Impact of MammaPrint on Clinical Decision-Making in South African Patients with Early-Stage Breast Cancer.

The aim of the study was to evaluate the impact of MammaPrint on treatment decision-making in patients with breast cancer. Clinicopathologic information of all breast cancer patients referred for MammaPrint testing in South Africa was collected from 2007 until 2014. A total of 107 patients (109 tumors) with estrogen receptor/progesterone receptor positive and human epidermal growth factor receptor-2 negative tumors were selected with tumors ≥10 mm, or when 1-3 nodes were involved without extra-nodal extension. None of the clinical indicators correlated significantly with the MammaPrint risk classification, which changed the decision for adjuvant chemotherapy in 52% of patients. Of 60 patients who were clinically high risk, 62% had a low-risk MammaPrint result and of the 47 clinically low -risk patients 40% had a high-risk MammaPrint result. This study indicates that MammaPrint could reduce the need for adjuvant chemotherapy by 17% using the selection criteria stipulated. The significant impact on treatment decisions confirmed the clinical utility of MammaPrint independent of standard clinicopathologic risk factors as supported by long-term clinical outcome studies.

Genomic medicine and risk prediction across the disease spectrum.

Genomic medicine is based on the knowledge that virtually every medical condition, disease susceptibility or response to treatment is caused, regulated or influenced by genes. Genetic testing may therefore add value across the disease spectrum, ranging from single-gene disorders with a Mendelian inheritance pattern to complex multi-factorial diseases. The critical factors for genomic risk prediction are to determine: (1) where the genomic footprint of a particular susceptibility or dysfunction resides within this continuum, and (2) to what extent the genetic determinants are modified by environmental exposures. Regarding the small subset of highly penetrant monogenic disorders, a positive family history and early disease onset are mostly sufficient to determine the appropriateness of genetic testing in the index case and to inform pre-symptomatic diagnosis in at-risk family members. In more prevalent polygenic non-communicable diseases (NCDs), the use of appropriate eligibility criteria is required to ensure a balance between benefit and risk. An additional screening step may therefore be necessary to identify individuals most likely to benefit from genetic testing. This need provided the stimulus for the development of a pathology-supported genetic testing (PSGT) service as a new model for the translational implementation of genomic medicine in clinical practice. PSGT is linked to the establishment of a research database proven to be an invaluable resource for the validation of novel and previously described gene-disease associations replicated in the South African population for a broad range of NCDs associated with increased cardio-metabolic risk. The clinical importance of inquiry concerning family history in determining eligibility for personalized genotyping was supported beyond its current limited role in diagnosing or screening for monogenic subtypes of NCDs. With the recent introduction of advanced microarray-based breast cancer subtyping, genetic testing has extended beyond the genome of the host to also include tumor gene expression profiling for chemotherapy selection. The decreasing cost of next generation sequencing over recent years, together with improvement of both laboratory and computational protocols, enables the mapping of rare genetic disorders and discovery of shared genetic risk factors as novel therapeutic targets across diagnostic boundaries. This article reviews the challenges, successes, increasing inter-disciplinary integration and evolving strategies for extending PSGT towards exome and whole genome sequencing (WGS) within a dynamic framework. Specific points of overlap are highlighted between the application of PSGT and exome or WGS, as the next logical step in genetically uncharacterized patients for whom a particular disease pattern and/or therapeutic failure are not adequately accounted for during the PSGT pre-screen. Discrepancies between different next generation sequencing platforms and low concordance among variant-calling pipelines caution against offering exome or WGS as a stand-alone diagnostic approach. The public reference human genome sequence (hg19) contains minor alleles at more than 1 million loci and variant calling using an advanced major allele reference genome sequence is crucial to ensure data integrity. Understanding that genomic risk prediction is not deterministic but rather probabilistic provides the opportunity for disease prevention and targeted treatment in a way that is unique to each individual patient.

