[Show abstract][Hide abstract] ABSTRACT: Background: Biomarkers that can be used to accurately assess the residual risk of disease recurrence in women with hormone receptor-positive breast cancer are clinically valuable. We evaluated the prognostic value of the Breast Cancer Index (BCI), a continuous risk index based on a combination of HOXB13:IL17BR and molecular grade index, in women with early breast cancer treated with either tamoxifen alone or tamoxifen plus octreotide in the NCIC MA.14 phase III clinical trial (ClinicalTrials.gov Identifier NCT00002864; registered 1 November 1999). Methods: Gene expression analysis of BCI by real-time polymerase chain reaction was performed blinded to outcome on RNA extracted from archived formalin-fixed, paraffin-embedded tumor samples of 299 patients with both lymph node-negative (LN-) and lymph node-positive (LN+) disease enrolled in the MA.14 trial. Our primary objective was to determine the prognostic performance of BCI based on relapse-free survival (RFS). MA.14 patients experienced similar RFS on both treatment arms. Association of gene expression data with RFS was evaluated in univariate analysis with a stratified log-rank test statistic, depicted with a Kaplan-Meier plot and an adjusted Cox survivor plot. In the multivariate assessment, we used stratified Cox regression. The prognostic performance of an emerging, optimized linear BCI model was also assessed in a post hoc analysis. Results: Of 299 samples, 292 were assessed successfully for BCI for 146 patients accrued in each MA.14 treatment arm. BCI risk groups had a significant univariate association with RFS (stratified log-rank p = 0.005, unstratified log-rank p = 0.007). Adjusted 10-year RFS in BCI low-, intermediate-, and high-risk groups was 87.5%, 83.9%, and 74.7%, respectively. BCI had a significant prognostic effect [hazard ratio (HR) 2.34, 95% confidence interval (CI) 1.33-4.11; p = 0.004], although not a predictive effect, on RFS in stratified multivariate analysis, adjusted for pathological tumor stage (HR 2.22, 95% CI 1.22-4.07; p = 0.01). In the post hoc multivariate analysis, higher linear BCI was associated with shorter RFS (p = 0.002). Conclusions: BCI had a strong prognostic effect on RFS in patients with early-stage breast cancer treated with tamoxifen alone or with tamoxifen and octreotide. BCI was prognostic in both LN- and LN+ patients. This retrospective study is an independent validation of the prognostic performance of BCI in a prospective trial.
Full-text · Article · Dec 2016 · Breast cancer research: BCR
[Show abstract][Hide abstract] ABSTRACT: In resource-constrained environments many patients with human epidermal growth factor receptor 2 (HER2)+ early breast cancer are currently not offered adjuvant anti-HER2 therapy. For patients who might be able to receive the tyrosine kinase inhibitor (TKI) lapatinib (e.g. after patent expiration), it is important to identify subgroups of patients for whom anti-HER2 TKI therapy could be beneficial. To do this, we used data from 2489 patients with centrally confirmed HER2+ disease enrolled in the adjuvant Tykerb Evaluation After Chemotherapy (TEACH) trial, investigating the effect of lapatinib in patients with HER2+ early breast cancer not treated with trastuzumab. We performed subgroup analyses and number-needed-to-treat (NNT) calculations using patient and tumour associated predictors. Hormone receptor negative (HR-) patients on lapatinib had a significantly prolonged disease-free survival (DFS) compared to HR- patients on placebo (hazard ratio 0.64, P=0.003). For patients with HR- disease, starting treatment with lapatinib ≤1 year from diagnosis improved DFS by 12.1% [2.1-22.1] at 2 years and 15.7% [4.1-27.2] at 5 years. Depending on lymph node status and time since diagnosis the NNT for recurrence (at 5 years) was between 5.9 (node positive patients <1 year from diagnosis) and 15.9. These numbers are in range with numbers reported for up-front adjuvant trastuzumab for HR unselected patients (e.g. 15.6 for DFS at 4 years in HERA). In a subgroup analysis of the adjuvant TEACH trial, we show that anti-HER2 monotherapy with a TKI is beneficial as adjuvant therapy in a subgroup of patients. NNT in HER2+ HR- patients are in range with those reported from up-front adjuvant trastuzumab trials.
