Jane Mendez

Gene expression abnormalities in histologically normal breast epithelium of breast cancer patients

Normal‐appearing epithelium of cancer patients can harbor occult genetic abnormalities. Data comprehensively comparing gene expression between histologically normal breast epithelium of breast cancer patients and cancer‐free controls are limited. The present study compares global gene expression between these groups. We performed microarrays using RNA from microdissected histologically normal terminal ductal‐lobular units (TDLU) from 2 groups: (i) cancer normal (CN) (TDLUs adjacent to untreated ER+ breast cancers (n = 14)) and (ii) reduction mammoplasty (RM) (TDLUs of age‐matched women without breast disease (n = 15)). Cyber‐T identified differentially expressed genes. Quantitative RT‐PCR (qRT‐PCR), immunohistochemistry (IHC), and comparison to independent microarray data including 6 carcinomas in situ (CIS), validated the results. Gene ontology (GO), UniProt and published literature evaluated gene function. About 127 probesets, corresponding to 105 genes, were differentially expressed between CN and RM (p < 0.0009, corresponding to FDR <0.10). 104/127 (82%) probesets were also differentially expressed between CIS and RM, nearly always (102/104 (98%)) in the same direction as in CN vs. RM. Two‐thirds of the 105 genes were implicated previously in carcinogenesis. Overrepresented functional groups included transcription, G‐protein coupled and chemokine receptor activity, the MAPK cascade and immediate early genes. Most genes in these categories were under‐expressed in CN vs. RM. We conclude that global gene expression abnormalities exist in normal epithelium of breast cancer patients and are also present in early cancers. Thus, cancer‐related pathways may be perturbed in normal epithelium. These abnormalities could be markers of disease risk, occult disease, or the tissues response to an existing tumor.

Gene expression in histologically normal epithelium from breast cancer patients and from cancer-free prophylactic mastectomy patients shares a similar profile

Introduction:We hypothesised that gene expression in histologically normal (HN) epithelium (NlEpi) would differ between breast cancer patients and usual-risk controls undergoing reduction mammoplasty (RM), and that gene expression in NlEpi from cancer-free prophylactic mastectomy (PM) samples from high-risk women would resemble HN gene expression.Methods:We analysed gene expression in 73 NlEpi samples microdissected from frozen tissue. In 42 samples, we used microarrays to compare gene expression between 18 RM patients and 18 age-matched HN (9 oestrogen receptor (ER)+, 9 ER−) and 6 PM patients. Data were analysed using a Bayesian approach (BADGE), and validated with quantitative real-time PCR (qPCR) in 31 independent NlEpi samples from 8 RM, 17 HN, and 6 PM patients.Results:A total of 98 probe sets (86 genes) were differentially expressed between RM and HN samples. Performing hierarchical analysis with these 98 probe sets, PM and HN samples clustered together, away from RM samples. qPCR validation of independent samples was high (84%) and uniform in RM compared with HN patients, and lower (58%), but more heterogeneous, in RM compared with PM patients. The 86 genes were implicated in many processes including transcription and the MAPK pathway.Conclusion:Gene expression differs between the NlEpi of breast cancer cases and controls. The profile of cancer cases can be discerned in high-risk NlEpi from cancer-free breasts. This suggests that the profile is not an effect of the tumour, but may mark increased risk and reveal the earliest genomic changes of breast cancer.

Early Dysregulation of Cell Adhesion and Extracellular Matrix Pathways in Breast Cancer Progression

Proliferative breast lesions, such as simple ductal hyperplasia (SH) and atypical ductal hyperplasia (ADH), are candidate precursors to ductal carcinoma in situ (DCIS) and invasive cancer. To better understand the relationship of breast lesions to more advanced disease, we used microdissection and DNA microarrays to profile the gene expression of patient-matched histologically normal (HN), ADH, and DCIS from 12 patients with estrogen receptor positive sporadic breast cancer. SH were profiled from a subset of cases. We found 837 differentially expressed genes between DCIS-HN and 447 between ADH-HN, with >90% of the ADH-HN genes also present among the DCIS-HN genes. Only 61 genes were identified between ADH-DCIS. Expression differences were reproduced in an independent cohort of patient-matched lesions by quantitative real-time PCR. Many breast cancer-related genes and pathways were dysregulated in ADH and maintained in DCIS. Particularly, cell adhesion and extracellular matrix interactions were overrepresented. Focal adhesion was the top pathway in each gene set. We conclude that ADH and DCIS share highly similar gene expression and are distinct from HN. In contrast, SH appear more similar to HN. These data provide genetic evidence that ADH (but not SH) are often precursors to cancer and suggest cancer-related genetic changes, particularly adhesion and extracellular matrix pathways, are dysregulated before invasion and even before malignancy is apparent. These findings could lead to novel risk stratification, prevention, and treatment approaches.

