ABSTRACT
BACKGROUND: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. PATIENTS AND METHODS: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. RESULTS: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. CONCLUSION: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Phthalazines/adverse effects , Germ Cells/pathology , BRCA1 Protein/geneticsABSTRACT
BACKGROUND: Given numerous publications and clinical trials regarding axillary management in breast cancer, we sought to summarize this complex literature to help clarify this field for clinicians. This systematic review focuses on the role of irradiation of the axillary nodes (locoregional nodal irradiation [LRNI]) in the management of the axilla in patients with early-stage breast cancer in various clinical settings. METHODS: We searched MEDLINE and EMBASE databases, the Cochrane library, the proceedings of the ASCO, the ASTRO, the ESMO, the ESTRO, and the San Antonio Breast Cancer Symposium (2016-2019) meetings. The quality of the studies was assessed with design-specific tools. The study was registered in PROSPERO. RESULTS: We included one systematic review, one individual patient data (IPD) meta-analysis, and five randomized controlled trials (RCTs). After axillary lymph node dissection (ALND), LRNI resulted in small benefits in breast cancer specific mortality, locoregional recurrence, and distant metastases-free survival but not overall survival. After a positive sentinel node biopsy (SLNB), LRNI may provide equivalent locoregional control and disease-free survival (DFS) compared to ALND with a lower risk of lymphedema. No randomized data is available for the neoadjuvant setting. CONCLUSIONS: The summary of the role of radiation, is relevant to radiation oncologists for choosing the correct cohort of patient requiring LRNI and to surgeons making clinical decisions regarding the timing and type of breast reconstruction offered to patients.
Subject(s)
Breast Neoplasms , Lymph Nodes , Axilla/pathology , Breast Neoplasms/drug therapy , Breast Neoplasms/radiotherapy , Breast Neoplasms/surgery , Female , Humans , Lymph Node Excision/methods , Lymph Nodes/pathology , Lymphatic Metastasis/pathology , Sentinel Lymph Node BiopsyABSTRACT
The World Health Organization (WHO) has declared a pandemic of COVID-19, the disease caused by the recently described SARS-CoV-2. The relevance and importance of mass diagnosis in order to find the asymptomatic individuals is widely recognized as a mandatory tool to reinforce the control measures for monitoring virus circulation and reduce the spreading of SARS-CoV-2. Here, we described quickness and cheaper strategies of direct RT-qPCR (in the absence of RNA isolation) and compared the results to those obtained using standard RNA isolation procedure. The tests varied using pure, diluted samples, combined with Proteinase K (PK) or Lysis Buffer. Our findings showed consistently that PK pre-treated samples in the absence of RNA extraction procedures presents similar results to those obtained by standard RNA isolation procedures. On average, 16 samples extracted with the MagMAX™ CORE Kit, take around 2 h, costing an average of USD 5, the pre-treatment of samples using PK, on the other hand, would cut the value to less than USD 0.30 and reduce the time of procedure in more than 1 ½ hours. The present study suggests the use of PK treatment instead of RNA isolation in order to reduce costs and time in processing samples for molecular diagnosis of SARS-CoV-2.
Subject(s)
COVID-19 Nucleic Acid Testing/methods , COVID-19/diagnosis , Endopeptidase K/pharmacology , RNA, Viral/analysis , SARS-CoV-2/isolation & purification , COVID-19 Nucleic Acid Testing/economics , Humans , SARS-CoV-2/geneticsABSTRACT
Background: Breast assessment sites (bass) were developed to provide expedited and coordinated care for patients being evaluated for breast cancer (bca) in Ontario. We compared the diagnostic and treatment intervals for patients diagnosed at a bas and for those diagnosed through a usual care (uc) route. Methods: This population-based, cross-sectional study of patients diagnosed with bca in Ontario during 2007-2015 used linked administrative data. "Diagnostic interval" was the time from the earliest cancer-related health care encounter before diagnosis to diagnosis; "treatment interval" was the time from diagnosis to treatment. Diagnosis at a bas was determined from the patient's biopsy and mammography institutions. Interval lengths for the bas and uc groups were compared using multivariable quantile regression, stratified by detection method. Results: The diagnostic interval was shorter for patients who were bas-diagnosed than for those who were uc-diagnosed, with adjusted median differences of -4.0 days [95% confidence interval (ci): -3.2 days to -4.9 days] for symptomatic patients and -5.4 days (95% ci: -4.7 days to -6.1 days) for screen-detected patients. That association was modified by stage at diagnosis, with larger differences in patients with early-stage cancers. In contrast, the treatment interval was longer in patients who were bas-diagnosed than in those who were uc-diagnosed, with adjusted median differences of 4.2 days (95% ci: 3.8 days to 4.7 days) for symptomatic patients and 4.2 days (95% ci: 3.7 days to 4.8 days) for screen-detected patients. Conclusions: Diagnosis of bca through a bas was associated with a shorter diagnostic interval, but a longer treatment interval. Although efficiencies in the diagnostic interval might help to reduce distress experienced by patients, the longer treatment intervals for patients who are bas-diagnosed remain a cause for concern.
Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/therapy , Aged , Cross-Sectional Studies , Female , Humans , Middle AgedABSTRACT
Background: In Ontario, there is no clearly defined standard of care for staging for distant metastasis in women with newly diagnosed and biopsy-confirmed breast cancer whose clinical presentation is suggestive of early-stage disease. This guideline addresses baseline imaging investigations for women with newly diagnosed primary breast cancer who are otherwise asymptomatic for distant metastasis. Methods: The medline and embase databases were systematically searched for evidence from January 2000 to April 2019, and the best available evidence was used to draft recommendations relevant to the use of baseline imaging investigation in women with newly diagnosed primary breast cancer who are otherwise asymptomatic. Final approval of this practice guideline was obtained from both the Staging in Early Stage Breast Cancer Advisory Committee and the Report Approval Panel of the Program in Evidence-Based Care. Recommendations: These recommendations apply to all women with newly diagnosed primary breast cancer (originating in the breast) who have no symptoms of distant metastasis Staging tests using conventional anatomic imaging [chest radiography, liver ultrasonography, chest-abdomen-pelvis computed tomography (ct)] or metabolic imaging modalities [integrated positron-emission tomography (pet)/ct, integrated pet/magnetic resonance imaging (mri), bone scintigraphy] should not be routinely ordered for women newly diagnosed with clinical stage i or stage ii breast cancer who have no symptoms of distant metastasis, regardless of biomarker status. In women newly diagnosed with stage iii breast cancer, baseline staging tests using either anatomic imaging (chest radiography, liver ultrasonography, chest-abdomen-pelvis ct) or metabolic imaging modalities (pet/ct, pet/mri, bone scintigraphy) should be considered regardless of whether the patient is symptomatic for distant metastasis and regardless of biomarker profile.
Subject(s)
Breast Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Female , Humans , Middle Aged , Neoplasm Metastasis , Neoplasm StagingABSTRACT
Several emerging viral agents related to gastroenteritis are distributed in human and animal populations and may contaminate the environment due to anthropic activities. The objective of this study was to analyze the seasonal contamination by enteric virus and coliforms in water from streams in the Vale do Taquari, draining a large number of pig farms. Microbiological contamination was evidenced by the detection of total and thermotolerant coliforms, reaching their peak in December. Hepatitis E virus (HEV), Enterovirus-G (EV-G) genome, and Sapelovirus-A (SV-A) genome were not detected. On the other hand, Rotavirus (RV) was detected in 3% (1/32) of the samples, whereas Teschovirus-A (PTV) was detected in 6% (2/32). This is the first detection of PTV in environmental samples in Brazil, pointing that the virus is being shedded from swine herds to watersheds. Human mastadenovirus (HAdV) was the most frequent detected viral agent in 9.3% (3/32) with values of 2.54 × 105, 7.13 × 104, and 3.09 × 105 genome copies/liter (gc/L). The circulation of coliforms and viral pathogens is noticeable due to anthropic activities and to the management of animal waste from the pig farming. In this way, enteric viruses can assist in monitoring the quality of watersheds and in tracking sources of contamination.
