Paul E Goss

Massachusetts General Hospital, Boston, Massachusetts, United States

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Publications (137)1324.04 Total impact

  • Cancer Research 05/2015; 75(9 Supplement):P4-11-19-P4-11-19. DOI:10.1158/1538-7445.SABCS14-P4-11-19 · 9.28 Impact Factor
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    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.
    Breast cancer research: BCR 04/2015; 17(1):56. DOI:10.1186/s13058-015-0568-1 · 5.88 Impact Factor
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    ABSTRACT: The identification of patients with metastatic triple-negative breast cancer (mTNBC) who are expected to benefit from platinum-based chemotherapy is of interest. We conducted a single-arm phase II clinical trial of single-agent platinum for mTNBC with biomarker correlates. Patients with mTNBC received first- or second-line cisplatin (75 mg/m(2)) or carboplatin (area under the concentration-time curve 6) by physician's choice once every 3 weeks. Coprimary end points were objective response rate (RR) and response prediction by p63/p73 gene expression. Secondary and exploratory end points included toxicity assessment, RR in cisplatin versus carboplatin, and RR in molecularly defined subgroups, including BRCA1/2 mutation carriers. Patients (N = 86; 69 as first-line therapy) received cisplatin (n = 43) or carboplatin (n = 43). RR was 25.6% (95% CI, 16.8% to 36%) and was numerically higher with cisplatin (32.6%) than with carboplatin (18.7%). RR was 54.5% in patients with germline BRCA1/2 mutations (n = 11). In patients without BRCA1/2 mutations (n = 66), exploratory analyses showed that a BRCA-like genomic instability signature (n = 32) discriminated responding and nonresponding tumors (mean homologous recombination deficiency-loss of heterozygosity/homologous recombination deficiency-large-scale state transitions [HRD-LOH/HRD-LST] scores were 12.68 and 5.11, respectively), whereas predefined analysis by p63/p73 expression status (n = 61), p53 and PIK3CA mutation status (n = 53), or PAM50 gene expression subtype (n = 55) did not. Five of the six long-term responders alive at a median of 4.5 years lacked germline BRCA1/2 mutations, and two of them had increased tumor HRD-LOH/HRD-LST scores. Platinum agents are active in mTNBC, especially in patients with germline BRCA1/2 mutations. A measure of tumor DNA repair function may identify patients without mutations who could benefit from platinum therapy agents. Prospective controlled confirmatory trials are warranted. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 04/2015; 33(17). DOI:10.1200/JCO.2014.57.6660 · 18.43 Impact Factor
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    ABSTRACT: To evaluate health related quality of life (HRQOL) in TEACH, a phase III randomized placebo controlled trial of 12months of adjuvant lapatinib in HER2 positive (HER2+) early breast cancer which demonstrated marginal benefit in disease-free survival. Women on TEACH completed the Short Form 36-item health survey (version2; SF-36v2) at the baseline, six and 12months after therapy initiation and six monthly thereafter. Mean changes were compared between treatment groups for two summary measures (Physical and Mental Component Summary scores; PCS and MCS) and eight domain measures (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health), and in patients discontinuing therapy. A five-point change was deemed a Minimally Clinically Important Difference (MCID). Response analysis compared the proportion of patients demonstrating a MCID in HRQOL, and a regression analysis identified predictors of worsening HRQOL. 3074 (97%) subjects completed baseline SF-36v2. During the initial 12months, summary SF-36v2 scores decreased in both arms but did not reach Minimally Clinically Important Difference (MCID) despite significant incidences of diarrhoea and rash in lapatinib treated patients. At six months, women receiving lapatinib had more significant reductions (p<0.01 versus placebo) in social functioning. Early treatment discontinuations were more frequent on lapatinib (32% versus 18%), and were associated with more substantial decrements of HRQOL in both arms. For those discontinuing primarily due to adverse events, decrements in HRQOL reached MCID in Mental Summary scores (MCS) only. Lower baseline HRQOL was a significant predictor of worsening HRQOL (p<0.05). Despite frequent but usually mild toxicities, adjuvant lapatinib is not associated with clinically significant decreases in overall HRQOL. These placebo-controlled results may also help to inform physicians and patients using lapatinib in metastatic HER2 positive breast cancer. GlaxoSmithKline. The AVON Foundation NY supported PEG, DF and BM and The Friends of the Mater Foundation supported FB. Copyright © 2015 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 03/2015; 51(6). DOI:10.1016/j.ejca.2015.02.005 · 4.82 Impact Factor
  • Paul E Goss
    Clinical advances in hematology & oncology: H&O 01/2015; 13(1):20-22.
