NCIC CTG MA Research Articles

Development and Validation of a Nomogram to Predict Lymphedema After Axillary Surgery and Radiation Therapy in Women With Breast Cancer From the NCIC CTG MA.20 Randomized Trial

Regional nodal irradiation for women with breast cancer is known to be an important risk factor for the development of upper extremity lymphedema, but tools to accurately predict lymphedema risks for individual patients are lacking. This study sought to develop and validate a nomogram to predict lymphedema risk after axillary surgery and radiation therapy in women with breast cancer. Data from 1832 women accrued on the MA.20 trial between March 2000 and February 2007 were used to create a prognostic model with National Cancer Institute Common Toxicity Criteria Version 2.0 grade 2 or higher lymphedema as the primary endpoint. Multivariable logistic regression estimated model performance. External validation was performed on data from a single large academic cancer center (N = 785). In the MA.20 trial cohort, 3 risk factors were predictive of lymphedema risk: body mass index (adjusted odds ratio, 1.05 per unit body mass index; 95% confidence interval [CI], 1.03-1.08, P < .001), extent of axillary surgery (adjusted odds radio for 8-11 lymph nodes removed, 3.28 [95% CI, 1.53-7.89] P = .004; 12-15 lymph nodes, 4.04 [95% CI, 1.76-10.26] P = .002; ≥16 nodes, 5.08 [95% CI, 2.26-12.70] P < .001), and extent of nodal irradiation (adjusted odds radio for limited, 1.66 [95% CI, 1.08-2.56] P = .02; for extensive, 2.31 [95% CI, 1.28-4.10] P = .004). A nomogram was created from these data that predicted lymphedema risk with reasonable accuracy confirmed by both internal (concordance index, 0.69; 95% CI, 0.64-0.74) and external validation (concordance index, 0.71; 95% CI, 0.66-0.76). The nomogram created from the MA.20 randomized trial data using clinical information may be useful for lymphedema screening and risk stratification for therapeutic intervention trials.

New onset vasomotor symptoms but not musculoskeletal symptoms associate with clinical outcomes on extended adjuvant letrozole – Analyses from NCIC CTG MA.17

PurposeNew onset symptoms on adjuvant aromatase inhibitors for hormone receptor positive early breast cancer may associate with clinical outcomes. We performed this exploratory analysis of the association of new onset musculoskeletal (MSK) and vasomotor (VM) symptoms with clinical outcomes in the NCIC CTG MA.17 trial 5 years of extended adjuvant endocrine therapy with letrozole after tamoxifen. MethodsSymptoms were collected at baseline, 1, 6, and every 12 months on study. Multivariate Cox Models adjusting for age, nodal status, duration of tamoxifen and prior chemotherapy were used to compare disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) based on data collected before, and after, the unblinding between women with VM or MSK symptoms and those without. ResultsData post-unblinding showed new VM symptoms on extended letrozole significantly improved DFS and DDFS when occurring 1 month (DFS HR 0.52, 95% CI, 0.28–0.96; p = 0.04; DDFS HR 0.49, 95% CI, 0.24–0.99; p = 0.046) and 6 months (DFS HR 0.43, 95% CI, 0.24–0.78; p = 0.006; DDFS HR 0.44, 95% CI, 0.22–0.85; p = 0.02) after treatment initiation. Those with new VM symptoms at 12 months also had a significantly better DFS (HR 0.47, 95% CI 0.26, 0.84; P = 0.01) and a trend in improved DDFS. Only a trend to improved OS was found for those with VM symptoms 6 month after treatment. No significant improvement was found for those with new MSK symptoms at any time point or for any endpoint. ConclusionsNew onset VM symptoms with extended letrozole may be useful in predicting treatment benefit.