No preview · Article · Mar 2016 · European journal of cancer (Oxford, England: 1990)
[Show abstract][Hide abstract] ABSTRACT: Asia is the world's largest continent comprising about 3/5 of the human population. Breast cancer is the most common type of cancer and the second leading cause of cancer-related deaths among women in Asia, accounting for 39% of all breast cancers diagnosed worldwide. The incidence of breast cancer in Asia varies widely across the continent and is still lower than in Western countries, but the proportional contribution of Asia to the global breast cancer rates is increasing rapidly in parallel to the socioeconomic development. However, the mortality-to-incidence ratios are much higher for Asia than for Western countries. Most Asian countries are low- and middle-income countries (LMICs) where breast cancer presents at a younger age and a later stage, and where patients are more likely to die from the disease than those in Western countries. Moreover, diagnostic workup, treatment and palliative services are inadequate in most Asian LMICs. In this review, we present an overview of the breast cancer risk factors and epidemiology, control measures, and cancer care among Asian countries.
[Show abstract][Hide abstract] ABSTRACT: Cancer is one of the leading causes of mortality worldwide, and an increasing threat in low-income and middle-income countries. Our findings in the 2013 Commission in The Lancet Oncology showed several discrepancies between the cancer landscape in Latin America and more developed countries. We reported that funding for health care was a small percentage of national gross domestic product and the percentage of health-care funds diverted to cancer care was even lower. Funds, insurance coverage, doctors, health-care workers, resources, and equipment were also very inequitably distributed between and within countries. We reported that a scarcity of cancer registries hampered the design of credible cancer plans, including initiatives for primary prevention. When we were commissioned by The Lancet Oncology to write an update to our report, we were sceptical that we would uncover much change. To our surprise and gratification much progress has been made in this short time. We are pleased to highlight structural reforms in health-care systems, new programmes for disenfranchised populations, expansion of cancer registries and cancer plans, and implementation of policies to improve primary cancer prevention.
Full-text · Article · Oct 2015 · The Lancet Oncology
[Show abstract][Hide abstract] ABSTRACT: Rash is a common side effect of lapatinib treatment. Since human leukocyte antigen (HLA) alleles have been implicated in multiple drug-induced cutaneous reactions, this study investigated the association of HLA alleles with lapatinib-induced rash. 1191 participants from a large lapatinib monotherapy trial underwent HLA genotyping, and allele carriage frequencies between rash cases and controls were compared. This analysis had adequate power to detect an association of common HLA alleles with rash, similar to those reported previously. No HLA alleles were significantly associated with lapatinib-induced rash, including the previously identified lapatinib hepatotoxicity biomarker HLA-DRB1*07:01 (p = 0.87). The present study is consistent with the view that lapatinib-induced rash is not the consequence of HLA-restricted, immune-mediated mechanisms.
No preview · Article · Aug 2015 · Pharmacogenomics
[Show abstract][Hide abstract] ABSTRACT: Worldwide, many patients with HER2+ (human epidermal growth factor receptor 2) early breast cancer (BC) do not receive adjuvant trastuzumab. Hazards of recurrence of these patients with respect to hormone receptor status of the primary tumor have not been described.
Using data from 1,260 patients randomized to placebo in the adjuvant TEACH trial, we report 10-year annual hazards of recurrence in HER2+ patients not treated with anti-HER2 therapy.
Disease-free survival (DFS) was 75% after 5 and 61% after 10 years, respectively. Patients with HER2+ hormone receptor positive (HR+ (hormone receptor positive); ER+ (estrogen receptor positive) or PR+ (progesterone receptor positive)) disease had a significantly better DFS than patients with HER2 + HR- (ER-/PR-) disease (hazard ratio 0.72, P = 0.02). This difference was explainable by a significantly higher hazard of recurrence in years 1-5 in HER2 + HR- compared to HER2 + HR+ patients, with a mean risk of recurrence of 9%/year for HR- versus 5%/years in HR+ patients (hazard ratio 0.59, P = 0.002 for years 1-5). The high early risk of recurrence of HER2 + HR- patients declined sharply over time, so that it was similar to that seen in HER2 + HR+ patients in years 6-10 (hazard ratio 0.97, P = 0.92 for years 6-10).
Our results show that outcomes in HER2+ patients with early BC not receiving anti-HER2 therapy strongly depend on HR expression. The very high early risk of relapse seen in HER2 + HR- patients is particularly relevant in health care settings with limited access to adjuvant anti-HER2 treatment. The event rates shown for subpopulations of HER2+ BC patients suggest that in resource-constrained environments patients with HER2 + HR- early BC should be prioritized for consideration of adjuvant anti-HER2 therapy.
