Displaying publications 21 - 40 of 210 in total

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  1. Fnu N, Kuan WC, Kong YC, Bustamam RS, Wong LP, Subramaniam S, et al.
    Ecancermedicalscience, 2022;16:1449.
    PMID: 36405936 DOI: 10.3332/ecancer.2022.1449
    Background: Evidence on the financial experiences of cancer survivors living in settings with pluralistic health systems remains limited. We explored the out-of-pocket costs, the resulting financial impact and the coping strategies adopted by cancer survivors in Malaysia, a middle-income country with a government-led tax-funded public health sector, and a predominantly for-profit private health sector.

    Methods: Data were derived from 20 focus group discussions that were conducted in five public and private Malaysian hospitals, which included 102 adults with breast, cervical, colorectal or prostate cancers. The discussions were segregated by type of healthcare setting and gender. Thematic analysis was performed.

    Results: Five major themes related to cancer costs emerged: 1) cancer therapies and imaging services, 2) supportive care, 3) complementary therapies, 4) non-medical costs and 5) loss of household income. Narratives on out-of-pocket medical costs varied not only by type of healthcare setting, clinical factors and socioeconomic backgrounds, but also by private health insurance ownership. Non-health costs (e.g. transportation, food) and loss of income were nonetheless recurring themes. Coping mechanisms that were raised included changing of cancer treatment decisions, continuing work despite ill health and seeking financial assistance from third parties. Unmet needs in coping with financial distress were especially glaring among the women.

    Conclusion: The long-term costs of cancer (medications, cancer surveillance, supportive care, complementary medicine) should not be overlooked even in settings where there is access to highly subsidised cancer care. In such settings, patients may also have unmet needs related to non-health costs of cancer and loss of income.

  2. Subramaniam S, Kong YC, Zaharah H, Uiterwaal CSPM, Richard A, Taib NA, et al.
    Ecancermedicalscience, 2021;15:1293.
    PMID: 34824616 DOI: 10.3332/ecancer.2021.1293
    Purpose: To measure the baseline prevalence of cardiovascular disease (CVD), its modifiable and non-modifiable risk factors in breast cancer patients, and determine their association with adjuvant treatment decision-making.

    Method: From 2016 to 2017, 2,127 women newly-diagnosed with breast cancer were prospectively recruited. Participants' cardiovascular biomarkers were measured prior to adjuvant treatment decision-making. Clinical data and medical histories were obtained from hospital records. Adjuvant treatment decisions were collated 6-8 months after recruitment. A priori risk of cardiotoxicity was predicted using the Cardiotoxicity Risk Score.

    Results: Mean age was 54 years. Eighty-five patients had pre-existing cardiac diseases and 30 had prior stroke. Baseline prevalence of hypertension was 47.8%. Close to 20% had diabetes mellitus, or were obese. Dyslipidaemia was present in 65.3%. The proportion of women presenting with ≥2 modifiable CVD risk factors at initial cancer diagnosis was substantial, irrespective of age. Significant ethnic variations were observed. Multivariable analyses showed that pre-existing CVD was consistently associated with lower administration of adjuvant breast cancer therapies (odds ratio for chemotherapy: 0.32, 95% confidence interval: 0.17-0.58). However, presence of multiple risk factors of CVD did not appear to influence adjuvant treatment decision-making. In this study, 63.6% of patients were predicted to have high risks of developing cardiotoxicities attributed to a high baseline burden of CVD risk factors and anthracycline administration.

    Conclusion: While recent guidelines recommend routine assessment of cardiovascular comorbidities in cancer patients prior to initiation of anticancer therapies, this study highlights the prevailing gap in knowledge on how such data may be used to optimise cancer treatment decision-making.

  3. Kong YC, Rauf N, Subramaniam S, Bustamam RS, Wong LP, Ho GF, et al.
    J Cancer Surviv, 2021 10;15(5):706-712.
    PMID: 33094415 DOI: 10.1007/s11764-020-00962-z
    PURPOSE: A considerable proportion of individuals who are diagnosed with cancer are at a working age. We aimed to gain an in-depth understanding of the challenges, and arising needs related to working after cancer in a setting with limited employment protection policies.

    METHODS: Focus group discussions were conducted with cancer patients who were diagnosed at least 1 year prior to recruitment, and either had paid work, were self-employed, currently unemployed, or currently retired (N = 66).