Prognostic and predictive effects of diabetes, hypertension, and coronary artery disease among women on extended adjuvant letrozole: NCIC CTG MA.17

BackgroundWomen with breast cancer and diabetes mellitus (DM) have poorer survival. Mechanisms include insulin dysregulation and/or DM related co-morbidities (CM). In MA.17 adjuvant letrozole (LET) after 5 years of tamoxifen (TAM) reduced the risk of recurrence and improved survival. We evaluated DM, hypertension (HTN), and coronary artery disease (CAD) as prognostic and predictive factors in MA.17. Patients and methodsDisease free survival, distant disease free survival (DDFS) and overall survival (OS) were compared using Cox regression model adjusting for other prognostic factors: in women treated by placebo (PLAC) based on the presence or absence of baseline DM (n = 462), HTN (n = 1627), CAD (n = 604) or any one of these CM (n = 2049), and between LET and PLAC groups in each CM. Analyses based on nodal status were performed. ResultsDM was neither prognostic nor predictive for women on extended LET. Women with one CM had similar outcomes on LET compared to women free of CM. For node positive women, the difference between LET and PLAC in DDFS was greater among women with one CM (hazard ratio [HR] = 0.30 [0.15–0.60], p = 0.001) compared to those without CM (HR = 0.72 [0.45–1.16], p = 0.17, p interaction = 0.04). Women on PLAC with HTN trended towards lower DDFS (HR = 1.50 [0.98–2.3], p = 0.06) and OS (HR = 1.61 [0.95–2.72], p = 0.08) than non-HTN women. HTN women had better DDFS on LET than non-HTN women. Women with one CM on PLAC had lower OS (HR = 2.10 [1.26–3.51], p = 0.004) than those free of CM. ConclusionsDM was not prognostic or predictive of outcomes. Women with CM who remain disease free after 5 years of TAM should be offered LET. HTN trended towards a negative prognosticator and outcomes among this group were improved on LET. More studies are needed to assess impact of adrenergic stimulation as a possible link to poorer breast cancer outcomes.

Assessment of the prognostic and predictive utility of the Breast Cancer Index (BCI): an NCIC CTG MA.14 study.

BackgroundBiomarkers 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).MethodsGene 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.ResultsOf 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).ConclusionsBCI 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0660-6) contains supplementary material, which is available to authorized users.

Competing risks of death in women treated with adjuvant aromatase inhibitors for early breast cancer on NCIC CTG MA.27

Competing risks of death in women treated with adjuvant aromatase inhibitors for early breast cancer on NCIC CTG MA.27

A phase I/II trial of epirubicin and docetaxel in locally advanced breast cancer (LABC) on 2-weekly or 3-weekly schedules: NCIC CTG MA.22.

This phase I/II neoadjuvant trial (ClinicalTrials.gov identifier NCT00066443) determined maximally-tolerated doses (MTD), dose-limiting toxicities, response-to-therapy, and explored the role of novel response biomarkers. MA.22 accrued T3N0, any N2 or N3, and T4 breast cancer patients. Treatment was 6 cycles of 3-weekly (Schedule A; N = 47) or 8 cycles of 2-weekly (Schedule B; N = 46) epirubicin/docetaxel chemotherapy in sequential phase I/II studies, with growth factor support. In phase I of each schedule, MTDs were based on DLT. In phase II, clinical responses (CR/PR) and pathologic complete responses (pCR) were assessed. Tumor biopsy cores were obtained pre-, mid-, and post-treatment: 3 for pathologic assessment; 3 for microarray studies. DLT for Schedule A was febrile neutropenia at 105 mg/m2 epirubicin and 75 mg/m2 docetaxel; for schedule B, it was fatigue at 75 mg/m2 for both agents. Phase II doses were 90 mg/m2 epirubicin/75 mg/m2 docetaxel for Schedule A and 60 mg/m2 (both agents) for Schedule B. Schedule A CR/PR and pCR rates were 90 and 10 %, with large reductions in tumor RNA content and integrity following treatment; Schedule B results were 93 and 0 %, with smaller reductions in RNA quality. Pre-treatment expression of several genes was associated with clinical response, including those within a likely amplicon at 17q12 (ERBB2, TCAP, GSDMB, and PNMT). The combination regimens had acceptable toxicity, good clinical response, induction of changes in tumor RNA content and integrity. Pre-treatment expression of particular genes was associated with clinical responses, including several near 17q12, which with ERBB2, may better identify chemoresponsiveness.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1392-x) contains supplementary material, which is available to authorized users.

