Veronique Kiak Mien Tan

Exome sequencing identifies highly recurrent MED12 somatic mutations in breast fibroadenoma

Fibroadenomas are the most common breast tumors in women under 30 (refs. 1,2). Exome sequencing of eight fibroadenomas with matching whole-blood samples revealed recurrent somatic mutations solely in MED12, which encodes a Mediator complex subunit. Targeted sequencing of an additional 90 fibroadenomas confirmed highly frequent MED12 exon 2 mutations (58/98, 59%) that are probably somatic, with 71% of mutations occurring in codon 44. Using laser capture microdissection, we show that MED12 fibroadenoma mutations are present in stromal but not epithelial mammary cells. Expression profiling of MED12-mutated and wild-type fibroadenomas revealed that MED12 mutations are associated with dysregulated estrogen signaling and extracellular matrix organization. The fibroadenoma MED12 mutation spectrum is nearly identical to that of previously reported MED12 lesions in uterine leiomyoma but not those of other tumors. Benign tumors of the breast and uterus, both of which are key target tissues of estrogen, may thus share a common genetic basis underpinned by highly frequent and specific MED12 mutations.

The feasibility and accuracy of sentinel lymph node biopsy in clinically node‐negative patients after neoadjuvant chemotherapy for breast cancer—a systematic review and meta‐analysis

The sentinel lymph node biopsy (SLNB) is now an accepted alternative to the axillary lymph node dissection for pathologic evaluation of the axilla in patients with early breast cancer. The use of SLNB after neoadjuvant chemotherapy (NAC) is controversial. This meta‐analysis aims to determine the feasibility and the accuracy of SLNB in the population of patients who are clinically node‐negative after NAC for breast cancer. J. Surg. Oncol. 2011;104:97–103.

Genomic landscapes of breast fibroepithelial tumors

Breast fibroepithelial tumors comprise a heterogeneous spectrum of pathological entities, from benign fibroadenomas to malignant phyllodes tumors. Although MED12 mutations have been frequently found in fibroadenomas and phyllodes tumors, the landscapes of genetic alterations across the fibroepithelial tumor spectrum remain unclear. Here, by performing exome sequencing of 22 phyllodes tumors followed by targeted sequencing of 100 breast fibroepithelial tumors, we observed three distinct somatic mutation patterns. First, we frequently observed MED12 and RARA mutations in both fibroadenomas and phyllodes tumors, emphasizing the importance of these mutations in fibroepithelial tumorigenesis. Second, phyllodes tumors exhibited mutations in FLNA, SETD2 and KMT2D, suggesting a role in driving phyllodes tumor development. Third, borderline and malignant phyllodes tumors harbored additional mutations in cancer-associated genes. RARA mutations exhibited clustering in the portion of the gene encoding the ligand-binding domain, functionally suppressed RARA-mediated transcriptional activation and enhanced RARA interactions with transcriptional co-repressors. This study provides insights into the molecular pathogenesis of breast fibroepithelial tumors, with potential clinical implications.

Trends in Post‐Mastectomy Reconstruction in an Asian Population: A 12‐Year Institutional Review

Post‐mastectomy breast reconstruction is an integral component of breast cancer treatment. It is often perceived that women in Asian countries have a lower rate of post‐mastectomy reconstruction than Western populations. This study describes trends in timing and types of breast reconstruction performed in the largest healthcare provider in Singapore, over a period of 12 years. It also reports on the oncological outcomes and surgical safety. A retrospective review of all patients who underwent post‐mastectomy reconstruction from January 2001 to December 2012 at the National Cancer Centre Singapore and Singapore General Hospital was performed. Six hundred and twenty post‐mastectomy reconstructions were performed in 579 patients. The proportion of reconstructions increased from 4% in 2001 to 18% in 2012. Younger patients (<50 years old) and those with early stage cancer were more likely to undergo reconstruction. Immediate breast reconstruction was favored by more than 90% of patients. Postoperatively, 9% developed acute surgical complications that were treated surgically; 6% had additional surgery for late complications. Only 4% had delay of adjuvant chemotherapy. At median follow‐up of 63 months (range 3–166), loco‐regional recurrence was 4%, and distant metastases 8%. Post‐mastectomy reconstruction for breast cancer is increasingly performed in our institution. Both younger age and lower stage disease were associated with choice for reconstruction in our study. Low rates of delay to adjuvant therapy were noted, and it may safely be offered to suitable women undergoing mastectomy.