    RESULTS: Three main themes were identified: (1) loss of income: While some participants were entitled for a 1-year cancer-specific sick leave, many other participants recounted having insufficient paid sick leave, forcing them to take prolonged unpaid leave to complete treatment; (2) dealing with side effects of cancer and its treatment: The need for workplace accommodations was highlighted including flexible working hours, lighter workloads, and dedicated rest areas to enable patients to cope better; (3) Discrimination and stigma at workplace: Some participants mentioned being passed over on a promotion, getting demoted, or being forced to resign once their cancer diagnosis was disclosed, highlighting an urgent need to destigmatize cancer in the workplace.

    CONCLUSION: In settings with limited employment protection policies, a cancer diagnosis severely impacts the working experiences of patients, leading to financial loss. Urgent interventions and legislative reforms are needed in these settings to address the unmet employment needs of cancer survivors.

    IMPLICATIONS FOR CANCER SURVIVORS: This study may facilitate planning of local solutions to fulfill the unmet employment needs following cancer, such as return-to-work navigation services.

  4. Teoh SP, Bustamam RS, Mustapha FI, Yip CH, Saad M, Somasundaram S, et al.
    J Cancer Policy, 2021 Dec;30:100300.
    PMID: 35559796 DOI: 10.1016/j.jcpo.2021.100300
    BACKGROUND: During periods of high community transmission of COVID-19, the public hospitals in Malaysia, an upper middle-income country, have been forced to scale down elective surgeries, prioritize cancer treatments based on treatment benefits, and postpone non-emergency imaging procedures. These inevitably led to disruptions in cancer care delivery within the public health care system. This study aims to explore the facilitators and barriers faced by healthcare providers and cancer survivors in cancer care, and to co-design a guideline to maintain the delivery of cancer care amid the disaster situations.

    METHOD: In-depth interviews (IDIs) will be conducted with Malaysian healthcare providers and cancer survivors and findings will be analysed thematically. The insights will be used in a subsequent phase to co-design a guideline to maintain the delivery of quality cancer care in Malaysia via a three-round modified Delphi survey with a broad range of cancer stakeholders.

    EXPECTED RESULTS: Findings derived from IDIs and existing literature will be included for rating across three rounds by the expert panel. Feedback provided will be refined until consensus on the best practises for cancer care continuity during crises is achieved.

    CONCLUSION: The output of the present study is not only expected to ensure the continuity of delivery of high-quality cancer care in Malaysia during the ongoing pandemic but also to be adapted during unforeseen crises in the near future.

    POLICY SUMMARY STATEMENT: Collaborative work between policy makers, public health physicians, members of the multidisciplinary oncology team as well as cancer survivors is vital in developing an evidenced- based contingency plan for maintaining access to cancer care.

  5. Song CV, Yip CH, Mohd Taib NA, See MH, Teoh LY, Monninkhof EM, et al.
    JCO Glob Oncol, 2022 Mar;8:e2100314.
    PMID: 35245099 DOI: 10.1200/GO.21.00314
    PURPOSE: Addressing unwarranted clinical variation in oncology practices is expected to lead to improved cancer outcomes. Particularly, the application and impact of treatment guidelines on breast cancer outcomes are poorly studied in resource-limited settings. We measured adherence to a set of locally developed adjuvant treatment guidelines in a middle-income setting. Importantly, the impact of guidelines adherence on survival following breast cancer was determined.

    METHODS: Data of 3,100 Malaysian women with nonmetastatic breast cancer diagnosed between 2010 and 2017 were analyzed. Adherence to the Malaysian Clinical Practice Guidelines for Management of Breast Cancer second Edition was measured. Outcomes comprised overall survival and event-free survival.

    RESULTS: Guideline adherence for chemotherapy, radiotherapy, hormonal therapy, and targeted therapy were 61.7%, 79.2%, 85.1%, and 26.2%, respectively. Older age was generally associated with lower adherence to guidelines. Compared with patients who were treated according to treatment guidelines, overall survival and event-free survival were substantially lower in patients who were not treated accordingly; hazard ratios for all-cause mortality were 1.69 (95% CI, 1.29 to 2.22), 2.59 (95% CI, 1.76 to 3.81), 3.08 (95% CI, 1.94 to 4.88), and 4.48 (95% CI, 1.98 to 10.13) for chemotherapy, radiotherapy, hormone therapy, and targeted therapy, respectively. Study inferences remain unchanged following sensitivity analyses.

    CONCLUSION: Our study findings appear to suggest that adherence to treatment guidelines that have been adapted for resource-limited settings may still provide effective guidance in improving breast cancer outcomes.