TLE3 is not a predictive biomarker for taxane sensitivity in the NCIC CTG MA.21 clinical trial

Background:TLE3, a nuclear transcriptional repressor downstream of WNT signalling pathways, has been hypothesised as predictive of benefit from adjuvant taxane.Methods: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.Results: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.Conclusions: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.

Metformin in breast cancer - an evolving mystery.

Metformin, a diabetes drug with well-established side effect and safety profiles, has been widely studied for its anti-tumor activities in a number of cancers, including breast cancer. But its mechanism of action in the clinical arena remains elusive. In a window of opportunity trial of metformin in non-diabetic breast cancer patients, Dowling and colleagues examined both the direct actions of the drug on cancer cells (as mediated by AMP kinase), as well as its indirect actions (as mediated by circulating insulin). The data suggest that short-term administration of metformin in this setting has anti-tumor effects significantly involving the indirect, insulin-dependent pathway. The role of the direct pathway remains to be determined. This study represents an important step forward in establishing one of several possible mechanisms for metformin, information that will be useful in determining candidate biomarkers to evaluate in large clinical trials of metformin, such as the ongoing NCIC CTG MA.32 trial of adjuvant metformin. The potential significance of these data for metformin in the treatment of breast cancer is discussed here.

RNA Disruption and Drug Response in Breast Cancer Primary Systemic Therapy.

As there is now evidence that switching clinical nonresponders early in primary systemic therapy to alternate treatment regimens can enhance survival in some breast cancer patients, the need for a robust intermediate endpoint that can guide treatment response across all tumor subtypes is urgent. Recently, chemotherapy drugs have been shown to induce a decrease in RNA quality in tumor cells from breast cancer biopsies in some patients at midtherapy, and that this has been associated with subsequent achievement of pathological complete response (pCR). The decrease in RNA quality has been shown to be associated with RNA disruption; aberrant RNA bands visualized by RNA electrophoresis have been associated with subsequent tumor cell death. The objectives of these studies are to show that a new assay based on induction of RNA disruption in tumor cells by chemotherapy can stratify at midtherapy, pCR responders from non-pCR responders irrespective of clinical response and to present early evidence that clinically useful RNA disruption can be detected as early as 14 days after initiation of treatment. RNA disruption in tumor cells was quantified by analysis of the RNA electrophoresis banding pattern and expressed as an RNA disruption index (RDI). To develop the RNA disruption assay (RDA), RDI was correlated with clinical outcome (pCR) from the NCIC-CTG MA.22 breast cancer clinical trial (ClinicalTrials.gov NCT00066443). RDA Zones were established by stratifying patients using RDI values into Zone 1, Zone 2, and Zone 3. Zone 3 included seven out of eight pCR responders, whereas Zone 1 contained no pCR responders. An intermediate zone (Zone 2) was established which contained one pCR. Subsequently, to determine early drug response, RNA disruption was examined by RDI after 14 days exposure to trastuzumab, zoledronic acid, or letrozole + cyclophosphamide ± sorafenib therapy. In MA.22, RDA stratified 23 of 85 patients in Zone 1 as pCR nonresponders, 24 patients in Zone 2, an intermediate zone, and 38 patients in Zone 3, pCR responders and non-pCR patients who share RDI comparable to those achieving pCR. In the early response studies, after 14 days exposure to chemotherapy, some RNA disruption as measured by RDI elevation could be detected in 3/12 trastuzumab, 7/15 zoledronic acid, 5/29 letrozole + cyclophosphamide, and 5/23 letrozole + cyclophosphamide + sorafenib patients. RDA is a novel intermediate endpoint that has promise for clinical utility for breast cancers early in response-guided primary systemic therapy.

