[Show abstract][Hide abstract] ABSTRACT: NCIC CTG MA.14 and NSABP B-29 trials examined the addition of Octreotide LAR (OCT) to 5 years of tamoxifen (TAM). Gallbladder toxicity led to B-29 discontinuation of OCT, and MA.14 OCT administration shortened to 2 years. Median follow-up was 9.8 years for 667 MA.14 patients and 6.8 years for 893 B-29 patients. The primary endpoint was disease-free survival (DFS), defined as time from randomization to time of breast cancer recurrence; second primary cancer other than squamous or basal cell skin carcinoma, cervical carcinoma in situ, or lobular breast carcinoma in situ; or death. The primary statistical test was a univariable pooled stratified log-rank test; multivariable assessment was with Cox regression. For MA.14, 97 % of patients were ≥50 years; for B-29, 62 %. MA.14 patients were 53 % lymph node negative (LN-) while B-29 were 100 % LN-; 33 % of MA.14 patients received adjuvant chemotherapy, 2 % concurrently, while B-29 had 53 % concurrent chemotherapy. MA.14 patients were 90% hormone receptor positive; B-29, 100 %. MA.14 patients experienced 5-year DFS of 80 % with TAM, 76 % with TAM + OCT; B-29 patients had 5-year DFS of 88 % for both arms. Pooled univariable TAM + OCT to TAM hazard ratio (HR) was 0.99 (95% CI 0.81-1.20; p = 0.69): for MA.14, HR = 0.94 (0.73-1.20; p = 0.50); for B-29, HR = 1.09 (0.80-1.50; p = 0.59). Multivariable pooled HR = 0.98 (0.81-1.20; p = 0.84). Older patients (p < 0.001), with higher T stage (p < 0.001), and LN + (p < 0.001) had shorter DFS. Addition of OCT to TAM did not significantly improve DFS; gallbladder toxicity shortened the additional administration of OCT. This does not negate targeting the insulin-IGF-I receptor family with less toxic therapeutics.
Breast Cancer Research and Treatment 08/2015; DOI:10.1007/s10549-015-3547-4 · 4.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In a prior substudy of the CAN-NCIC-MA.22 clinical trial (ClinicalTrials.gov identifier NCT00066443), we observed that neoadjuvant chemotherapy reduced tumor RNA integrity in breast cancer patients, a phenomenon we term "RNA disruption." The purpose of the current study was to assess in the full patient cohort the relationship between mid-treatment tumor RNA disruption and both pCR post-treatment and, subsequently, disease-free survival (DFS) up to 108 months post-treatment. To meet these objectives, we developed the RNA disruption assay (RDA) to quantify RNA disruption and stratify it into 3 response zones of clinical importance. Zone 1 is a level of RNA disruption inadequate for pathologic complete response (pCR); Zone 2 is an intermediate level, while Zone 3 has high RNA disruption. The same RNA disruption cut points developed for pCR response were then utilized for DFS. Tumor RDA identified >fourfold more chemotherapy non-responders than did clinical response by calipers. pCR responders were clustered in RDA Zone 3, irrespective of tumor subtype. DFS was about 2-fold greater for patients with tumors in Zone 3 compared to Zone 1 patients. Kaplan-Meier survival curves corroborated these findings that high tumor RNA disruption was associated with increased DFS. DFS values for patients in zone 3 that did not achieve a pCR were similar to that of pCR recipients across tumor subtypes, including patients with hormone receptor positive tumors that seldom achieve a pCR. RDA appears superior to pCR as a chemotherapy response biomarker, supporting the prospect of its use in response-guided chemotherapy.
Breast Cancer Research and Treatment 07/2015; DOI:10.1007/s10549-015-3498-9 · 4.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: TLE3, a nuclear transcriptional repressor downstream of WNT signalling pathways, has been hypothesised as predictive of benefit from adjuvant taxane.
MA.21 tissue microarrays were constructed from 1097 out of 2104 (52%) patients. TLE3 staining by immunohistochemistry used validated methodology. Continuous TLE3+ (percentage of cells staining positive) was assessed with both visual and automated scoring. The primary objective was to test the predictive effect of TLE3 on relapse-free survival using the MA.21 EC/T and CEF arms and the previously defined cut-point of 30% of cells staining positive in ⩾1 core/tumour.
MA.21 patients had 83.2% TLE3 positive (TLE3+) tumours by visual score and 80.6% TLE3+ by automated image analysis while the previously observed rate of TLE3+ cases was 58.6%. TLE3 expression was significantly associated with ER expression (91.2% of ER-positive tumours were TLE3+; P<0.0001). At median 8-year follow-up, there was no evidence of a predictive effect of TLE3 expression with respect to taxane benefit using the established 30% or exploratory quartile cut-points.
Proportionately more MA.21 patient tumours than expected were TLE3+. The pre-specified TLE3+ cut-point of 30% was not predictive of taxane benefit. TLE3 expression does not represent a viable biomarker for taxane benefit in breast cancer.British Journal of Cancer advance online publication, 18 August 2015; doi:10.1038/bjc.2015.271 www.bjcancer.com.