Incorporating microarray assessment of HER2 status in clinical practice supports individualised therapy in early-stage breast cancer.

Accurate determination of human epidermal growth factor receptor-2 (HER2) status is essential for optimal selection of breast cancer patients for gene targeted therapy. The analytical performance of microarray analysis using TargetPrint for assessment of HER2 status was evaluated in 138 breast tumours, including 41 fresh and 97 formalin-fixed paraffin embedded (FFPE) specimens. Reflex testing using immunohistochemistry/in situ hybridization (IHC/ISH) in four discordant cases confirmed the TargetPrint results, achieving 100% agreement regardless of whether fresh tissue or FFPE specimens were used. One equivocal IHC/ISH case was classified as HER2-positive based on the microarray result. The proven clinical utility in resolving equivocal and borderline cases justifies modification of the testing algorithm under these circumstances, to obtain a definitive positive or negative test result with the use of microarrays. Determination of HER2 status across three assay platforms facilitated improved quality assurance and led to a higher level of confidence on which to base treatment decisions.

MammaPrint Pre-screen Algorithm (MPA) reduces chemotherapy in patients with early-stage breast cancer.

BACKGROUND: Clinical and pathological parameters may overestimate the need for chemotherapy in patients with early-stage breast cancer. More accurate determination of the risk of distant recurrence is now possible with use of genetic tests, such as the 70-gene MammaPrint profile. OBJECTIVES: A health technology assessment performed by a medical insurer in 2009 introduced a set of test eligibility criteria - the MammaPrint Pre-screen Algorithm (MPA) - applied in this study to determine the clinical usefulness of a pathology-supported genetic testing strategy, aimed at the reduction of healthcare costs.Methods. An implementation study was designed to take advantage of the fact that the 70-gene profile excludes analysis of hormone receptor and human epidermal growth factor receptor 2 (HER2) status, which form part of the MPA based partly on immunohistochemistry routinely performed in all breast cancer patients. The study population consisted of 104 South African women with early-stage breast carcinoma referred for MammaPrint. For the MammaPrint test, RNA was extracted from 60 fresh tumours (in 58 patients) and 46 formalin-fixed, paraffin-embedded (FFPE) tissue samples. RESULTS: When applying the MPA for selection of patients eligible for MammaPrint testing, 95 of the 104 patients qualified. In this subgroup 62% (59/95) were classified as low risk. Similar distribution patterns for risk classification were obtained for RNA extracted from fresh tumours v. FFPE tissue samples. CONCLUSIONS: The 70-gene profile classifies approximately 40% of early-stage breast cancer patients as low-risk compared with 15% using conventional criteria. In comparison, more than 60% were shown to be low risk with use of the MPA validated in this study as an appropriate strategy to prevent chemotherapy overtreatment in patients with early-stage breast cancer.

Implementation of a breast cancer genetic service in South Africa - lessons learned.

BACKGROUND: Genetic testing for BRCA mutations has been available in the Western Cape of South Africa since 2005, but practical implementation of genetic counselling and testing has been challenging. OBJECTIVE: To describe an approach to breast cancer genetic counselling and testing developed in a resource-constrained environment at Tygerberg Hospital in Cape Town, Western Cape. METHODS: Genetic counselling is offered in a stepwise manner to our diverse patient population, with a focus on affected probands, and subsequent cascade testing. A record review of BRCA testing between 2005 and 2011 was performed. RESULTS; During this period 302 probands received genetic testing, with increasing numbers tested over time. Of 1 520 women treated for breast cancer since 2008, 226 (14.9%) accepted BRCA testing, and 39 tested positive (17.3% of those tested, and 2.6% of all women). Common founder mutations were detected in 11.9% of women (36/302), and comprised 73% (36/49) of mutations detected. Cascade testing increased after 2010: 16 female and 4 male family members of 19 probands accepted testing, with 6 positives being detected. CONCLUSION: A protocol-driven approach focusing on probands, with initial pre-test counselling by primary care staff has proven effective in establishing the service. Involvement of a clinical geneticist/genetic counsellor has permitted more detailed post-test counselling and increased use of cascade testing.