Abstract P4-11-06: TLE3 is not a predictive biomarker for taxane sensitivity in the NCIC CTG MA.21 clinical trial

Abstract Background: TLE3, a nuclear transcriptional repressor downstream of the WNT signaling pathway, has been identified as a candidate predictive biomarker of taxane benefit in early breast cancer. However, robust clinical evidence is required before implementing novel diagnostic biomarkers. We tested the hypothesis that TLE3 predicts for benefit from taxane containing polychemotherapy in the NCIC CTG MA.21 clinical trial. Methods: MA.21 accrued 2104 patients [701 each to cyclophosphamide, epirubicin, and 5 fluorouracil (CEF) and epirubicin and cyclophosphamide with filgrastim and epoetin alfa followed by paclitaxel (EC/T), 702 to doxorubicin and cyclophosphamide followed by paclitaxel (AC/T)] who were followed median 8 years by the final analysis. EC/T and CEF were not significantly different (p= 0.69) while AC/T was inferior to both EC/T and CEF (respectively, p=0.001 and p=0004). Tissue microarrays were constructed from 1097 of the 2104 patients. Patient characteristics were well balanced between those included in the TLE3 analysis and the full trial population. Up to four 0.6 mm tumor cores were stained for TLE3 expression by immunohistochemistry using a previously validated methodology. Continuous visual TLE3 score was the average % positive stain across all cores, while continuous automated score was sum of cells with positive stain/ total cells assessed in all cores. The primary objective used the EC/T (taxane-containing) and CEF (non-taxane; similar dose-density) arms for a test of predictive effect of TLE3 on relapse free survival. TLE3 was positive if &amp;gt;30% of cells stained, the established cut-point, with data available from at least 1 core/tumor. We also examined quartile cut-points, multivariate effects of TLE3, and compared AC/T and CEF. Results: MA.21 patients had 83.2% TLE3+ tumors by visual score and 80.6% TLE3+ by automated image analysis greater than the predicted rate of TLE3 positivity (58.6%) based on prior series and adjusting for clinicopathological features. TLE3 expression was significantly positively associated with ER expression (91.2% of ER+ were TLE3+; p&amp;lt;0.0001). There was no evidence of a predictive effect of TLE3 expression with respect to taxane benefit using the established 30% cut-point, nor quartile cut-points. The treatment and TLE3 interaction term for the EC/T by CEF comparison was not significant (stratified p=0.68, for manual TLE3; p=0.44, for automated TLE3). Conclusions: MA.21 patients had a much higher proportion of TLE3+ tumors than anticipated. Multiple assessments of TLE3 cut-points yielded no evidence that it was predictive of taxane benefit. In our trial TLE3 expression was not a biomarker for taxane benefit (EC/T vs CEF) when using either previously established or common quartile cut-offs for expression in breast cancer. Citation Format: John MS Bartlett, Torsten O Nielsen, Dongxia Gao, Karen A Gelmon, Mary Anne Quintayo, Jane Starczynski, Lei Han, Margot J Burnell, Mark N Levine, Lois E Shepherd, Judy-Anne W Chapman. TLE3 is not a predictive biomarker for taxane sensitivity in the NCIC CTG MA.21 clinical trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-06.

Abstract P6-01-10: Prognostic significance of breast cancer index (BCI) in node-positive hormone receptor positive early breast cancer: NCIC CTG MA.14