Breast carcinoma and phyllodes tumour: a case series

Malignant transformation of the epithelial component of phyllodes tumours (PT) is rare and only reported in literature as sporadic cases of carcinoma associated with PTs. We report the clinicopathological characteristics of in situ and invasive carcinoma coexisting with PT in 10 patients treated in our institution over an 11-year period from 1992 to 2012. Ten patients with coexisting PT and in situ or invasive carcinoma were identified from our records. Six had carcinoma found within the PT. All were female with a median age of 47 (43–72) years. One patient had a history of PT in the same breast while another had a history of PT in the same breast as well as invasive ductal carcinoma in the contralateral breast. The rest did not have any risk factors of breast cancer. Five patients had a preoperative core needle biopsy performed with the report of a fibroepithelial lesion. The rest of the patients had surgery upfront for their breast masses. Two patients who had ER/PR positive invasive carcinoma received adjuvant hormonal therapy. Patients were followed up for a mean of 3.6 years (9 months–10 years) and all patients were alive and recurrence free. PT associated with carcinoma is rare, and we present a series of cases that add to the limited current literature. It is often difficult to detect the presence of the carcinomatous component preoperatively. Hence, close examination of resected PT specimens must be carried out to allow prompt detection of any associated carcinomas, however rare, such that adequate treatment can be given.

Abstract B22: Inducing cell state transitions in triple-negative breast cancer (TNBC)

Triple-negative breast cancer (TNBC), as immunohistochemically defined by its estrogen receptor (ER)-negative, progesterone receptor (PR)-negative and human epidermal growth factor receptor-2 (HER2)-negative status, is an important subtype due to its biologically aggressive behavior and limited treatment options available. TNBC is associated with an overall poorer prognosis, with higher risk of disease recurrence/progression and shorter duration of treatment response, i.e., treatment resistance. Treatment resistance may be largely attributed to cancer stem cells (CSCs), which are intrinsically treatment resistant and continually self-renew, proliferate, and differentiate into different phenotypes. Activation of the cell biologic program, epithelial-mesenchymal transition (EMT), has been demonstrated to promote the dedifferentiation of heterogeneous subpopulations of cancer cells towards CSC phenotypes. We hypothesized that induction of the mesenchymal-epithelial transition (MET) program might disrupt CSC function, drive differentiation, and render greater susceptibility to conventional chemotherapy. In this study, we utilized high-throughput chemical-genetic screens to uncover a potent class of MET mediators. With the use of in vitro and in vivo models of TNBC, we showed that changing the malignant cell state to a differentiated phenotype by inducing MET reduced mammosphere formation, increased chemosensitivity, and decreased the tumor burden in NSG mice. Delving into the mechanisms of tumor differentiation via ChIP-seq, RNA-seq, and Gene Ontology analysis revealed differences in metabolic status between cell states, which might be exploited in the treatment of TNBC. We also assessed combinations of MET mediators, in order to increase the potency and durability of differentiation. Hence, this study assessed the role of differentiation in the treatment of TNBC and the efficacy of various MET mediators, singly and in combination, in inducing differentiation. Citation Format: Ser Yue Loo, Liping Toh, Elina Pathak, Wilson Tan, Siming Ma, Ju Yuan, Giridharan Periyasamy, Federico Torta, Jack Chan, Tira Tan, Yi Rong Sim, Veronique Tan, Benita Tan, Preetha Madhukumar, Wei Sean Yong, Kong Wee Ong, Chow Yin Wong, Markus R. Wenk, Roger Foo, Yoon-Sim Yap, Elaine Lim, Wai Leong Tam. Inducing cell state transitions in triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B22.

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.

Bilateral breast cancers in an Asian population, and a comparison between synchronous and metachronous tumours: BBC in an Asian population

Women with unilateral breast cancer have an increased risk of developing bilateral breast cancer (BBC). Patients with metachronous BBC (mBBC) usually have an earlier age of onset, and their prognoses have been shown to be either similar or poorer than those with synchronous BBC (sBBC). Given the differing presentation and characteristics of breast cancers in the Asian population and the West, this study aims to characterize Asian patients with BBC.