Subject(s)
Enteritis/veterinary , Swine Diseases/virology , Teschovirus/isolation & purification , Virus Shedding , Viruses/isolation & purification , Wastewater/virology , Animal Husbandry , Animals , Brazil , Enteritis/virology , Farms , Feces/virology , Genome, Viral , Humans , Swine , Swine Diseases/epidemiology , Teschovirus/genetics , Viruses/classification , Wastewater/microbiologyABSTRACT
Background: For women with lymph node (ln)-positive, estrogen receptor-positive, and her2 (human epidermal growth factor receptor 2)-negative breast cancer (bca), current guidelines recommend treatment with both hormonal therapy and chemotherapy. The 21-gene Recurrence Score (rs) assay might be helpful in selecting patients with bca who can be spared chemotherapy when they have 1-3 positive lns and a lower risk of recurrence. In the present study, we performed a cost-utility analysis comparing use of the 21-gene rs assay with current practice from the perspective of a Canadian health care payer. Methods: A Markov model was developed to determine costs and quality-adjusted life-years (qalys) over a patient's lifetime. Patient outcomes in both study groups were examined based on published clinical trials. Costs were derived primarily from published Canadian sources. Costs and outcomes were discounted at 1.5% annually, and costs are reported in 2016 Canadian dollars. A probabilistic analysis was used, and the model parameters were varied in a sensitivity analysis. Results: The results indicate that use of the 21-gene rs assay was less costly ($432 less) and more effective (0.22 qalys) than current practice. The probabilistic analysis revealed that 70% of the 10,000 simulated incremental cost-effectiveness ratios were in the southeast quadrant. The results were sensitive to the probability of a low rs and to the probability of receiving chemotherapy in the low-risk rs category and in current practice. Conclusions: Use of the 21-gene rs assay could be a cost-effective strategy for Ontario patients with estrogen receptor-positive, her2-negative early bca and 1-3 positive lns.
Subject(s)
Biological Assay/economics , Breast Neoplasms/economics , Breast Neoplasms/genetics , Antineoplastic Agents/adverse effects , Antineoplastic Agents/economics , Breast Neoplasms/drug therapy , Cost-Benefit Analysis , Female , Genes , Humans , Quality-Adjusted Life YearsABSTRACT
Background: In Canada, requests for public reimbursement of cancer drugs are predominately initiated by pharmaceutical manufacturers. Clinician-led submissions provide a mechanism to initiate the drug funding process when industry does not submit a request for funding consideration. Although such requests are resource-intensive to produce, Cancer Care Ontario (cco) has the capacity to facilitate clinician-led submissions. In 2014, cco began developing a cancer drug prioritization framework that allocates resources to systematically address a growing number of clinician-identified funding gaps with clinician-led submissions. Methods: Cancer site-specific drug advisory committees established by cco consist of health care practitioners whose roles include identifying and prioritizing funding gaps. The committees submit their identified gaps to a cross-cancer-site prioritization exercise in which the requests are ranked based on a set of guiding principles derived from health technology assessment. The requests are then sequentially allocated the resources needed to meet submission requirements. Whether the funding gap is of provincial or pan-Canadian relevance determines where the submission is filed for assessment. Results: Since its inception, the cco framework has identified 17 funding gaps in 9 cancer sites. In 4 prioritizations, the framework supported 6 submissions. As of June 2018, the framework had contributed to the eventual funding of more than 9 new drug-indication pairs, with more awaiting funding consideration. Conclusions: The cco prioritization framework has enabled clinicians to effectively and systematically identify, prioritize, and fill funding gaps not addressed by industry. Ultimately, the framework helps to ensure that patients can access evidence-informed and cost-effective therapies. The framework will continue to evolve as it encounters new challenges, including funding requests for rare indications.
Subject(s)
Medical Oncology/economics , Oncologists/organization & administration , Antineoplastic Agents/economics , Cost-Benefit Analysis , Financing, Organized , Humans , Neoplasms/economics , OntarioSubject(s)
Breast Neoplasms, Male , Breast Neoplasms , Humans , Male , Retrospective Studies , Treatment OutcomeABSTRACT
Background: Despite the fact that heterozygosity for a pathogenic ATM variant is present in 1%-2% of the adult population, clinical guidelines to inform physicians and genetic counsellors about optimal management in that population are lacking. Methods: In this narrative review, we describe the challenges and controversies in the management of women who are heterozygous for a pathogenic ATM variant with respect to screening for breast and other malignancies, to choices for systemic therapy, and to decisions about radiation therapy. Results: Given that the lifetime risk for breast cancer in women who are heterozygous for a pathogenic ATM variant is likely greater than 25%, those women should undergo annual mammographic screening starting at least by 40 years of age. For women in this group who have a strong family history of breast cancer, earlier screening with both magnetic resonance imaging and mammography should be considered. High-quality data to inform the management of established breast cancer in carriers of pathogenic ATM variants are lacking. Although deficiency in the ATM gene product might confer sensitivity to dna-damaging pharmaceuticals such as inhibitors of poly (adp-ribose) polymerase or platinum agents, prospective clinical trials have not been conducted in the relevant patient population. Furthermore, the evidence with respect to radiation therapy is mixed; some data suggest increased toxicity, and other data suggest improved clinical benefit from radiation in women who are carriers of a pathogenic ATM variant. Conclusions: As in the 2017 U.S. National Comprehensive Cancer Network guidelines, we recommend high-risk imaging for women in Ontario who are heterozygous for a pathogenic ATM variant. Currently, ATM carrier status should not influence decisions about systemic or radiation therapy in the setting of an established breast cancer diagnosis.