  6. Yip CH, Smith RA, Anderson BO, Miller AB, Thomas DB, Ang ES, et al.
    Cancer, 2008 Oct 15;113(8 Suppl):2244-56.
    PMID: 18837017 DOI: 10.1002/cncr.23842
    A key determinant of breast cancer outcome in any population is the degree to which cancers are detected at early stages of disease. Populations in which cancers are detected at earlier stages have lower breast cancer mortality rates. The Breast Health Global Initiative (BHGI) held its third Global Summit in Budapest, Hungary in October 2007, bringing together internationally recognized experts to address the implementation of breast healthcare guidelines for early detection, diagnosis, and treatment in low- and middle-income countries (LMCs). A multidisciplinary panel of experts specifically addressed the implementation of BHGI guidelines for the early detection of disease as they related to resource allocation for public education and awareness, cancer detection methods, and evaluation goals. Public education and awareness are the key first steps, because early detection programs cannot be successful if the public is unaware of the value of early detection. The effectiveness and efficiency of screening modalities, including screening mammography, clinical breast examination (CBE), and breast self-examination, were reviewed in the context of resource availability and population-based need by the panel. Social and cultural barriers should be considered when early detection programs are being established, and the evaluation of early detection programs should include the use of well developed, methodologically sound process metrics to determine the effectiveness of program implementation. The approach and scope of any screening program will determine the success of any early detection program as measured by cancer stage at diagnosis and will drive the breadth of resource allocation needed for program implementation.
  7. Distelhorst SR, Cleary JF, Ganz PA, Bese N, Camacho-Rodriguez R, Cardoso F, et al.
    Lancet Oncol, 2015 Mar;16(3):e137-47.
    PMID: 25752564 DOI: 10.1016/S1470-2045(14)70457-7
    Supportive care and palliative care are now recognised as critical components of global cancer control programmes. Many aspects of supportive and palliative care services are already available in some low-income and middle-income countries. Full integration of supportive and palliative care into breast cancer programmes requires a systematic, resource-stratified approach. The Breast Health Global Initiative convened three expert panels to develop resource allocation recommendations for supportive and palliative care programmes in low-income and middle-income countries. Each panel focused on a specific phase of breast cancer care: during treatment, after treatment with curative intent (survivorship), and after diagnosis with metastatic disease. The panel consensus statements were published in October, 2013. This Executive Summary combines the three panels' recommendations into a single comprehensive document covering breast cancer care from diagnosis through curative treatment into survivorship, and metastatic disease and end-of-life care. The recommendations cover physical symptom management, pain management, monitoring and documentation, psychosocial and spiritual aspects of care, health professional education, and patient, family, and caregiver education.
  8. Hickey M, Basu P, Sassarini J, Stegmann ME, Weiderpass E, Nakawala Chilowa K, et al.
    Lancet, 2024 Mar 09;403(10430):984-996.
    PMID: 38458217 DOI: 10.1016/S0140-6736(23)02802-7
    Globally, 9 million women are diagnosed with cancer each year. Breast cancer is the most commonly diagnosed cancer worldwide, followed by colorectal cancer in high-income countries and cervical cancer in low-income countries. Survival from cancer is improving and more women are experiencing long-term effects of cancer treatment, such as premature ovarian insufficiency or early menopause. Managing menopausal symptoms after cancer can be challenging, and more severe than at natural menopause. Menopausal symptoms can extend beyond hot flushes and night sweats (vasomotor symptoms). Treatment-induced symptoms might include sexual dysfunction and impairment of sleep, mood, and quality of life. In the long term, premature ovarian insufficiency might increase the risk of chronic conditions such as osteoporosis and cardiovascular disease. Diagnosing menopause after cancer can be challenging as menopausal symptoms can overlap with other common symptoms in patients with cancer, such as fatigue and sexual dysfunction. Menopausal hormone therapy is an effective treatment for vasomotor symptoms and seems to be safe for many patients with cancer. When hormone therapy is contraindicated or avoided, emerging evidence supports the efficacy of non-pharmacological and non-hormonal treatments, although most evidence is based on women older than 50 years with breast cancer. Vaginal oestrogen seems safe for most patients with genitourinary symptoms, but there are few non-hormonal options. Many patients have inadequate centralised care for managing menopausal symptoms after cancer treatment, and more information is needed about cost-effective and patient-focused models of care for this growing population.
