NSMs) are increasingly performed to obtain the best aesthetic and psychological outcomes in breast cancer treatment. However, merely preserving the nipple-areolar complex (NAC) does not guarantee a good outcome. Darkly pigmented NACs and a tendency for poor scarring outcomes are particular challenges when treating Asian patients. Herein, we review the reconstructive outcomes following NSM at Singapore General Hospital. Methods All breasts reconstructed following NSM over an 11-year period from 2005 to 2015 were reviewed. Information was collected from the patients’ records on mastectomy indications, operative details, and complications. Patient satisfaction, breast sensation, and aesthetic outcomes were evaluated in 15 patients. Sensation was quantified using the Semmes-Weinstein monofilament test. Results A total of 142 NSMs were performed in 133 patients for breast cancer (n=122, 85.9%) or risk reduction (n=20, 14.1%). Of the procedures, 114 (80.2%) were autologous reconstructions, while 27 (19.0%) were reconstructions with implants. Complications occurred in 28 breasts (19.7%), with the most common complication being NAC necrosis, which occurred in 17 breasts (12.0%). Four breasts (2.8%) had total NAC necrosis. The overall mean patient satisfaction score was 3.0 (good). The sensation scores were significantly diminished in the skin envelope, areola, and nipple of breasts that had undergone NSM compared to non-operated breasts (P<0.05). Half of the subset of 15 patients in whom aesthetic outcomes were evaluated had reduced nipple projection. Conclusions Immediate reconstruction after NSM was performed with a low complication rate in this series, predominantly through autologous reconstruction. Patients should be informed of potential drawbacks, including NAC necrosis, reduced nipple projection, and diminished sensation

Adipose-enriched peri-tumoral stroma, in contrast to myofibroblast-enriched stroma, prognosticates poorer survival in breast cancers

Despite our understanding of the genetic basis of intra-tumoral heterogeneity, the role of stromal heterogeneity arising from an altered tumor microenvironment in affecting tumorigenesis is poorly understood. In particular, extensive study on the peri-tumoral stroma in the morphologically normal tissues surrounding the tumor is lacking. Here, we examine the heterogeneity in tumors and peri-tumoral stroma from 8 ER+/PR+/HER2- invasive breast carcinomas, through multi-region transcriptomic profiling by microarray. We describe the regional heterogeneity observed at the intrinsic molecular subtype, pathway enrichment, and cell type composition levels within each tumor and its peri-tumoral region, up to 7 cm from the tumor margins. Moreover, we identify a pro-inflammatory adipose-enriched peri-tumoral subtype which was significantly associated with poorer overall survival in breast cancer patients, in contrast to an adaptive immune cell- and myofibroblast-enriched subtype. These data together suggest that peri-tumoral heterogeneity may be an important determinant of the evolution and treatment of breast cancers.National Medical Research Council (NMRC)Published versionThis research was supported by the: National Medical Research Council Singapore; NCC Cancer Fund (all to K.S.); and NCC Research Fund (NCCSPG-YR2015-JAN-7) (to K.S. and V.K.M.T.). H.S.H.L. is supported by the NUS Research Scholarship and NUS Medicine Graduate Studies Award. We thank Breast Cancer Now as well as Cancer Research UK [CRUK/07/012, KCL-BCN-Q3]. We thank Breast Cancer Now [KCL-BCN-Q3], the Medical Research Council [MR/X012476/1], as well as the Cancer Research UK City of London Centre Award [CTRQQR-2021/100004] in funding this project

An in-depth exploration of the post-test informational needs of BRCA1 and BRCA2 pathogenic variant carriers in Asia

Identification of one's status as a BRCA1/2 pathogenic variant carrier often marks the start of navigating challenging decisions related to cancer risk management and result disclosure. Carriers report unmet informational needs, but studies have yet to explore the specific aspects of and how best to fulfill these needs. This study aims to explore the informational needs of BRCA1/2 pathogenic variant carriers in Asia to inform for the design of educational materials to support risk management decision-making.Published versio

Associations between Pre-Diagnostic Physical Activity with Breast Cancer Characteristics and Survival

Physical activity (PA) is known to reduce breast cancer (BC) risk and improve patient prognosis. However, the association between pre-diagnostic PA and the aggressiveness of BC is unclear. We investigated the associations between PA, BC tumour characteristics, and survival. This retrospective observational study included 7688 BC patients from the Singapore Breast Cancer Cohort (2010&ndash;2016). PA information from the questionnaire included intensity (light/moderate/vigorous) and duration (&lt;1 h/1&ndash;2 h/&gt;2 h per week). A PA score (1&ndash;5) incorporating intensity and duration was calculated. Associations between PA score and tumour characteristics such as stage, histological grade, nodal and hormone receptor status were examined using multinomial regression. Moreover, 10-year overall survival was estimated using Cox regression analysis in 6572 patients after excluding patients with invalid survival data and stage IV disease. Breast tumours associated with higher PA score were more likely to be non-invasive (ORinvasive&nbsp;vs.&nbsp;non-invasive(reference) [95% CI]: 0.71 [0.58&ndash;0.87], p-trend = 0.001), of lower grade (ORpoorly&nbsp;vs.&nbsp;well differentiated(reference): 0.69 [0.52&ndash;0.93], p = 0.014), ER-positive (ORER-negative&nbsp;vs.&nbsp;ER-positive(reference): 0.94 [0.89&ndash;1.00], p-trend = 0.049), PR-positive (ORPR-negative&nbsp;vs.&nbsp;PR-positive(reference): 0.82 [0.67&ndash;0.99], p = 0.041), HER2-negative (ORHER2-negative&nbsp;vs.&nbsp;HER2-positive(reference): 1.29 [1.02&ndash;1.62], p-trend = 0.002), and less likely to be of HER2-overexpressed subtype (ORHER2-overexpressed&nbsp;vs.&nbsp;Luminal A(reference): 0.89 [0.81&ndash;0.98], p-trend = 0.018). These associations (odds ratios) were more pronounced among post-menopausal patients. A higher PA score did not improve survival. Higher levels of pre-diagnostic PA were associated with less aggressive tumours in BC patients. This illustrated another benefit of PA in addition to its known role in BC risk reduction

Mammography screening is associated with more favorable breast cancer tumor characteristics and better overall survival: Case-only analysis of 3,739 Asian breast cancer patients.

Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO)401