Subject(s)
Ataxia Telangiectasia Mutated Proteins/genetics , Breast Neoplasms/genetics , Mutation , Breast Neoplasms/diagnosis , Breast Neoplasms/therapy , Clinical Decision-Making/methods , Early Detection of Cancer/methods , Female , Genetic Predisposition to Disease , Heterozygote , Humans , Neoplasm Proteins/geneticsABSTRACT
AIMS: Male breast cancer is a rare disease with limited evidence-based guidelines for treatment. This study aimed to identify demographic, pathological and clinical factors associated with its prognosis. MATERIALS AND METHODS: A retrospective review of 161 male breast cancer patients diagnosed at a single institution from 1987 to June 2017 was conducted. Patient demographics, disease characteristics, treatment and outcome were extracted and included in competing-risk analysis and the univariate Cox proportional hazard model for univariate analysis. Factors with P < 0.10 were included in multivariable analysis. RESULTS: The mean age at diagnosis was 67 years (standard deviation = 11.2) and the median follow-up duration was 5.3 years (range 0-25 years). There were 48 deaths, including 23 cancer-specific deaths. The actuarial median survival was 19.9 years. In multivariable analysis, factors associated with overall survival were size of tumours (hazard ratio 2.0; 95% confidence interval 1.4-2.7, P < 0.0001) and diagnosis of metastatic disease (hazard ratio 8.7; 95% confidence interval 1.9-40.6; P = 0.006). Of 138 patients without metastases at diagnoses, 11 had local-regional recurrence and 26 had distant metastases. In the multivariable model for local-regional recurrence, a more recent year of diagnosis was associated with reduced risk (hazard ratio 0.9, 95% confidence interval 0.8-1.0, P = 0.008), whereas more positive lymph nodes was associated with higher risk (hazard ratio 2.2, 95% confidence interval 1.2-4.0, P = 0.01). A higher risk of metastases was associated with more positive lymph nodes (hazard ratio 1.9; 95% confidence interval 1.1-3.3; P = 0.03) and tumour size (hazard ratio 1.8; 95% confidence interval 1.1-2.9; P = 0.01). A higher risk of any recurrence or metastases was associated with the number of positive nodes (hazard ratio 1.9; 95% confidence interval 1.2-3.0; P = 0.005) and tumour size (hazard ratio 1.6; 95% confidence interval 1.1-2.2; P = 0.01). CONCLUSION: In general, tumour size and more positive lymph nodes were associated with worse prognosis. Larger powered studies are needed to identify prognostic factors with smaller effect sizes.
Subject(s)
Breast Neoplasms, Male/therapy , Adult , Aged , Aged, 80 and over , Breast Neoplasms, Male/pathology , Female , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Treatment OutcomeABSTRACT
AIMS: To examine the efficacy and safety of non-vitamin K oral anticoagulants in people with both atrial fibrillation and diabetes mellitus. METHODS: We reviewed efficacy and safety data from the warfarin-controlled phase III non-vitamin K oral anticoagulants trials (ARISTOTLE, RE-LY, ROCKET-AF, ENGAGE AF-TIMI 48) and their post hoc analyses with regard to diabetes status. We also reviewed the updated literature regarding this population. RESULTS: At baseline 20-40% of the participants in the phase III non-vitamin K oral anticoagulants trials had diabetes mellitus at baseline. This population, in comparison with those without diabetes, was more likely to have other comorbidities, such as hypertension and coronary artery disease; thus, their cardiovascular risk was higher. Participants with diabetes had higher rates of stroke and systemic embolism than participants without diabetes. This risk was decreased using non-vitamin K oral anticoagulants, with no significant interaction by diabetic status or the specific drug used. Overall, compared with warfarin, non-vitamin K oral anticoagulants were safe and reduced the incidence of major bleeding in people with atrial fibrillation and diabetes, although the results varied with the different non-vitamin K oral anticoagulants. CONCLUSIONS: The efficacy and safety of non-vitamin K oral anticoagulants compared with warfarin generally extend to participants with diabetes mellitus, although dedicated randomized trials or real-world data are lacking.