Influence of genetic factors on the development of breast cancer in the older woman.

Although the major part of the burden of disease for female breast cancer occurs at older age, less is known about the development and progression in this age group than in women under 60 years of age. As the world population continues to age, the percentage of elderly is increasing in all communities and the incidence of breast cancer will rise accordingly. Improving detection and diagnosis, and a better understanding of the mechanisms that play a role in this age group, will not only improve quality of life in older sufferers but could also contribute to the management of this disease in the adult population as well. Development of breast cancer in the older woman is influenced by many variables that may differ from the risk factors that are involved in younger women. In addition to well-described variables at younger ages such as family history, hormonal exposure, lifestyle factors and pre-existing benign breast disease, in older women age-related changes in breast tissue, biochemistry, inflammatory responses and the immune system, as well as accumulation of DNA damage and spontaneous mutations are suspected to contribute to the complex relationship between ageing and breast cancer. We review the available data on the role of age-related changes and genetic mutations in the development of breast cancer in older women as well as their effects on estrogen metabolism and free oxygen radical inactivation.

Time for a re-evaluation of mammography in the young? Results of an audit of mammography in women younger than 40 in a resource restricted environment.

Mammography in younger women is considered to be of limited value. In a resource restricted environment without access to magnetic resonance imaging (MRI) and with a high incidence of breast cancer in the young, mammography remains an important diagnostic tool. Recent technical advances and better regulation of mammography make a reassessment of its value in these conditions necessary. Data of all the mammograms performed at a tertiary hospital and private breast clinic between January 2003 and July 2009 in women less than 40 years of age were collected. Indications were the presence of a mass, follow-up after primary cancer therapy, and screening for patients perceived at high risk due to a family history or the presence of atypical hyperplasia. Data acquired were as follows: Demographics, prior breast surgery, indication for mammography, outcome of mammography, diagnostic procedures, and their results. Of 2,167 mammograms, 393 were performed for a palpable mass, diagnostic mammography. In these, the overall cancer detection rate was 40%. If the mammography was reported as breast imaging reporting and data system (BIRADS(®)) 5 versus BIRADS(®) 3 and 4 versus BIRADS(®) 1 and 2, a final diagnosis of malignancy was established in 96, 48, and 5%, respectively. Of 367 mammograms done for the follow-up after primary treatment of breast cancer, seven cancers were diagnosed for a detection rate of 1.9%. Of 1,312 mammograms performed for screening, the recall rate was 4%; the biopsy rate 2%, and the cancer diagnosis rate 3/1,000 examinations. In contrast to past series, this series has shown that recent advances in mammography have made it a useful tool in the management of breast problems in young women, notably in a resource-restricted environment. Women for screening should be selected carefully.

Surgeon-read screening mammography: an analysis of 11,948 examinations.

INTRODUCTION: Mammography was pioneered by surgeons but is now the domain of radiologists. With ever-increasing cost pressures it must be examined whether interpretation of mammography by clinicians and radiation technologists is comparable to that of breast radiologists. We present the largest series of surgeon-read screening mammography to date. METHODS: All mammography performed between 2003 and 2009 at a comprehensive breast centre was recorded prospectively. First assessment was by a radiation technologist and consensus established after second reading by a breast surgeon, who took responsibility for the reading. Data recorded were: age, hormonal replacement therapy, prior breast surgery, indications for mammography and outcomes. Outcomes were classified based using the Breast Imaging Reporting and Data System (BIRADS). Indeterminate lesions were imaged further or underwent tissue acquisition. All BIRADS 5 lesions underwent tissue acquisition. RESULTS: Of 11,948 mammograms, 538 were reported as indeterminate/compatible with malignancy; 240 biopsies were performed, and 87 cancers diagnosed. In 40-49-year-old women (4,956 mammograms), the recall rate was 4.2%, the biopsy rate was 1.6%, the malignancy rate of biopsy was 23.7% and the cancer diagnosis rate was 3.6/1,000 examinations; for 50-69-year-old women these figures were 6,546, 4.7, 2.2, 44.1% and 10.0/1,000, respectively, and in women older than 70 years, they were 446, 5.6, 3.4, 33.3% and 11.2/1,000, respectively. Of all cancers, 32.2% were non-invasive; of invasive cancers, 49.1% were 10 mm or less in diameter and 75% were node negative. CONCLUSIONS: These results are similar to those in high-quality organized screening programs. The role of breast surgeons in mammography interpretation should be expanded.