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    ABSTRACT: Treatment-emergent symptoms with adjuvant tamoxifen and aromatase inhibitors (AIs) have been associated with superior recurrence-free survival (RFS). We hypothesized that MA.27 anastrozole- or exemestane-treated patients with new or worsening vasomotor and/or joint symptoms would have improved RFS. MA.27 randomly assigned 7,576 postmenopausal women with breast cancer to 5 years of anastrozole or exemestane. Patient-reported symptoms were collected using the Common Terminology Criteria for Adverse Events version 3.0 at protocol-specified baseline and 6- and 12-month clinical visits. Symptoms were considered present with either vasomotor and/or joint complaints. Associations between symptoms and baseline patient characteristics were examined with χ(2) and Fisher's exact tests. Subsequent effects of new or worsening symptoms on RFS were examined with landmark analyses and stratified univariable and multivariable Cox models. We examined the effects of 3-month symptoms arising from unplanned clinic visits as a result of severe toxicity. Patients were assessable if eligible for the MA.27 trial, received some trial therapy, and had no disease recurrence at the end of a symptom assessment period; 96% of patients (n = 7,306 patients) were included at 6 months, and 96% (n = 7,246) were included at 12 months. Thirty-four percent of patients had baseline symptoms. For patients without baseline symptoms, 25% and 52% had new symptoms by 6 and 12 months, respectively. Neither treatment-emergent nor baseline symptoms significantly impacted RFS (P > .10) in patients with or without baseline symptoms. In MA.27, anastrozole or exemestane treatment-emergent symptoms were not associated with improved RFS. Women should be supported through treatment and encouraged to remain on their AI regardless of their symptoms. © 2014 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 12/2014; 33(3). DOI:10.1200/JCO.2014.57.6926 · 18.43 Impact Factor
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    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.
    Breast Cancer Research and Treatment 12/2014; 149(1). DOI:10.1007/s10549-014-3219-9 · 4.20 Impact Factor
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    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.
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    ABSTRACT: Background 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. Methods 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-658) contains supplementary material, which is available to authorized users.
    BMC Cancer 09/2014; 14(1):658. DOI:10.1186/1471-2407-14-658 · 3.32 Impact Factor
  • Journal of Clinical Oncology 08/2014; 32(33). DOI:10.1200/JCO.2014.57.9235 · 18.43 Impact Factor
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    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.
    Molecular Endocrinology 08/2014; DOI:10.1210/me.2014-1147 · 4.20 Impact Factor
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    ABSTRACT: Cancer is one of the major non-communicable diseases posing a threat to world health. Unfortunately, improvements in socioeconomic conditions are usually associated with increased cancer incidence. In this Commission, we focus on China, India, and Russia, which share rapidly rising cancer incidence and have cancer mortality rates that are nearly twice as high as in the UK or the USA, vast geographies, growing economies, ageing populations, increasingly westernised lifestyles, relatively disenfranchised subpopulations, serious contamination of the environment, and uncontrolled cancer-causing communicable infections. We describe the overall state of health and cancer control in each country and additional specifi c issues for consideration: for China, access to care, contamination of the environment, and cancer fatalism and traditional medicine; for India, aff ordability of care, provision of adequate health personnel, and sociocultural barriers to cancer control; and for Russia, monitoring of the burden of cancer, societal attitudes towards cancer prevention, eff ects of inequitable treatment and access to medicine, and a need for improved international engagement.