Abstract Background: The continuous linear Breast Cancer Index (BCI) risk index combines the ratio of genes HOXB13 to IL17BR (H/I) and the molecular grade index (MGI) (Zhang et al, Clinical Cancer Research, 2013). The BCI signature was developed for node-negative breast cancer patients treated with tamoxifen. We examine here whether linear BCI is prognostic for node-positive hormone-receptor positive tamoxifen-treated patients. Methods: MA.14 randomly assigned 667 hormone positive (HR+), postmenopausal women to 5 years of tamoxifen (TAM) +/- 2 years of octreotide LAR (TAM-OCT). A representative subgroup of 299 patients underwent gene expression profiling by RT-PCR for linear BCI. We performed exploratory analyses restricted to node positive patients. The primary objective was to assess the prognostic effect of BCI on relapse-free survival (RFS). RFS was defined as the time from randomization to the time of recurrence of the primary disease alone, including local and ipsilateral nodal recurrence and metastatic disease, and censoring at longest follow-up or death from another cause. With a median 9.8 years follow-up, the association of BCI with RFS was assessed by multivariate Cox regression including treatment, stratification factors (other than nodal status), and baseline patient and tumor characteristics. Patients were defined to be low risk based on BCI if the adjusted Cox survival was &amp;gt;95%, where adjustment was by trial treatment, stratification factors, and baseline patient and tumor characteristics, including IGF-1, IGFBP-3, and C-peptide. Results: 292 of 299 patient samples passed internal analytical quality control; 116 node positive ER+ve patients had 34 (29.3%) relapses, with adjusted Cox survival at 9.6 years of 87.8%. Fifty-two of the 116 patients (45%) did not receive adjuvant chemotherapy, and experienced 11 (21%) RFS events. In the 116 patients, higher continuous BCI value was associated with shorter RFS (p=0.002): hazard ratio (HR) 1.49 (95% CI 1.16-1.91). Smaller pathologic T had significantly (p=0.03) better RFS HR=0.39, (95%CI 0.17-0.90). With MA.14 patient mean BCI of 5.09532, Cox survival at 4.1 years was 95.2%; 17/34 (50%) who recurred had failed by this time. Discussion: In this subgroup analysis, we found that BCI and tumor size were significant prognostic factors for node-positive hormone-receptor positive patients who were treated with tamoxifen. Citation Format: Dennis Sgroi, Paul Goss, Judy-Anne Chapman, Elizabeth Richardson, Shemeica Binns, Yi Zhang, Cathy Schnabel, Mark Erlander, Kathy Pritchard, Lei Han, Lois Sheperd, Michael Pollack. Prognostic significance of breast cancer index (BCI) in node-positive hormone receptor positive early breast cancer: NCIC CTG MA.14 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-01-10.

Abstract P4-11-11: CADER prognostic gene signature for disease free survival in hormone receptor positive breast cancer: NCIC CTG MA.12 phase III placebo-controlled tamoxifen trial

Abstract Background: The copy number aberration derived endocrine response (CADER) gene signature was developed as a prognostic marker for hormone receptor positive breast cancer; it combines information derived from both gene expression and copy number aberration and was trained on samples from both the neoadjuvant and adjuvant settings (see separate CADER nanostring assay methodology abstract, Luo et al). We examined the effects of CADER on outcome in the MA.12 trial to evaluate the association of CADER and PAM 50 with relapse. Methods: From 1993 to 2000, MA.12 accrued 672 women to a placebo-controlled pre-menopausal trial of adjuvant tamoxifen with locally assessed hormone receptor +/- tumors. The 9.7 years median follow-up was used here. A secondary endpoint was disease free survival (DFS), defined as time from randomization to the earliest date of recurrence or death; censoring was at the last date the patient was known to be alive. Stratification factors were type of chemotherapy (CMF vs CEF vs AC), hormone receptor status (ER and/or PgR positive vs ER and PgR negative), and nodal status (0 vs 1–3 vs 4–9 vs 10+). Exact Fisher tests were used to compare baseline characteristics of those assessed, or not, for CADER. We examined the effects of the CADER classifications (sensitive, indeterminate, resistant) for hormone receptor positive patients. The prognostic effects of CADER, and preexisting qPCR PAM50 ROR-S, and PAM50 intrinsic subtype (Chia et al, CCR 16, 4465, 2012) on DFS were examined with stratified multivariate Cox regression, adjusted for treatment and baseline patient characteristics. An interaction test with treatment was used to assess evidence for CADER as a predictive signature. Graphical depiction was with adjusted Cox survivor plots. Results: CADER was assessed in 434 (65%) of the 672 patients: 213 patients on the tamoxifen arm; 221, on the placebo arm. Proportionately more patients profiled for CADER underwent CEF adjuvant chemotherapy (p=0.03) so we performed only stratified analyses. Of the 434 patients, 317 (73%) had hormone receptor breast tumors. The CADER classifications significantly impacted DFS (p=0.04): hazard ratio (HR) of indeterminate CADER to sensitive=2.29 (95% CI 0.93-5.62; p=0.07); HR of resistant to sensitive=3.72 (95% CI 1.33-10.42, p=0.01). Patients with low ROR-S had longer DFS (p=0.04), while PAM50 intrinsic subtype did not significantly impact DFS (p=0.51). CADER and ROR-S were not predictive factors. Conclusions: In MA.12 hormone-receptor patients, both CADER and ROR-S had significant prognostic effects on disease free survival. Neither CADER nor PAM50 ROR were predictive in this placebo-controlled tamoxifen trial. We confirmed here the earlier clinical prognostic relevance of CADER that was seen during the signature’s development. Citation Format: Matthew J Ellis, Bingshu Chen, Judy-Anne W Chapman, Jingqin Luo, Diana Ma, Lois Shepherd, Jeremy Hoog, Samuel Leung, Elaine Mardis, Sherri R Davies, Torsten O Nielsen, Vivien Bramwell. CADER prognostic gene signature for disease free survival in hormone receptor positive breast cancer: NCIC CTG MA.12 phase III placebo-controlled tamoxifen trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-11.