Features Associated with Successful Recruitment of Diverse Patients onto Cancer Clinical Trials: Report from the American College of Surgeons Oncology Group

BackgroundThe clinical trials mechanism of standardized treatment and follow-up for cancer patients with similar stages and patterns of disease is the most powerful approach available for evaluating the efficacy of novel therapies, and clinical trial participation should protect against delivery of care variations associated with racial/ethnic identity and/or socioeconomic status. Unfortunately, disparities in clinical trial accrual persist, with African Americans (AA) and Hispanic/Latino Americans (HA) underrepresented in most studies.Study DesignWe evaluated the accrual patterns for 10 clinical trials conducted by the American College of Surgeons Oncology Group (ACOSOG) 1999–2009, and analyzed results by race/ethnicity as well as by study design.ResultsEight of 10 protocols were successful in recruiting AA and/or HA participants; three of four randomized trials were successful. Features that were present among all of the successfully recruiting protocols were: (1) studies designed to recruit patients with regional or advanced-stage disease (2 of 2 protocols); and (2) studies that involved some investigational systemic therapy (3 of 3 protocols).DiscussionAA and HA cancer patients can be successfully accrued onto randomized clinical trials, but study design affects recruitment patterns. Increased socioeconomic disadvantages observed within minority-ethnicity communities results in barriers to screening and more advanced cancer stage distribution. Improving cancer early detection is critical in the effort to eliminate outcome disparities but existing differences in disease burden results in diminished eligibility for early-stage cancer clinical trials among minority-ethnicity patients.

Considerations for Clinicians in the Diagnosis, Prevention, and Treatment of Breast Cancer-Related Lymphedema: Recommendations from a Multidisciplinary Expert ASBrS Panel : Part 1: Definitions, Assessments, Education, and Future Directions

Sarah A. McLaughlin, MD, Alicia C. Staley, MBA, MS, BS, Frank Vicini, MD, FACR, FABS, Paul Thiruchelvam, BSc, MD, PhD, FRCS, Nancy A. Hutchison, MD, CLT-LANA, Jane Mendez, MD, Fiona MacNeill, FRCS, MD, FEBS, Stanley G. Rockson, MD, Sarah M. DeSnyder, MD, Suzanne Klimberg, MD, PhD, Michael Alatriste, LMT, CLT, Francesco Boccardo, MD, PhD, FACS, Mark L. Smith, MD, FACS, and Sheldon M. Feldman, MD, FACS

Considerations for Clinicians in the Diagnosis, Prevention, and Treatment of Breast Cancer-Related Lymphedema, Recommendations from an Expert Panel: Part 2: Preventive and Therapeutic Options

Sarah A. McLaughlin, MD, Sarah M. DeSnyder, MD, Suzanne Klimberg, MD, PhD, Michael Alatriste, LMT, CLT, Francesco Boccardo, MD, PhD, FACS, Mark L. Smith, MD, FACS, Alicia C. Staley, MBA, MS, BS, Paul T. R. Thiruchelvam, BSc, MD, PhD, FRCS, Nancy A. Hutchison, MD, CLT-LANA, Jane Mendez, MD, Fiona MacNeill, FRCS, MD, FEBS, Frank Vicini, MD, FACR, FABS, Stanley G. Rockson, MD, and Sheldon M. Feldman, MD, FACS

Transdisciplinary studies of surgical oncology trial accrual : A national institutes of health/national cancer institute roadmap-affiliated project update

A key objective of the National Institutes of Health Roadmap Initiative during the past 2 years has been to address scientific problems and issues through innovative research collaborations that cut across disciplines, traditions, and agendas.

60 – Solitary Metastases

Over the past 30 years, new and advanced breast cancer multimodality treatments have resulted in improved median survival times for patients with metastatic breast cancer. Breast cancer most commonly metastasizes to bone, followed by lung, brain, and liver. Until now, the treatment focus for metastatic breast cancer has been on palliative care rather than cure. However, a more aggressive treatment approach may be appropriate for patients with metastatic disease limited to a solitary lesion or to multiple lesions at a single organ site. Improved diagnostic, staging, and surgical techniques may allow curative surgery in these carefully selected patients with acceptable morbidity and very low mortality. In addition, studies have shown that the molecular phenotype of breast cancer determines the timing, pattern, and outcome of metastatic disease, and metastatic lesions may alter their receptor expression profile from their primary tumor. The main goal of such curative surgery would be prolonged disease-free survival and improved quality of life. Provided that the breast cancer primary is controlled, there is a long disease-free period, and the patient has a good performance status, surgery is an important component in the multimodality approach to breast cancer solitary metastases.