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    ABSTRACT: Exemestane, a steroidal aromatase inhibitor, reduced invasive breast cancer incidence by 65% among 4,560 postmenopausal women randomly assigned to exemestane (25 mg per day) compared with placebo in the National Cancer Institute of Canada (NCIC) Clinical Trials Group MAP.3 (Mammary Prevention 3) trial, but effects on quality of life (QOL) were not fully described. Menopause-specific and health-related QOL were assessed by using the four Menopause-Specific Quality of Life Questionnaire (MENQOL) domains and the eight Medical Outcomes Study Short Form Health Survey (SF-36) scales at baseline, 6 months, and yearly thereafter. MENQOL questionnaire completion was high (88% to 98%) in both groups at each follow-up visit. Change scores for each MENQOL and SF-36 scale, calculated at each assessment time relative to baseline, were compared by using the Wilcoxon rank-sum test. Clinically important worsened QOL was defined as a MENQOL change score increase of more than 0.5 (of 8) points and an SF-36 change score decrease of more than 5 (of 100) points from baseline. Exemestane had small negative effects on women's self-reported vasomotor symptoms, sexual symptoms, and pain, which occurred mainly in the first 6 months to 2 years after random assignment. However, these changes represented only a small excess number of women being given exemestane with clinically important worsening of QOL at one time or another; specifically, 8% more in the vasomotor domain and 4% more each in the sexual domain and for pain. No other between-group differences were observed. Overall, slightly more women in the exemestane arm (32%) than in the placebo arm (28%) discontinued assigned treatment. Exemestane given for prevention has limited negative impact on menopause-specific and health-related QOL in healthy postmenopausal women at risk for breast cancer.
    Journal of Clinical Oncology 04/2014; 32(14). DOI:10.1200/JCO.2013.51.2483 · 18.43 Impact Factor
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    ABSTRACT: Cancer is one of the major non-communicable diseases posing a threat to world health. Unfortunately, improvements in socioeconomic conditions are usually associated with increased cancer incidence. In this Commission, we focus on China, India, and Russia, which share rapidly rising cancer incidence and have cancer mortality rates that are nearly twice as high as in the UK or the USA, vast geographies, growing economies, ageing populations, increasingly westernised lifestyles, relatively disenfranchised subpopulations, serious contamination of the environment, and uncontrolled cancer-causing communicable infections. We describe the overall state of health and cancer control in each country and additional specific issues for consideration: for China, access to care, contamination of the environment, and cancer fatalism and traditional medicine; for India, affordability of care, provision of adequate health personnel, and sociocultural barriers to cancer control; and for Russia, monitoring of the burden of cancer, societal attitudes towards cancer prevention, effects of inequitable treatment and access to medicine, and a need for improved international engagement.
    The Lancet Oncology 04/2014; 15(5):489-538. DOI:10.1016/S1470-2045(14)70029-4 · 24.73 Impact Factor
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    ABSTRACT: Liver injury is a serious adverse event leading to permanent discontinuation of lapatinib in affected patients. This study aimed to validate previously associated major histocompatibility complex (MHC) variants as predictors of risk of liver injury by using a large, randomized, placebo-controlled trial of lapatinib in human epidermal growth factor receptor 2-positive, early-stage breast cancer (Tykerb Evaluation After Chemotherapy [TEACH]: Lapatinib Versus Placebo In Women With Early-Stage Breast Cancer). The frequency of ALT elevation cases was compared among four MHC variants in 1,194 patients randomly assigned to lapatinib. Cumulative ALT elevation time courses during treatment were also compared between carriers and noncarriers of specified MHC variants. In lapatinib-treated patients, there was a significant difference in ALT case incidence between HLA carriers and noncarriers. The highly correlated alleles HLA-DRB1*07:01 and HLA-DQA1*02:01 (study frequency, 22.4%) were associated with ALT elevation (odds ratio, 14) between cases (n = 37) and controls (n = 1,071). These associations strengthened at higher ALT elevation thresholds and in Hy's Law cases. In lapatinib-treated patients, the overall risk for National Cancer Institute-Common Terminology Criteria for Adverse Events grade 3 ALT elevation (> 5× upper limit of normal) was 2.1%; HLA allele carriers had an increased risk of 7.7%; in noncarriers, risk was reduced to 0.5%, comparable to ALT elevation for all patients receiving placebo. The increase in ALT case incidence in the lapatinib arm showed no evidence of plateau during 1 year of lapatinib treatment. These results validate HLA-DRB1*07:01 allele carriage as a predictor of increased risk of lapatinib-induced liver injury and implicate an immune pathology. The HLA association could support clinical management of patients experiencing hepatotoxicity during lapatinib treatment.