Subject(s)
Atrial Fibrillation/drug therapy , Diabetes Mellitus/epidemiology , Factor Xa Inhibitors/therapeutic use , Stroke/prevention & control , Anticoagulants/therapeutic use , Antithrombins/therapeutic use , Atrial Fibrillation/complications , Atrial Fibrillation/epidemiology , Clinical Trials, Phase III as Topic , Comorbidity , Coronary Artery Disease/epidemiology , Hemorrhage/chemically induced , Hemorrhage/epidemiology , Humans , Hypertension/epidemiology , Stroke/epidemiology , Stroke/etiology , Treatment OutcomeABSTRACT
The objective of this study was to estimate the lifetime risk of breast cancer in women with a BRCA1 or BRCA2 mutation with and without at least 1 first-degree relative with breast cancer. A total of 2835 women with a BRCA1 or BRCA2 mutation were followed. Age- and gene-specific breast cancer rates were calculated. The relative risks of breast cancer for subjects with a family history of breast cancer, compared to no family history were calculated. The mean age at baseline was 41.1 years, and they were followed for a mean of 6.0 years. The estimated penetrance of breast cancer to age 80 years was 60.8% for BRCA1 and 63.1% for BRCA2. For all BRCA carriers, the penetrance of breast cancer to age 80 for those with no first-degree relative with breast cancer was 60.4% and 63.3% for those with at least 1 first-degree relative with breast cancer. The risk of breast cancer for BRCA carriers with no first-degree relative with breast cancer is substantial, and as a result, clinical management for these women should be the same as those for women with an affected relative.
Subject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/genetics , Genetic Predisposition to Disease , Ovarian Neoplasms/genetics , Adult , Age Factors , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Female , Germ-Line Mutation , Heterozygote , Humans , Middle Aged , Mutation , Ovarian Neoplasms/pathology , Risk FactorsABSTRACT
BACKGROUND: This clinical practice guideline was developed to determine the level of evidence supporting the clinical utility of commercially available multigene profiling assays and to provide guidance about whether certain breast cancer patient populations in Ontario would benefit from alternative tests in addition to Oncotype dx (Genomic Health, Redwood City, CA, U.S.A.). METHODS: A systematic electronic Ovid search of the medline and embase databases sought out systematic reviews and primary literature. A systematic review and practice guideline was written by a working group and was then reviewed and approved by Cancer Care Ontario's Molecular Oncology Advisory Committee. RESULTS: Twenty-four studies assessing the clinical utility of Oncotype dx, Prosigna (NanoString Technologies, Seattle, WA, U.S.A.), EndoPredict (Myriad Genetics, Salt Lake City, U.S.A.), and MammaPrint (Agendia, Irvine, CA, U.S.A.) were included in the evidence base. CONCLUSIONS: The clinical utility of multigene profiling assays is currently established for an appropriate subset of patients with estrogen receptor-positive, her2-negative, node-negative breast cancer for whom a decision to give chemotherapy is difficult to make. For patients with estrogen receptor-positive tumours who receive tamoxifen alone, Oncotype dx, Prosigna, and EndoPredict validly identify a low-risk population with favourable outcomes, indicating that a low-risk assay result is actionable and the decision to withhold chemotherapy is supported. Clinical evidence indicates that a high Oncotype dx recurrence score can predict for chemotherapy benefit, but a high Prosigna or EndoPredict score, although prognostic, is not, based on clinical trial evidence, directly actionable. Prosigna and EndoPredict are statistically more likely to identify a population at risk for recurrence beyond 5 years, but that information is currently not actionable because of a lack of interventional studies.