Prevention of aromatase inhibitor-induced bone loss using risedronate: the SABRE trial.

PURPOSE To investigate the management of bone health in women with early breast cancer (EBC) who were scheduled to receive anastrozole. PATIENTS AND METHODS Postmenopausal women with hormone receptor-positive EBC were assigned to one of three strata by risk of fragility fracture. Patients with the highest risk (H) received anastrozole 1 mg/d plus risedronate 35 mg/wk orally. Patients with moderate-risk (M) were randomly assigned in a double-blind manner to anastrozole and risedronate (A + R) or to anastrozole and placebo (A + P). Patients with lower-risk (L) received anastrozole (A) alone. Calcium and vitamin D were recommended for all patients. Lumbar spine and total hip bone mineral density (BMD) were assessed at baseline, 12 months, and 24 months. Results At 24 months, in the M group, treatment with A + R resulted in a significant increase in lumbar spine and total hip BMD compared with A + P treatment (2.2% v -1.8%; treatment ratio, 1.04; P < .0001; and 1.8% v -1.1%; treatment ratio, 1.03; P < .0001, respectively). In the H stratum, lumbar spine and total hip BMD increased significantly (3.0%; P = .0006; and 2.0%; P = .0104, respectively). Patients in the L stratum showed a significant decrease in lumbar spine BMD (-2.1%; P = .0109) and a numerical decrease in total hip BMD (-0.4%; P = .5988). Safety profiles for anastrozole and risedronate were similar to those already established. CONCLUSION In postmenopausal women at risk of fragility fracture who were receiving adjuvant anastrozole for EBC, the addition of risedronate at doses established for preventing and treating osteoporosis resulted in favorable effects in BMD during 24 months.

Breast cancer in young women in a limited-resource environment.

BACKGROUND: Despite the higher incidence of breast cancer in young women in developing countries, there is a paucity of data on their management. We present the clinicopathological features and outcome of treatment of women 35 years or younger with breast cancer in a resource-restricted environment. METHODS: A total of 141 patients who were diagnosed with primary breast cancer at 35 years or younger from January 2000 to June 2008 were retrieved from the cancer registry of a breast clinic at a tertiary hospital and a private breast health center in South Africa. Clinicopathological features, treatment, and survival were analyzed. RESULTS: Two patients presented with TNM stage 0 (1.4%), 14 with stage I (9.9%), 47 with stage II (33.35%), 47 with stage III (33.3%), and 31 with stage IV (21.9%). Tumor grade was 3 in 47%, grade 2 in 37%, and grade 1 in 16% of patients. One hundred and four patients with stage 0-III disease underwent treatment with curative intent, 83 had a mastectomy, and 12 had breast-conserving surgery. Ninety patients (86.5%) had chemotherapy, 68 (65.4%) had radiotherapy, and 50 (48.1%) had hormonal therapy. Of 93 patients who completed primary therapy, 4 developed contralateral cancers, 3 had locoregional recurrence, 8 developed synchronous locoregional and distant recurrence, and 19 relapsed with distant metastasis only. The 2-year disease-free and overall survival for stage 0-III disease was 48 and 56%, respectively. CONCLUSIONS: Young women with breast cancer in a resource-limited environment have similar adverse clinicopathological features to those in developed countries. Their disease is more advanced at presentation with poorer outcome. Increased awareness, better systemic therapy, and more comprehensive genetic studies are essential to improve the dismal outcome.