  9. Lim CT, Yip CH, Chang KW
    Singapore Med J, 1994 Feb;35(1):74-6.
    PMID: 8009287
    Meconium ileus, rare in Malaysia, accounts for 3.7% of all neonatal intestinal obstructions (excluding imperforate anus) seen in the University Hospital, Kuala Lumpur, from 1980-1990. This paper retrospectively reviews our clinical experience with 5 cases of meconium ileus seen over a 12-year period from 1980-1991 in the University Hospital, Kuala Lumpur. Three of the neonates were Malays, and two were Punjabis. Four of them were full-term and one preterm. The birth weights ranged from 1900 to 3700 g, with a mean of 2670 g. One of them also had a sibling with meconium ileus. Two of them were found to have foetal ascites and one had intestinal obstruction, antenatally by ultrasonography. The remaining two were symptomatic soon after birth. Extensive calcification was observed on plain abdominal radiographs in three babies and dilated bowels in the other two. All of them underwent laparotomy and uncomplicated meconium ileus was confirmed in two cases, meconium peritonitis in two and one meconium pseudocyst in addition to meconium peritonitis. There was one intraoperative death, and one long-term survivor who did not have cystic fibrosis. The remaining three did not have additional features suggestive of cystic fibrosis, and finally succumbed to respiratory infection. Sweat test was not done to confirm the diagnosis for logistic reasons. The management of such patients proved to be a challenge to clinicians because of the rarity of this condition.
  10. Yip CH, Chang KW
    Singapore Med J, 1991 Oct;32(5):363-4.
    PMID: 1788587
    An eighteen month old phenotypically and genotypically normal male child was admitted with a left inguinal hernia and a right undescended testis. At operation, he was found to have a uterus, bilateral fallopian tubes, and a vagina in the left hernial sac. Bilateral orchidopexies and excision of the persistent Mullerian duct structures were carried out. This rare case of persistent Mullerian duct syndrome is due to a defect in Mullerian regression, which is in turn controlled by the Mullerian inhibiting substance (MIS). Orchidopexy with excision of the persistent Mullerian duct structures is usually not possible without damage to the vas deferens which is closely adherent to the wall of the uterus. The alternative of leaving the persistent Mullerian duct structures alone and performing a staged or primary orchidopexy has been suggested.
  11. Agarwal G, Pradeep PV, Aggarwal V, Yip CH, Cheung PS
    World J Surg, 2007 May;31(5):1031-40.
    PMID: 17387549
    Breast cancer is the leading cause of cancer-related deaths in Asia, and in recent years is emerging as the commonest female malignancy in the developing Asian countries, overtaking cancer of the uterine cervix. There have been no studies objectively comparing data and facts relating to breast cancer in the developed, newly developed, and developing Asian countries thus far.
  12. Yip CH, Buccimazza I, Hartman M, Deo SV, Cheung PS
    World J Surg, 2015 Mar;39(3):686-92.
    PMID: 25398564 DOI: 10.1007/s00268-014-2859-6
    Breast cancer is the most common cancer in women world-wide. Incidence rates in low- and middle-income countries (LMICs) are lower than in high income countries; however, the rates are increasing very rapidly in LMICs due to social changes that increase the risk of breast cancer. Breast cancer mortality rates in LMICs remain high due to late presentation and inadequate access to optimal care. Breast Surgery International brought together a group of breast surgeons from different parts of the world to address strategies for improving outcomes in breast cancer for LMICs at a symposium during International Surgical Week in Helsinki, Finland in August 2013. A key strategy for early detection is public health education and breast awareness. Sociocultural barriers to early detection and treatment need to be addressed. Optimal management of breast cancer requires a multidisciplinary team. Surgical treatment is often the only modality of treatment available in low-resource settings where modified radical mastectomy is the most common operation performed. Chemotherapy and radiotherapy require more resources. Endocrine therapy is available but requires accurate assessment of estrogen receptors status. Targeted therapy with trastuzumab is generally unavailable due to cost. The Breast Health Global Initiative guidelines for the early detection and appropriate treatment of breast cancer in LMICs have been specifically designed to improve breast cancer outcomes in these regions. Closing the cancer divide between rich and poor countries is a moral imperative and there is an urgent need to prevent breast cancer deaths with early detection and optimal access to treatment.