ABSTRACT
Cimaglermin alfa (GGF2) is a recombinant human protein growth factor in development for heart failure. Phase I trials were suspended when two cimaglermin alfa-treated subjects experienced concomitant elevations in serum aminotransferases and total bilirubin, meeting current US Food and Drug Administration criteria for a serious liver safety signal (i.e., "Hy's Law"). We assayed mechanistic biomarkers in archived clinical trial serum samples which confirmed the hepatic origin of the aminotransferase elevations in these two subjects and identified apoptosis as the major mode of hepatocyte death. Using a mathematical model of drug-induced liver injury (DILIsym) and a simulated population, we estimated that the maximum hepatocyte loss in these two subjects was <13%, which would not result in liver dysfunction sufficient to significantly increase serum bilirubin levels. We conclude that the two subjects should not be considered Hy's Law cases and that mechanistic biomarkers and modeling can aid in refining liver safety risk assessment in clinical trials.
Subject(s)
Alanine Transaminase/blood , Bilirubin/blood , Clinical Trials as Topic , Liver/drug effects , Models, Statistical , Neuregulin-1/adverse effects , Risk Assessment/methods , Apoptosis , Biomarkers/blood , Humans , Liver/pathology , Recombinant Proteins/adverse effectsABSTRACT
In 2001, genetic testing for BRCA1 and BRCA2 was introduced in Ontario, for women at high-risk of breast or ovarian cancer. To date over 30,000 individuals have been tested throughout Ontario. Testing was offered to all Ontario residents who were eligible under any of 13 criteria. We report the results of tests conducted at Mount Sinai Hospital from 2007 to 2014. A total of 4726 individuals were tested, 764 (16.2%) were found to carry a pathogenic variant (mutation). Among 3684 women and men who underwent testing without a known familial BRCA mutation, 331 (9.0%) were found to carry a mutation. Among 1042 women and men tested for a known family mutation, 433 (41.6%) were positive. There were 603 female mutation carriers, of these, 303 were affected with breast or ovarian cancer (50%) and 16 with another cancer (2.3%). Of 284 unaffected female carriers, 242 (85%) were tested for a known family mutation and 42 (15%) were the first person in the family to be tested. By placing greater emphasis on recruiting unaffected female relatives of known mutation carriers for testing, greater than one-half of newly identified carriers will be unaffected.
Subject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Genetic Predisposition to Disease , Genetic Testing , Mutation , Adult , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Female , Humans , Male , Middle Aged , Ontario , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolismABSTRACT
BACKGROUND: This systematic review addresses the question "What is the optimal targeted therapy for female patients with early-stage human epidermal growth factor receptor 2 (her2)-positive breast cancer?" METHODS: The medline and embase databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major guideline organizations were also searched. RESULTS: Sixty publications relevant to the targeted therapy portion of the systematic review were identified. In four major trials (hera, National Surgical Adjuvant Breast and Bowel Project B-31, North Central Cancer Treatment Group N9831, and Breast Cancer International Research Group 006), adjuvant trastuzumab for 1 year was superior in disease-free survival (dfs) and overall survival (os) to no trastuzumab; trastuzumab showed no benefit in one trial (pacs 04). A shorter duration of trastuzumab (less than 1 year compared with 1 year) was evaluated, with mixed results for dfs: one trial showed superiority (finher), one trial could not demonstrate noninferiority (phare), another trial showed equivalent results (E 2198), and one trial is still ongoing (persephone). Longer trastuzumab duration (hera: 2 years vs. 1 year) showed no improvement in dfs or os and a higher rate of cardiac events. Newer her2-targeted agents (lapatinib, pertuzumab, T-DM1, neratinib) have been or are still being evaluated in both adjuvant and neoadjuvant trials, either by direct comparison with trastuzumab alone or combined with trastuzumab. In the neoadjuvant setting (neoaltto, GeparQuinto, Neosphere), trastuzumab alone or in combination with another anti-her2 agent (lapatinib, pertuzumab) was compared with either lapatinib or pertuzumab alone and showed superior or equivalent rates of pathologic complete response. In the adjuvant setting, lapatinib alone or in combination with trastuzumab, compared with trastuzumab alone (altto) or with placebo (teach), was not superior in dfs. The results of the completed aphinity trial, evaluating the role of dual her2 blockade with trastuzumab and pertuzumab, are highly anticipated. Ongoing trials are evaluating trastuzumab as a single agent without adjuvant chemotherapy (respect) and in patients with low her2 expression (National Surgical Adjuvant Breast and Bowel Project B-47). CONCLUSIONS: Taking into consideration disease characteristics and patient preference, 1 year of trastuzumab should be offered to all patients with her2-positive breast cancer who are receiving adjuvant chemotherapy. Cardiac function should be regularly assessed in this patient population.
ABSTRACT
The Breast Cancer Disease Site Group of Cancer Care Ontario identified the need for new guidelines for the adjuvant systemic therapy of early-stage breast cancer. The specific question to be addressed was "What is the optimal adjuvant systemic therapy for female patients with early-stage operable breast cancer, when patient and disease factors are considered?" A systematic review was prepared based on literature searches conducted using the medline and embase databases for the period January 2008 to March 5, 2012, and updated to May 12, 2014. Guidelines were located from that search, from the Standards and Guidelines Evidence directory of cancer guidelines, and from the Web sites of major guideline organizations. The literature located was subdivided into the broad categories of chemotherapy, hormonal therapy, and therapy targeted to her2 (human epidermal growth factor receptor 2). Although several of the systemic therapies discussed in this guideline can be considered in the neoadjuvant setting, the review focused on trials with rates of disease-free and overall survival as endpoints and thus excluded several trials that used pathologic complete response as a primary endpoint. Based on the systematic review, the working group drafted recommendations on the use of chemotherapy, hormonal therapy, and targeted therapy; based on their professional experience, they also drafted recommendations on patient and disease characteristics and recurrence risk. The literature review and draft recommendations were circulated to a consensus panel of medical oncologists who had expertise in breast cancer and who represented the regions of Ontario. Items without initial consensus were discussed at an in-person consensus meeting held in Toronto, November 23, 2012. The final recommendations are those for which consensus was reached before or at the meeting. Some of the key evidence was revised after the updated literature search. Evidence reviews for systemic chemotherapy, endocrine therapy, and targeted therapy for her2-positive disease are reported in separate articles in this supplement. The full three-part 1-21 evidence-based series, including complete details of the development and consensus processes, can be found on the Cancer Care Ontario Web site at https://www.cancercare.on.ca/toolbox/qualityguidelines/diseasesite/breast-ebs.
ABSTRACT
BACKGROUND: The Program in Evidence-Based Care (pebc) of Cancer Care Ontario recently created an evidence-based consensus guideline on the systemic treatment of early breast cancer. The evidence for the guideline was compiled using a systematic review to answer the question "What is the optimal systemic therapy for patients with early-stage, operable breast cancer, when patient and disease factors are considered?" The question was addressed in three parts: cytotoxic chemotherapy, endocrine treatment, and human epidermal growth factor receptor 2 (her2)-directed therapy. METHODS: For the systematic review, the medline and embase databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also searched. The basic search terms were "breast cancer" and "systemic therapy" (chemotherapy, endocrine therapy, targeted agents, ovarian suppression), and results were limited to randomized controlled trials (rcts), guidelines, systematic reviews, and meta-analyses. RESULTS: Several hundred documents that met the inclusion criteria were retrieved. The Early Breast Cancer Trialists' Collaborative Group meta-analyses encompassed many of the rcts found. Several additional studies that met the inclusion criteria were retained, as were other guidelines and systematic reviews. Chemotherapy was reviewed mainly in three classes: anti-metabolite-based regimens (for example, cyclophosphamide-methotrexate-5-fluorouracil), anthracyclines, and taxane-based regimens. In general, single-agent chemotherapy is not recommended for the adjuvant treatment of breast cancer in any patient population. Anthracycline-taxane-based polychemotherapy regimens are, overall, considered superior to earlier-generation regimens and have the most significant impact on patient survival outcomes. Regimens with varying anthracycline and taxane doses and schedules are options; in general, paclitaxel given every 3 weeks is inferior. Evidence does not support the use of bevacizumab in the adjuvant setting; other systemic therapy agents such as metformin and vaccines remain investigatory. Adjuvant bisphosphonates for menopausal women will be discussed in later work. CONCLUSIONS: The results of this systematic review constitute a comprehensive compilation of the high-level evidence that is the basis for the 2014 pebc guideline on systemic therapy for early breast cancer. Use of cytotoxic chemotherapy is presented here; the results addressing endocrine therapy and her2-targeted treatment, and the final clinical practice recommendations, are published separately in this supplement.