Cancer Research 05/2015; 75(9 Supplement):P4-11-06-P4-11-06. DOI:10.1158/1538-7445.SABCS14-P4-11-06 · 9.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Low vitamin D levels have been associated with poor breast cancer outcomes in observational studies. We examined the association of vitamin D blood levels with relapse-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS) in the MA.21 randomized clinical trial. Fasting blood was collected pre-chemotherapy in 934/2104 (44.4 %) of subjects; 25 hydroxy vitamin D was measured (radioimmunoassay, Diasorin) in one batch. Vitamin D was assessed as a transformed continuous factor, and categorically (quartiles and clinical classifications). Univariate and multivariate prognostic analyses (adjusted for treatment, stratification factors, and baseline imbalances) were performed using Cox models. Most patients were young (median 47.8 years), white (91.6 %) and premenopausal (69.4 %) with grade III (52 %), HER2 negative or missing (89.5 %), ER positive (61.9 %), T1-2 (89.4 %), N + (72.7 %) breast cancer. Compared to the full population, those with vitamin D levels were more likely to be white, PS 1 or 2, to have undergone mastectomy, and to have an ER + tumor. Mean vitamin D was 69.7 nmol/L (27.9 ng/ml) and did not vary by tumor subtype. The majority (80.5 %) had levels >50 nmol/L (20 ng/ml), considered adequate by Institute of Medicine. Continuous vitamin D was not multivariately associated with RFS, BCSS, or OS (p = 0.36, 0.26, 0.33, respectively); categorical vitamin D was also not associated with outcome. Vitamin D associations with RFS did not differ within ER/HER2 subgroups. There was no evidence that vitamin D blood level was associated with RFS, BCSS, and OS in MA.21; the majority of subjects had adequate vitamin D levels at study entry.
Breast Cancer Research and Treatment 04/2015; 150(3):605-11. DOI:10.1007/s10549-015-3355-x · 4.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Metformin may improve metabolic factors (insulin, glucose, leptin, highly sensitive C-reactive protein [hs-CRP]) associated
with poor breast cancer outcomes. The NCIC Clinical Trials Group (NCIC CTG) MA.32 investigates effects of metformin vs placebo
on invasive disease-free survival and other outcomes in early breast cancer. Maintaining blinding of investigators to outcomes,
we conducted a planned, Data Safety Monitoring Committee–approved, analysis of the effect of metformin vs placebo on weight
and metabolic factors at six months, including examination of interactions with baseline body mass index (BMI) and insulin,
in the first 492 patients with paired blood samples.
JNCI Journal of the National Cancer Institute 03/2015; 107(3). DOI:10.1093/jnci/djv006 · 15.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PAM50-defined breast cancer intrinsic subtypes and risk-of-relapse (ROR) scores are prognostic and predictive of endocrine therapy and some chemotherapy. We investigated the prognostic and predictive effect of PAM50 classifications by chemotherapy type. NCIC CTG MA.21 randomized 2,104 patients to doxorubicin, cyclophosphamide, and paclitaxel (AC/T); dose-intense cyclophosphamide, epirubicin, and flurouracil (CEF); or dose-dense, dose-intense epirubicin, cyclophosphamide, and paclitaxel (EC/T). Patients were ≤60 years, with node-positive or high-risk node-negative disease, with median 8-year follow-up. Intrinsic subtypes and ROR were determined from RNA extracted from formalin-fixed paraffin-embedded sections by the NanoString PAM50 test. Univariate effects on relapse-free survival (RFS) were assessed with stratified log-rank test; multivariate analyses utilized stratified Cox regression. Among 1094 cases completing PAM50 intrinsic subtyping, 27 % were classified
as luminal A, 23 % luminal B, 18 % HER2E, and 32 % basal-like. CEF and EC/T were superior to AC/T (p = 0.01). Higher continuous ROR was multivariately associated with worse RFS (p = 0.03), although categorical ROR was neither prognostic nor predictive. Intrinsic subtypes had a significant multivariate prognostic effect on RFS (p = 0.002). Compared with luminal A, hazard ratios were luminal B = 1.48 (95 % CI 0.92–2.37); HER2E = 2.68 (95 % CI 1.60–4.48); and basal-like = 1.97 (95 % CI 1.10–3.53). Intrinsic subtypes were not predictive of treatment benefit (AC/T vs. EC/T + CEF); however, subgroup analysis indicated subtypes (non-luminal vs. luminal) was predictive of taxane benefit (EC/T vs. CEF; p = 0.05). Both NanoString PAM50 subtypes and continuous ROR had significant prognostic effects on RFS for breast cancer patients treated with CEF, EC/T, and AC/T. Non-luminal tumors differentially responded to EC/T (with taxane) over CEF.
Breast Cancer Research and Treatment 01/2015; 149(2). DOI:10.1007/s10549-014-3259-1 · 4.20 Impact Factor
[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: Venous thromboembolism (VTE) has an increased incidence in patients with multiple myeloma (MM), especially during chemotherapy. Mechanisms including upregulation of procoagulant factors, such as factor VIII, have been postulated. The National Cancer Institute of Canada Clinical Trials Group MY.10 phase III clinical trial compared thalidomide-prednisone to observation for 332 patients with MM post-autologous stem cell transplantation (ASCT), with a primary endpoint of overall survival and various secondary endpoints including the incidence of VTE. One hundred and fifty-three patients had biomarker data, including D-dimer, factor VIII and thrombin anti-thrombin (TAT) levels collected post-ASCT at baseline and 2 months after intervention investigating in-vivo thrombin generation. Differences between the time-points included a significant reduction over time in D-dimer, factor VIII and TAT levels in the observation group and sustained elevation of D-dimer, significant increase in factor VIII and reduction in TAT levels in the thalidomide-prednisone group. Eight VTE events were reported in this subset of study patients, all in the thalidomide-prednisone arm, with a trend to increase in D-dimer levels over time in those patients with VTE. This study provides physiological and clinical evidence for an increased risk of VTE associated with thalidomide-prednisone maintenance therapy post-ASCT for MM.
British Journal of Haematology 10/2014; 168(4). DOI:10.1111/bjh.13176 · 4.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than standard treatment. Patients and Methods We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life. Results For the intention-to-treat population, the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, -9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P < .001) and need for hospitalization (P < .001), and preserved quality of life (P = .04). Conclusion For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life. (C) 2014 by American Society of Clinical Oncology
[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.