Changing Dogma and Decreased Collateral Damage in Breast Cancer Care

Since the times of the Edwin Papyrus in 1500 BC to the present, the diagnosis and treatment of breast cancer has evolved greatly. In early times, breast cancer was incurable, and the outcomes were dismal despite the therapies with hot and cold. In the more modern era, we have transitioned from the Halstedian principles of radical surgical procedures to the systemic approach to breast cancer treatment. Why not combine surgery with adjuvant therapies, such as chemotherapy and radiation, to allow use of less radical operations? Drs. Bernard Fisher and Umberto Veronesi both challenged the dogma during their time with pivotal clinical trials, such as the National Surgical Adjuvant Breast and Bowel Project studies B-04 and B-06 and the Milan Trials. With data, many more trials, and a better understanding of tumor biology, the field of breast cancer surgery keeps evolving. We continue to question the right balance between overtreatment and undertreatment and the potential morbidities associated with such therapies. Furthermore, it is important to consider how the prescribed therapy will affect the patient’s disease-free survival, overall survival, and quality of life. This issue of Annals of Surgical Oncology will provide you with thought-provoking manuscripts as we continue to challenge dogma and decrease the collateral damage of breast cancer treatment. It contains some of the scientific content as well as meeting content from the annual meeting of the American Society of Breast Surgeons (ASBrS), which was held in Las Vegas in April and had a record attendance of more than 1720 registrants from across 41 countries, including 232 international attendees, representing a global discussion of advances in breast cancer care. First, what about upper extremity lymphedema related to breast cancer treatments? The ASBrS convened an international multidisciplinary consensus panel to discuss this important topic, and the manuscripts describe the recommendations from this panel and sheds some light on the prevention, diagnosis, and new treatment strategies for this potentially debilitating condition. For years, we have been advising our patients after axillary lymphadenectomy to avoid phlebotomy and blood pressure measurements on the affected arm and to use an upper extremity compression garment during air flights, but what is the evidence to support these recommendations? Also, is it possible to stratify the risk of lymphedema and identify patients who might benefit from techniques, such as axillary reverse mapping (ARM) and/or lymphatic microsurgical preventative healing approach (LYMPHA)? ARM entails mapping upper extremity lymphatics with blue dye allowing for differentiation of lymphatics draining the breast (radioactive) and the upper extremity (blue). In the only prospective study, Yue et al. randomized 265 patients to undergo axillary lymph node dissection (ALND) versus ALND ? ARM. With 20-month follow-up, lymphedema developed in 33% of patients in the ALND group and 6% of the ALND ? ARM group. LYMPHA is a surgical approach for the primary prevention of arm lymphedema following axillary nodal dissection. The idea of LYMPHA was conceived 10 years ago, and the preliminary results were published a few years after. LYMPHA couples lymphovenous bypass (LVA) with ALND performing an anastomosis dunking the transected main lymphatic trunk(s) into a lateral branch of the axillary vein distal to a competent valve. Furthermore, which patients with lymphedema refractory to physical therapy and compression garments would benefit from lymph node transfer surgery? With improved understanding of the Society of Surgical Oncology 2017

BRCA1 and BRCA2 in Breast Cancer and Ovarian Cancer

Mutations of the BRCA1 and BRCA2 genes are known to confer an increased risk of breast cancer and ovarian cancer. These gene mutations are inherited in an autosomal dominant fashion and are highly penetrant in causing cancer. The lifetime risk of breast cancer is 57–65 % in carriers of BRCA1 mutations and 45–49 % in those with BRCA2 mutations. Ovarian cancer risk is 40 % and 18 %, respectively. Features in the personal and family history that suggest a genetic predisposition syndrome include history of breast or ovarian cancer at a young age, multiple breast cancers in the same person, multiple family members with breast or ovarian cancers, men with breast cancer, and Ashkenazi Jewish heritage. Genetic testing and genetic counseling are available to patients considered to be at high risk for these mutations. Management recommendations unique to this clinical scenario include specific screening guidelines for breast and ovarian cancers, chemoprophylaxis, and prophylactic operations. Prophylactic surgery is associated with dramatically reduced risk of developing cancer, with maximum benefit when performed at a young age; however, there are psychosocial and familial implications of these operations. Patients suspected of or confirmed to have a mutation of the BRCA1 or BRCA2 gene require multidisciplinary coordinated surveillance and cancer care.