Treatment-associated musculoskeletal and vasomotor symptoms and relapse-free survival in the NCIC CTG MA.27 adjuvant breast cancer aromatase inhibitor trial.

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.

Prognostic and predictive significance of PAM50 intrinsic subtypes in the NCIC CTG MA.21 phase III chemotherapy trial.

11019 Background: Breast cancer intrinsic subtypes defined by the 50-gene PAM50 test were reported to be prognostic and predictive in endocrine therapy trials. MA21 randomized 2,104 patients to rec...

Effect of serum HER2, TIMP-1, and CAIX on outcome in HER2+ metastatic breast cancer patients treated in first line with lapatinib or trastuzumab combined with taxane: NCIC CTG MA.31.

617 Background: The lapatinib-taxane combination led to shorter PFS than trastuzumab-taxane in HER2+ metastatic breast cancer. We investigated the prognostic and predictive effects of pretreatment ...

Outcomes of 3-weekly doxorubicin and cyclophosphamide followed by paclitaxel (AC/T) in a randomized trial (RCT) compared to a case-control matched British Columbia (BC) breast cancer population.

1037 Background: NCIC CTG MA.21 was a North American RCT of 3 adjuvant chemotherapies (adjCT), of which one was 3-weekly AC/T. We compared Relapse Free Survival (RFS) for this standardised adjCT given in MA.21 to that in a general population from a BC database, using a matched case-control design. Methods: Matching was based on age +/- 3 years (y) and MA.21 stratification factors: number of positive nodes [NP], surgery type, and estrogen receptor (ER). Patients (pts) who received > 1 cycle of AC/T were included. RFS was defined as time from randomisation (per protocol, AC/T started within 5 days) to recurrence for MA.21, and from first AC/T to recurrence for BC. A sensitivity analysis using HER2 negative (HER2-) pts was done, as testing and trastuzumab (TZ) use changed over time. RFS was estimated with Cox survivor plots, adjusting for factors significant in multivariate Cox step-wise forward regression. Results: 473 of 671 BC pts were matched to 473 of 696 MA.21 pts. Median follow up was 8 y and median t...

Prognostic associations of 25OH vitamin D in NCIC CTG MA.21, a phase III adjuvant RCT of three chemotherapy regimens (EC/T, CEF, AC/T) in high-risk breast cancer (BC).

504 Background: Low vitamin D (VitD) has been associated with poor outcomes in BC. We examined in MA.21 the association of VitD blood levels with relapse-free-survival (RFS) in all patients, and in...

Lapatinib or trastuzumab with taxane therapy as first-line treatment in metastatic breast cancer (MBC): A biomarker analysis in NCIC CTG MA.31.

601 Background: Lapatinib (L) was associated with shorter progression-free survival (PFS) than trastuzumab (T) when combined with a taxane (Tax) as first line therapy for HER2+ MBC. We report the e...

Pharmacokinetic analysis of tamoxifen metabolites in premenopausal women with early breast cancer: A substudy of NCIC CTG MA.12 randomized clinical trial.

1524 Background: The clinical impact of CYP2D6 genetic polymorphisms on tamoxifen (Tam) remains unclear. Active metabolite levels of Tam can be influenced by drug interaction and compliance. This s...

Effects of adjuvant exemestane versus anastrozole on bone mineral density for women with early breast cancer (MA.27B): a companion analysis of a randomised controlled trial

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.