Counseling for male BRCA mutation carriers: a review.

BRCA mutations in women confer a high risk for breast and ovarian cancers. The risks to male carriers are poorly understood and risk management strategies undescribed. This review summarizes current evidence and gives recommendations for counseling male BRCA mutation carriers. Reported risks for breast, prostate, pancreatic, gastric and hematologic cancers are higher in male BRCA mutation carriers vs non-carriers. Especially in male BRCA2 mutation carriers under age 65 prostate and pancreatic cancer risks are increased. The risk increase for primary cancers of organs like the liver, bone and brain is difficult to assess as these organs are common sites for metastases. Reports on colorectal cancer and melanoma risks are inconclusive. On the current limited evidence available, male BRCA mutation carriers should be regarded as at high risk for breast, prostate, gastric, pancreatic and colorectal cancers; surveillance by appropriate investigations should start at age 40 years.

Conservative management of breast cancer in the elderly in a developing country.

BACKGROUND: The cost effective treatment of cancer in developing countries remains challenging. In the elderly with possible limited life expectancy, the health expenditure associated with standard treatment regimes should be carefully considered. We present the results of conservative management of breast cancer in the aged in a resource-limited environment. METHODS: Patients aged 70 or older with early breast cancer were treated with tumour excision or simple mastectomy and adjuvant tamoxifen. The records of patients presenting to the Breast Unit between January 1990 and December 2004 were retrieved and demographic, clinical, pathological and oncological data were reviewed. Survival statistics were calculated using the life table method. RESULTS: A total of 483 patients above 70 years of age were identified. One hundred and eighty eight patients were managed according to the conservative protocol. Forty-one had a simple mastectomy and 147 tumour excision. Their mean age was 77.3 years. The mean follow-up is 62 months. Thirty-one patients (16.4%) were not compliant with tamoxifen use. TNM staging was 0 in 4 patients, I in 42 patients, II in 116 patients and III in 26 patients. There was no 30-day mortality. The cumulative incidence of local recurrence was 3.3% at 5 and 10 years. The cumulative incidence of regional recurrence was 3.3% at 5 years and 4.5% at 10 years. The cumulative incidence of distant recurrence was 6.2% at 5 years and 12.2% at 10 years. The cumulative overall, disease specific and disease free survival at 10 years was 59%, 88% and 81% respectively. CONCLUSION: Limited surgery and tamoxifen provide excellent control of breast cancer in the elderly in a resource restricted environment. Radiotherapy and axillary dissection and can be safely omitted thereby reducing health care resource utilization.

Locally advanced breast cancer in developing countries: the place of surgery.

Most breast cancer patients in developing countries still present with locally advanced breast cancer (LABC). Because surgery is the most widely available treatment modality, we examine its place in the management of LABC. Historically, single local treatment modalities have had disappointing results, and multimodality therapy has become the norm for combatting LABC. Combining surgery and radiotherapy will lead to superior local control rates. Surgery should precede radiotherapy. Preoperative systemic treatment-with the possible exception of cyclophosphamide, methotrexate, 5-fluououracil (CMF) chemotherapy-does not influence surgical complication rates. Hormonal therapy is understudied and underutilized; its benefits become apparent only in prolonged follow-up. Sequencing of local and systemic treatments does not influence oncologic outcome, but failure to respond to preoperative systemic therapy may identify patients with a poor prognosis. With multimodality management including hormonal therapy, chemotherapy, radiotherapy, and surgery, local control rates of more than 80% and 5-year survival rates of more than 50% have become the norm.