No preview · Article · Apr 2015 · Breast cancer research: BCR
[Show abstract][Hide abstract] ABSTRACT: Breast cancer (BC) has been associated with pregnancy if diagnosed within 5-10 years after delivery (pregnancy-associated BC, PABC). PABC carries a poor prognosis compared to sporadic BC in Western populations. Data are limited regarding PABC in Asian populations, where longer periods of breastfeeding, higher birth rates and a lower median age of BC at diagnosis have been noted, all of which are known to influence prognosis. We used two datasets of women treated for early BC in Shanghai 1990-2012 (n = 10,161 and n = 7,411). For the analysis of BC risk after pregnancy we compared the distribution of pregnancy in our dataset to that in Shanghai using age-specific fertility rates. For disease-free survival (DFS) evaluation, we restricted our data to women ≤45 years. Women <30 years had a significantly elevated BC risk within 5 years of completing a pregnancy compared to women who had not been pregnant in the previous 5 years. In women aged 20-24 the relative risk (RR) was 3.33 (P = 0.012), and for women aged 25-29 the RR was 1.76 (P = 0.0074). For women >30, the RR was decreased. Patients with PABC had a higher risk of recurrence or death (hazard ratio (HR) for DFS 1.72, P = 0.019) compared to women with non-PABC by univariable analysis. Age was eliminated from the multivariable model by backward selection, resulting in tumor stage (3 versus 1, HR 3.08, P < .001) and recent pregnancy (HR 1.62, P < 0.05) as significant independent prognosticators. Having had a full-term pregnancy in the previous 5 years was associated with a 62 % increased risk of recurrence. We show that recent full-term pregnancy significantly elevates BC risk in women <30 in Shanghai, and that women diagnosed with PABC have a particularly adverse prognosis. Health care providers and women in Asian populations should be made aware of these results.
Full-text · Article · Dec 2014 · Breast Cancer Research and Treatment
[Show abstract][Hide abstract] ABSTRACT: To show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death.
MA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years of octreotide 90 mg, given by depot intramuscular injections monthly. Event-free survival was the primary endpoint of MA.14; at median 7.9 years, the tamoxifen+octreotide and tamoxifen arms had similar event-free survival (P = 0.62). Overall survival was a secondary endpoint, and the two trial arms also had similar overall survival (P = 0.86). We used the median 9.8 years follow-up to examine by intention-to-treat, the multivariate time-to-breast cancer-specific (BrCa) and other cause (OC) mortality with log-normal survival analysis adjusted by treatment and stratification factors. We tested whether baseline factors including Insulin-like growth factor 1 (IGF1), IGF binding protein-3, C-peptide, body mass index, and 25-hydroxy vitamin D were associated with (1) all cause mortality, and if so and (2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models.
The analyses were performed on 329 patients allocated tamoxifen and 329 allocated tamoxifen+octreotide. The median age of MA.14 patients was 60.1 years: 447 (82%) < 70 years and 120 (18%) ≥ 70 years. There were 170 deaths: 106 (62.3%) BrCa; 55 (32.4%) OC, of which 24 were other malignancies, 31 other causes of death; 9 (5.3%) patients with unknown cause of death were excluded from competing risk assessments. BrCa and OC deaths were not significantly different by treatment arm (P = 0.40): tamoxifen patients experienced 50 BrCa and 32 OC deaths, while tamoxifen + octreotide patients experienced 56 BrCa and 23 OC deaths. Proportionately more deaths (P = 0.004) were from BrCa for patients < 70 years, where 70% of deaths were due to BrCa, compared to 54% for those ≥ 70 years of age. The proportion of deaths from OC increased with increasing body mass index (BMI) (P = 0.02). Higher pathologic T and N were associated with more BrCa deaths (P < 0.0001 and 0.002, respectively). The cumulative hazard plot for BrCa and OC mortality indicated the concurrent accrual of both types of death throughout follow-up, that is the existence of competing risks of mortality. MA.14 therapy did not impact mortality (P = 0.77). Three baseline patient and tumor characteristics were differentially associated with cause of death: older patients experienced more OC (P = 0.01) mortality; patients with T1 tumors and hormone receptor positive tumors had less BrCa mortality (respectively, P = 0.01, P = 0.06). Additionally, step-wise cause-specific models indicated that patients with node negative disease experienced less BrCa mortality (P = 0.002); there was weak evidence that, lower C-peptide (P = 0.08) was associated with less BrCa mortality, while higher BMI (P = 0.01) was associated with worse OC mortality.
We demonstrate here a new paradigm of simultaneous testing of therapeutics directed at multiple diseases for which postmenopausal women are concurrently at risk. Octreotide LAR did not significantly impact breast cancer or other cause mortality, although different baseline factors influenced type of death.