P345 Perioperative outcomes of therapeutic breast surgery in the elderly

Dear Editor, Female Singaporeans currently have a life expectancy of 84.5 years1 and a lifetime risk of 6.5% of developing breast cancer.2 It is estimated that by the year 2050, 11.2% of the population will be aged more than 80 years.3 One in 16 women will develop breast cancer by the age of 80, and there will potentially be 1500 cases of newly diagnosed breast cancer among octogenarians each year. Surgery is curative in early breast cancer and various centres have reported no difference in the cancer specifi c survival rates of the elderly age group compared to their younger counterparts, 5 to 10 years after surgery for breast cancer.4,5 Surgery is also indicated in advanced breast cancer as a form of palliation in patients with fungating and bleeding tumours. Despite its therapeutic role, Lavelle et al6 found that the proportion of older women receiving surgery fell with increasing comorbidity and many clinicians still do not discuss surgical options with elderly patients. We wanted to objectively report the postsurgical mortality and morbidity of the very elderly, aged above 80 years in our institution. We also hoped to identify risk factors that may predict for a poorer outcome. To our knowledge, this is the fi rst study in an Asian population.

Abstract P6-08-52: Predicting the likelihood of additional non sentinel lymph node metastasis in early breast cancer: Novel sentinel nodal station status versus Singapore General Hospital nomogram

Background: Sentinel lymph node biopsy (SLNB) has been widely used in early breast cancer patients for the detection of axillary nodal metastasis. We were the first to describe 2 novel sentinel nodal stations (SNS) in relation to the intercostobrachial nerve (ICB) and the medial pectoral neurovascular bundle (MP) at which sentinel lymph nodes (SLN) were consistently identified, even only with the use of blue dye. In a pilot study involving 176 cases, we have shown that the ICB and MP SNS represent sequential echelons of SLN draining the breast. It was observed that the status of the MP SNS can be used in predicting the likelihood of additional non sentinel lymph node metastasis in early breast cancer. Thus, we aim to compare this against the Singapore General Hospital (SGH) nomogram, the existing standard predictive model in the local population. The SGH nomogram was developed from predictors in the Memorial Sloan-Kettering Cancer Centre (MSKCC) nomogram. It uses only 3 pathological parameters: lymphovascular invasion, number of positive and negative SLN. This has been shown to be at least equal if not better than the MSKCC nomogram as a predictive model in the Singapore population. Methods : All patients who underwent oncologic breast surgery and SLNB (using the SNS identification technique) at the Department of Surgical Oncology, National Cancer Centre Singapore from February 2012 to December 2013 inclusive were reviewed. Patients who fulfilled the following selection criteria were included in the study: [1] invasive ductal or lobular carcinoma, [2] SLN identified in both ICB and MP SNS,[3] axillary clearance done with total lymph nodes ≥ 10, based on a positive SLNB. The performance of the MP SNS status and SGH nomogram in predicting the likelihood of additional non sentinel lymph node metastasis was compared with the calculation of the area under the receiver-operating characteristic curve (AUC). Results: A total of 49 patients were identified. Majority of the patients had early breast cancers: 94% had tumour size ≤5cm and 71% had N1 disease. The median number of total SLN, ICB and MP nodes identified were 3 (range 2-14), 2 (range 1-7) and 1 (range 1-12) respectively. The median number of positive and negative SLN were both 1 (range 1-5 and 0-9 respectively). The positive predictive value of MP SNS status for additional non sentinel lymph node metastasis was 76.5% (95% CI: 50.1-93.2). The strong association was proven by an odds ratio of 7.15 (95% CI 1.86-27.50, p-value: 0.002). The negative predictive value of MP SNS for eventual N stage was 93.8% (95% CI: 79.2-99.2). In most of the cases, the nodal stage remained at N1 in the presence of negative MP node. The model with MP SNS status yielded an AUC of 0.706 (95% CI: 0.579-0.832) which was higher than that of the SGH nomogram, 0.658 (95% CI: 0.503-0.813). Conclusions: The novel MP SNS proved to be a single parameter which predicts the likelihood of additional non sentinel lymph nodes metastasis better than the SGH nomogram. More importantly, from the clinical point of view, the MP SNS status can be made available intra-operatively and hence guide the decision for further axillary dissection. Citation Format: Sue Zann Lim, Puay Hoon Tan, Gay Hui Ho, Preetha Madhukumar, Yirong Sim, Shaun Shi Yan Tan, Cindy Lim, Veronique Kiak Mien Tan, Kong Wee Ong. Predicting the likelihood of additional non sentinel lymph node metastasis in early breast cancer: Novel sentinel nodal station status versus Singapore General Hospital nomogram [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-52.