    Journal of Clinical Oncology 03/2014; 32(22). DOI:10.1200/JCO.2013.52.9867 · 18.43 Impact Factor
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    ABSTRACT: Bosutinib is an oral, selective Src/Abl tyrosine kinase inhibitor with activity in breast cancer (BC). We evaluated bosutinib plus exemestane as second-line therapy in previously treated hormone receptor-positive (HR+) locally advanced or metastatic BC.Methods.This was a phase II study with patients enrolled in a single-arm safety lead-in phase. Patients receiving bosutinib at 400 mg or 300 mg/day (based on toxicity) plus exemestane at 25 mg/day were monitored for adverse events (AEs) and dose-limiting toxicities for 28 days, and initial efficacy was assessed. After the lead-in and dose-determination phase, randomized evaluation of combination therapy versus exemestane was planned.Results.Thirty-nine of 42 patients (93%) experienced treatment-related AEs including diarrhea in 28 (67%) and hepatotoxicity in 11 (26%); overall serious treatment-related AEs were recorded in 4 (10%). No liver toxicity met Hy's law criteria. Dose-limiting toxicities occurred in 5 of 13 patients receiving 400 mg (38%) and 3 of 26 patients receiving 300 mg (12%) of bosutinib; all resolved on treatment discontinuation. One patient (300 mg/day) achieved confirmed partial response; three (400 mg/day, n = 2; 300 mg/day, n = 1) maintained stable disease for >24 weeks; a best response of progressive disease occurred in 15 of 42 patients (36%). Median progression-free survival was 12.3 weeks (80% confidence interval: 11.0-15.6).Conclusion.The risk-benefit profile of bosutinib at 300 mg/day plus exemestane resulted in early study termination before the randomized portion. Alternative bosutinib regimens merit investigation in BC.
    The Oncologist 03/2014; 19(4). DOI:10.1634/theoncologist.2014-0022 · 4.54 Impact Factor
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    ABSTRACT: Endocrine therapy resistance in hormone receptor-positive (HR+) breast cancer (BC) may involve crosstalk between HRs and growth factor signaling pathways. We evaluated bosutinib, a dual Src/Abl tyrosine kinase inhibitor that has previously demonstrated some antitumor activity in BC, plus letrozole as first-line endocrine therapy in locally advanced or metastatic HR+/HER2- BC.Methods.Sixteen postmenopausal women were enrolled in a phase II study evaluating the safety/efficacy of bosutinib plus letrozole. In the single-arm safety/dose-confirming lead-in (part 1), patients received oral bosutinib at 400 mg/day plus letrozole at 2.5 mg/day; adverse events (AEs) and dose-limiting toxicities (DLTs) were monitored, and initial efficacy was assessed. A randomized efficacy/safety phase (part 2) was planned to evaluate the combination versus letrozole monotherapy.Results.Fifteen of 16 subjects experienced treatment-related AEs, most commonly diarrhea (69%). Treatment-related hepatotoxicity AEs (primarily alanine aminotransferase [ALT] or aspartate aminotransferase [AST] elevations) occurred in 6 of 16 patients (38%). Four of 15 evaluable patients (27%) experienced a DLT (grade 3/4 ALT/AST elevations, n = 2; grade 3 rash, n = 1; grade 3 diarrhea or vomiting, n = 1), including 1 Hy's law hepatotoxicity case. All DLTs resolved following treatment discontinuation. One patient achieved confirmed partial response; one had stable disease for >24 weeks. Study termination occurred before part 2.Conclusion.The unfavorable risk-benefit ratio did not warrant further investigation of bosutinib plus letrozole.