[Show abstract][Hide abstract] ABSTRACT: Despite recently implemented access to care programs, Mexican breast cancer (BC) mortality rates remain substantially above those in the US. We conducted a survey among Mexican Oncologists to determine whether practice patterns may be responsible for these differences.
A web-based survey was sent to 851 oncologists across Mexico using the Vanderbilt University REDCap database. Analyses of outcomes are reported using exact and binomial confidence bounds and tests.
138 participants (18.6% of those surveyed) from the National capital and 26 Mexican states, responded. Respondents reported that 58% of newly diagnosed BC patients present with stage III-IV disease; 63% undergo mastectomy, 52% axillary lymph node dissection (ALND) and 48% sentinel lymph node biopsy (SLNB). Chemotherapy is recommended for tumors > 1 cm (89%), positive nodes (86.5%), triple-negative (TN) (80%) and HER2 positive tumors (58%). Trastuzumab is prescribed in 54.3% and 77.5% for HER2 < 1 cm and > 1 cm tumors, respectively. Tamoxifen is indicated for premenopausal hormone receptor (HR) positive tumors in 86.5% of cases and aromatase inhibitors (AI’s) for postmenopausal in 86%. 24% of physicians reported treatment limitations, due to delayed or incomplete pathology reports and delayed or limited access to medications.
Even though access to care programs have been recently applied nationwide, women commonly present with advanced BC, leading to increased rates of mastectomy and ALND. Mexican physicians are dissatisfied with access to appropriate medical care. Our survey detects specific barriers that may impact BC outcomes in Mexico and warrant further investigation.
[Show abstract][Hide abstract] ABSTRACT: Bone fractures are a major consequence of osteoporosis. There is a direct relationship between serum estrogen concentrations and osteoporosis risk. Aromatase inhibitors (AIs) greatly decrease serum estrogen levels in postmenopausal women, and increased incidence of fractures is a side effect of AI therapy. We performed a discovery case-cohort genome-wide association study (GWAS) using samples from 1071 patients, 231 cases and 840 controls, enrolled in the MA.27 breast cancer AI trial to identify genetic factors involved in AI-related fractures, followed by functional genomic validation. Association analyses identified 20 GWAS SNP signals with p<5E-06. After removal of signals in gene deserts and those composed entirely of imputed SNPs, we applied a functional validation "decision cascade" that resulted in validation of the CTSZ-SLMO2-ATP5E, TRAM2-TMEM14A and MAP4K4 genes. These genes all displayed estradiol (E2)-dependent induction in human fetal osteoblasts transfected with estrogen receptor (ER)α and their knockdown altered the expression of known osteoporosis-related genes. These same genes also displayed SNP-dependent variation in E2 induction that paralleled the SNP-dependent induction of known osteoporosis genes such as osteoprotegerin (OPG). In summary, our case-cohort GWAS identified SNPs in or near CTSZ-SLMO2-ATP5E, TRAM2-TMEM14A and MAP4K4 that were associated with risk for bone fracture in ER-positive breast cancer patients treated with AIs. These genes displayed E2-dependent induction; their knockdown altered the expression of genes related to osteoporosis; and they displayed SNP genotype dependent variation in E2 induction. These observations may lead to the identification of novel mechanisms associated with fracture risk in postmenopausal women treated with AIs.
No preview · Article · Aug 2014 · Molecular Endocrinology
[Show abstract][Hide abstract] ABSTRACT: The health burden of cancer is increasing in China, with more than 1·6 million people being diagnosed and 1·2 million people dying of the disease each year. As in most other countries, breast cancer is now the most common cancer in Chinese women; cases in China account for 12·2% of all newly diagnosed breast cancers and 9·6% of all deaths from breast cancer worldwide. China's proportional contribution to global rates is increasing rapidly because of the population's rising socioeconomic status and unique reproductive patterns. In this Review we present an overview of present control measures for breast cancer across China, and emphasise epidemiological and socioeconomic diversities and disparities in access to care for various subpopulations. We describe demographic differences between China and high-income countries, and also within geographical and socioeconomic regions of China. These disparities between China and high-income countries include younger age at onset of breast cancer; the unique one-child policy; lower rates of provision and uptake for screening for breast cancer; delays in diagnosis that result in more advanced stage of disease at presentation; inadequate resources; and a lack of awareness about breast cancer in the Chinese population. Finally, we recommend key measures that could contribute to improved health outcomes for patients with breast cancer in China.
No preview · Article · Jun 2014 · The Lancet Oncology