  13. Yip CH, Taib NA, Tan GH, Ng KL, Yoong BK, Choo WY
    World J Surg, 2009 Jan;33(1):54-7.
    PMID: 18958521 DOI: 10.1007/s00268-008-9782-7
    Axillary nodal status is one of the most important prognostic factors in breast cancer. In the present study we used it to determine the predictors of axillary lymph node metastases in breast cancer and to determine if there is a group of patients in whom minimal axillary surgery is indicated.
  14. Lin WY, Camp NJ, Ghoussaini M, Beesley J, Michailidou K, Hopper JL, et al.
    Hum Mol Genet, 2015 Jan 01;24(1):285-98.
    PMID: 25168388 DOI: 10.1093/hmg/ddu431
    Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
  15. Bhoo-Pathy N, Verkooijen HM, Wong FY, Pignol JP, Kwong A, Tan EY, et al.
    Int J Cancer, 2015 Nov 15;137(10):2504-12.
    PMID: 26018878 DOI: 10.1002/ijc.29617
    The value of adjuvant radiotherapy in triple-negative breast cancer (TNBC) is currently debated. We assessed the association between adjuvant radiotherapy and survival in a large cohort of Asian women with TNBC. Women diagnosed with TNBC from 2006 to 2011 in five Asian centers (N = 1,138) were included. Survival between patients receiving mastectomy only, breast-conserving therapy (BCT, lumpectomy and adjuvant radiotherapy) and mastectomy with radiotherapy were compared, and adjusted for demography, tumor characteristics and chemotherapy types. Median age at diagnosis was 53 years (range: 23-96 years). Median tumor size at diagnosis was 2.5 cm and most patients had lymph node-negative disease. The majority of patients received adjuvant chemotherapy (n = 861, 76%) comprising predominantly anthracycline-based regimes. In 775 women with T1-2, N0-1, M0 TNBCs, 5-year relative survival ratio (RSR) was highest in patients undergoing mastectomy only (94.7%, 95% CI: 88.8-98.8%), followed by BCT (90.8%, 95% CI: 85.0-94.7%), and mastectomy with radiotherapy (82.3%, 95% CI: 73.4-88.1%). The adjusted risks of mortality between the three groups were not significantly different. In 363 patients with T3-4, N2-3, M0 TNBCs, BCT was associated with highest 5-year RSR (94.1%, 95% CI: 81.3-99.4%), followed by mastectomy with radiotherapy (62.7%, 95% CI: 54.3-70.1%), and mastectomy only (58.6%, 95% CI: 43.5-71.6%). Following multivariable adjustment, BCT and mastectomy with radiotherapy remained significantly associated with lower mortality risk compared to mastectomy only. Overall, adjuvant radiotherapy was associated with higher survival in women aged <40 years, but not in older women. Adjuvant radiotherapy appears to be independently associated with a survival gain in locally advanced as well as in very young TNBC.
  16. Darabi H, Beesley J, Droit A, Kar S, Nord S, Moradi Marjaneh M, et al.
    Sci Rep, 2016 Sep 07;6:32512.
    PMID: 27600471 DOI: 10.1038/srep32512
    Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.
  17. Breast Cancer Association Consortium, Mavaddat N, Dorling L, Carvalho S, Allen J, González-Neira A, et al.
    JAMA Oncol, 2022 Mar 01;8(3):e216744.
    PMID: 35084436 DOI: 10.1001/jamaoncol.2021.6744
    IMPORTANCE: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction.

    OBJECTIVE: To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies.

    DESIGN, SETTING, AND PARTICIPANTS: The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021.

    EXPOSURES: Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.

    MAIN OUTCOMES AND MEASURES: The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes.

    RESULTS: The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2- high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+ERBB2+ and HR-ERBB2+ subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger.

    CONCLUSIONS AND RELEVANCE: The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.

  18. Michailidou K, Beesley J, Lindstrom S, Canisius S, Dennis J, Lush MJ, et al.
    Nat Genet, 2015 Apr;47(4):373-80.
    PMID: 25751625 DOI: 10.1038/ng.3242
    Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
  19. Dunning AM, Michailidou K, Kuchenbaecker KB, Thompson D, French JD, Beesley J, et al.
    Nat Genet, 2016 Apr;48(4):374-86.
    PMID: 26928228 DOI: 10.1038/ng.3521
    We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
  20. Ghoussaini M, French JD, Michailidou K, Nord S, Beesley J, Canisus S, et al.
    Am J Hum Genet, 2016 Oct 06;99(4):903-911.
    PMID: 27640304 DOI: 10.1016/j.ajhg.2016.07.017
    Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.
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