    The Oncologist 03/2014; 19(4). DOI:10.1634/theoncologist.2014-0021 · 4.54 Impact Factor
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    ABSTRACT: Treatment of breast cancer with aromatase inhibitors is associated with damage to bones. NCIC CTG MA.27 was an open-label, phase 3, randomised controlled trial in which women with breast cancer were assigned to one of two adjuvant oral aromatase inhibitors-exemestane or anastrozole. We postulated that exemestane-a mildly androgenic steroid-might have a less detrimental effect on bone than non-steroidal anastrozole. In this companion study to MA.27, we compared changes in bone mineral density (BMD) in the lumbar spine and total hip between patients treated with exemestane and patients treated with anastrozole. In MA.27, postmenopausal women with early stage hormone (oestrogen) receptor-positive invasive breast cancer were randomly assigned to exemestane 25 mg versus anastrozole 1 mg, daily. MA.27B recruited two groups of women from MA.27: those with BMD T-scores of -2·0 or more (up to 2 SDs below sex-matched, young adult mean) and those with at least one T-score (hip or spine) less than -2·0. Both groups received vitamin D and calcium; those with baseline T-scores of less than -2·0 also received bisphosphonates. The primary endpoints were percent change of BMD at 2 years in lumbar spine and total hip for both groups. We analysed patients according to which aromatase inhibitor and T-score groups they were allocated to but BMD assessments ceased if patients deviated from protocol. This study is registered with ClinicalTrials.gov, NCT00354302. Between April 24, 2006, and May 30, 2008, 300 patients with baseline T-scores of -2·0 or more were accrued (147 allocated exemestane, 153 anastrozole); and 197 patients with baseline T-scores of less than -2·0 (101 exemestane, 96 anastrozole). For patients with T-scores greater than -2·0 at baseline, mean change of bone mineral density in the spine at 2 years did not differ significantly between patients taking exemestane and patients taking anastrozole (-0·92%, 95% CI -2·35 to 0·50 vs -2·39%, 95% CI -3·77 to -1·01; p=0·08). Respective mean loss in the hip was -1·93% (95% CI -2·93 to -0·93) versus -2·71% (95% CI -4·32 to -1·11; p=0·10). Likewise for those who started with T-scores of less than -2·0, mean change of spine bone mineral density at 2 years did not differ significantly between the exemestane and anastrozole treatment groups (2·11%, 95% CI -0·84 to 5·06 vs 3·72%, 95% CI 1·54 to 5·89; p=0·26), nor did hip bone mineral density (2·09%, 95% CI -1·45 to 5·63 vs 0·0%, 95% CI -3·67 to 3·66; p=0·28). Patients with baseline T-score of -2·0 or more taking exemestane had two fragility fractures and two other fractures, those taking anastrozole had three fragility fractures and five other fractures. For patients who had baseline T-scores of less than -2·0 taking exemestane, one had a fragility fracture and four had other fractures, whereas those taking anastrozole had five fragility fractures and one other fracture. Our results demonstrate that adjuvant treatment with aromatase inhibitors can be considered for breast cancer patients who have T-scores less than -2·0. Canadian Cancer Society Research Institute, Pfizer, Canadian Institutes of Health Research.
    The Lancet Oncology 03/2014; 15(4). DOI:10.1016/S1470-2045(14)70035-X · 24.73 Impact Factor
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    ABSTRACT: Background Breast cancer is the most common malignancy in women in Brazil. Differences between patients with public versus private health care coverage regarding general characteristics, disease presentation, treatment of primary tumors, and clinical outcomes have not been fully investigated. Methods A national, retrospective cohort of 3142 patients drawn from a representative sample of Brazilian medical centers was selected. Clinical and demographic data and type of health care coverage were retrieved by chart review. Groups were compared using the Chi-square test. The log-rank test was used for comparison of disease-free survival, post-relapse and overall survival. Multivariate Cox regression modeling with adjustment for patient characteristics and stage at diagnosis was performed. All p-values are two sided. Results Patients with public health coverage presented with more advanced disease at diagnosis (p<0.001). Disease-free survival and overall survival for patients presenting with stage 0-II disease did not differ according to type of health care coverage while a significant difference in outcomes was seen for stage III-IV patients (p=0.002 and p=0.008, respectively). In a Cox multivariate analysis, no association was found for type of health coverage with either disease-free survival or overall survival, but there was an association for post-relapse survival (p<0.001). Conclusion In Brazil breast cancer patients with public health coverage present with more advanced disease and this possibly explains worse disease free and overall survival when compared to those with private coverage. Impact Earlier diagnosis and treatment of breast cancer could improve outcomes of women with public health coverage in Brazil.
    Cancer Epidemiology Biomarkers & Prevention 10/2013; 23(1). DOI:10.1158/1055-9965.EPI-13-0693 · 4.32 Impact Factor

Publication Stats

6k Citations
1,324.04 Total Impact Points

Institutions

  • 2006–2015
    • Massachusetts General Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2008–2014
    • Queen's University
      Kingston, Ontario, Canada
    • University of Vermont
      Burlington, Vermont, United States
  • 2004–2013
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Radiology
      Boston, Massachusetts, United States
  • 1999–2013
    • University of Toronto
      • • Department of Medicine
      • • Department of Nutritional Sciences
      Toronto, Ontario, Canada
  • 2006–2012
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1997–2008
    • UHN: Toronto General Hospital
      Toronto, Ontario, Canada
  • 2005
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 1999–2005
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 2002–2004
    • University Health Network
      • Department of Medical Oncology
      Toronto, Ontario, Canada
  • 1999–2004
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada