NCIC CTG MA Research Articles

P1-06-08: Effect of Treatment Emergent Symptoms on Relapse Free Survival: NCIC CTG MA.12 a Randomized Placebo-Controlled Trial of Tamoxifen after Adjuvant Chemotherapy in Pre-Menopausal Women in Early Breast Cancer.

Abstract Background: Evidence from the ATAC trial that vasomotor or joint symptomatology by 3 months is associated with reduced recurrence after 3 months led to an interest in examining this phenomenon in other aromatase inhibitor trials. We examined here whether there is such an association in the context of a placebo-controlled tamoxifen therapy trial. Methods: NCIC CTG MA.12 is a randomized placebo-controlled trial of tamoxifen (TAM) after adjuvant chemotherapy for pre-menopausal women with early breast cancer. Eligible patients were included if they received some protocol therapy, were alive and disease-free at 3 months: 1.) without prior grade 3/4 vasomotor or joint symptoms (N=293; only 3 patients had prior grade 1/2 vasomotor or joint symptoms); separately, 2.) all patients with/without prior vasomotor or joint symptoms (N=631). Vasomotor symptom at 3 months was adverse reporting of any grade of hot flashes and/or sweating, while joint symptom was any adverse event reporting of pain -joint, pain -muscle, pain -bone, arthritis, joint -function, or musculoskeletal —other. Exact Fisher tests were used to examine associations between baseline patient and tumour characteristics, treatment arm, and the development of symptomatology. Univariate testing of effect of symptomatology on relapse-free survival (RFS) was with a stratified Cox model, and multivariate was with stratified step-wise forward Cox modeling. Results: MA.12 accrued 672 patients, and the median follow-up for this investigation was 9.7 years. Excluding patients with prior vasomotor or joint symptoms, 27.3% of 293 patients reported vasomotor or joint symptoms by three months, all of which was vasomotor. Meanwhile, 20.8% of all 631 patients had symptomatology by 3 months: 19.2% reported vasomotor alone, 1.1% joint alone, and 0.5% both. With no prior symptoms, 23.4% on placebo (P) and 31.7% on TAM developed symptomatology; age was the only baseline factor with significant differences at 3 months (p=0.01), with under 40 years 18% of women on TAM and 8% on P, and 50 or older, 21% on TAM and 14% on P being symptomatic. For all patients, 20.1% on P and 21.4% on TAM reported symptomatology by 3 months, and there was weak evidence that those >50 on TAM had more symptoms (p=0.06). Vasomotor and joint symptoms did not exhibit significant univariate or multivariate effects on RFS (without prior symptoms, respectively, p=0.98 and p=0.90; for all patients, p=0.99 and p=0.93). Discussion: We did not observe any association of vasomotor or joint symptoms by 3 months and relapse-free survival after 3 months in the MA.12 placebo-controlled trial of tamoxifen therapy in premenopausal women. This mirrors the results we observed in our MA.27 trial of exemestane versus anastrozole in postmenopausal women, and points to the simple metric of early symptomatology not being a universal predictor of reduced relapse. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-08.

P2-12-23: How Should We Assess Tumour Size (T Stage) in Patients with Multicentric/Multifocal Breast Cancer? Results from the NCIC CTG MA.5 Randomized Trial of CEF vs. CMF in Pre-Menopausal Women with Node Positive Breast Cancer.

Abstract Background A common clinical conundrum in breast cancer management is whether pathologic T stage in women with multicentric or multifocal disease should be taken as the diameter of the largest focus or as the sum of all foci in the breast. Most staging systems, such as the American Joint Committee on Cancer (AJCC), simply use the largest tumour focus for staging. We examine here the impact of alternate methods of estimating tumour size including measures of total tumour size, volume and surface area. Methods: NCIC CTG MA.5 is a randomized trial of CEF versus CMF in pre-menopausal women with node positive breast cancer. Median follow up is 10 years. Pathologically reported patient tumour dimensions for up to 3 foci were utilized to examine the effects of tumour size on Breast-Cancer-Free-Interval (BCFI). BCFI is defined as the time from randomization until recurrence: first local invasive or DCIS, regional, distant, contralateral invasive or DCIS. Tumour size was estimated as 1) pathologic T stage as per AJCC criteria; 2) largest dimension of largest tumour focus (cm); 3) sum of largest dimension(s) of tumour foci (cm); 4) sum of surface area(s) of tumour foci (cm2), and 5) sum of volume of tumour foci (cm3). Step-wise forward unstratified Cox regression was used to assess the different effects of tumour size. Results: This study accrued 710 patients, 37% with T1 tumours, 52% with T2 tumours and 9% with T3 tumours; 61% had 1 to 3 positive lymph nodes. 59% hormone receptor positive. Higher pathologic T stage (p=0.001) and greater surface area (p=0.02) were associated with shorter BCFI, as was lymphovascular invasion (p=0.03), and # of lymph nodes involved (p<0.0001). Administration of anthracycline therapy led to significantly longer BCFI (0.003). The sum of largest tumour sizes (p=0.33) and sum of tumour volume (p=0.34) were not significantly associated with BCFI. Additionally, when the less complete locally reported tumour grade data were included, higher tumour grade was associated with shorter BCFI (p<0.0001). Conclusions: Consideration of multicentric and multifocal disease was an important adjunct to standard pathologic tumour size as was estimation of tumour surface area in this chemotherapy trial of node positive premenopausal women. However, simply adding together the diameters of tumours in patients with multicentric or multifocal disease did not add any additional prognostic information in this high risk patient population. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-23.

P2-14-02: NCIC CTG MA.27: Clinical Tolerability and Overall Survival of Racial and Ethnic Minority Women on Aromatase Inhibitor Therapy.

Abstract Background Aromatase inhibitors (AIs) are standard adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. We previously reported that racial/ethnic minority women receiving an AI in NCIC CTG MA.17 experienced fewer hot flashes, fatigue, and arthralgias than Caucasians (Moy B et al. Ann Oncol 2006;17:1637). Here we examined whether race affected clinical outcomes in the MA.27 AI trial comparing exemestane (E) with anastrozole (A). Methods: Fisher's exact test was used to compare observed side effects (0 vs grades 1–5) between minority and Caucasian women. Adverse events (AE), including menopausal symptoms, were assessed according to the Common Terminology Criteria of the National Cancer Institute (version 3.0). ITT univariate test of race effects on overall survival (OS) was determined with a stratified log-rank test, while multivariate testing was with stratified Cox regression. Results: Among 7312 for whom race was known, distribution was: Caucasian (n=6939; 95%); black (n=235; 3%); Asian/Native Hawaiian/Pacific Islander (n=93); 1%; American Indian (n=39; 1%); and mixed race (n=6). Among women treated with E, minorities reported a significantly lower incidence of hot flashes (45% vs. 56%; p=0.003) and fatigue (34% vs. 46%; p=0.001) compared to Caucasians. Similarly with A, minority women reported significantly fewer hot flashes (47% vs. 58%; p=0.002) and lower cholesterol (12% vs. 18%; p=0.01); however, they reported more headaches than Caucasians (16% vs. 10%; p=0.01). Caucasian women were more likely to discontinue therapy due to AE or side effects (32% vs. 24%). There was a significant OS interaction (p=0.02) between race and treatment with minority women on E having fewer deaths than those on A. Caucasian women had HR of E to A of 0.98 (95% CI 0.81−1.20), p=0.85, while minorities had HR of E to A of 0.72 (95% CI 0.33−1.58), p=0.41. Conclusions: Minority women tolerated AIs better and were also more compliant than Caucasians, supporting our previous findings. A significant interaction between race and type of AI therapy for OS was seen, favoring exemestane in minority women. Replication of these findings in larger cohorts is necessary. Since race/ethnicity may serve as a surrogate for genetic differences, our findings suggest pharmacogenomic differences which require further research. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-14-02.

P2-12-28: Studies of a Malignancy-Associated Protein, Osteopontin, in NCIC CTG MA.14, a Randomized Trial of Tamoxifen Versus Combined Tamoxifen and Octreotide LAR in Adjuvant Treatment of Women with Early Breast Cancer.

Abstract Background We have shown, in women with metastatic breast cancer (BC), that high baseline plasma osteopontin (OPN) levels and increases over time are associated with poor survival. In primary BC, increased immunohistochemical (IHC) expression of OPN in tumour is associated with poorer survival and is elevated in lymph node metastases relative to primary tumour. Our current study evaluates tumour and baseline/serial plasma OPN levels after resection of primary BC. Methods: In NCIC CTG MA.14, 667 postmenopausal women post surgery received 5 yrs Tamoxifen (T) +/− 2 yrs monthly Octreotide LAR. There were no differences in survival outcomes between arms. OPN was assayed by IHC in primary BC. OPN was measured in plasma at baseline (up to 4 mos post randomization) and serially in recurrent (18 mos time window) versus non-recurrent cases, by ELISA. Statistical Analysis: IHC and plasma OPN had Box-Cox variance stabilization transformations (power 0.5; logarithm). Descriptive characterization of both OPN measurements is provided for all patients, by baseline patient and tumour characteristics, and by recurrence status. Univariate stratified log-rank statistics and hazard ratios with 95% CI were generated for intention to treat (ITT), event free survival (EFS), relapse fee survival (RFS), overall survival, any bone RFS, and non-bone RFS. Stratified step-wise forward Cox regression was used, with factor added if p<0.05. Results: From 667 MA.14 patients, 647 patients were assessed for OPN: 462 (69%) by IHC; 387 (58%) at baseline in plasma (with 2,542 samples total from serial sampling). IHC % tumor positivity had mean 33.9% (95% CI 30.2%-37.9%), while baseline plasma OPN was mean 46.1 (44.6−47.6) ng/ml. In 80 women with recurrence, mean OPN during the recurrence window was 60.7 (52.8−69.8) ng/ml. Neither baseline IHC or plasma OPN levels were significantly associated with any of the endpoints in either univariate or multivariate analyses. Older age (p=0.02), greater nodal involvement (p=0.001), higher baseline body mass index (p<0.0001), and higher tumour grade (p<0.0001) were multivariately associated with shorter EFS. Baseline plasma OPN was not correlated with IHC OPN (Pearson 0.02, p=0.73). Discussion: Mean baseline OPN plasma level 46.1 ng/ml (median 45 ng/ml) in MA.14 was similar to our previous findings in healthy women (median 47 ng/ml). In contrast, we previously showed that 63% of 158 women with a new diagnosis of metastatic BC had elevated OPN levels with median value 177 ng/ml. Our results thus far suggest that tumor and plasma levels, while associated with prognosis in metastatic BC, may not be so in primary BC following surgery. However, in MA.14, the 80 women with recurrent BC had significantly higher mean OPN in the recurrence window, 60.7 ng/ml, than at baseline. We will present further analyses exploring this finding. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-28.

P1-06-07: TIMP-1 in Combination with HER2 and TOP2A for Prediction of Benefit from Adjuvant Anthracyclines in High Risk Breast Cancer Patients.

Abstract Purpose: HER2 amplification, TOP2A aberrations and absence of TIMP-1 (Tissue Inhibitor of Metalloproteinase-1) expression in breast carcinomas have been associated with incremental benefit from anthracycline-containing adjuvant chemotherapy in several reports. In the DBCG 89D trial, we demonstrated that the predictive value of these markers improved when they were combined in a profile and the present study was undertaken to validate these findings in NCIC CTG MA.5, a similar but independent clinical trial. Design: TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to CEF or CMF in the MA.5 trial. Patients were classified according to 2 predefined marker profiles — the HT profile (HER2, TIMP-1) and the 2T profile (TOP2A, TIMP-1) and the statistical analyses were performed as closely as possible to the analytical approach used previously in the MA.5 trial and when analysing the biomarker profiles in the DBCG 89D trial. Results: 98 (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. 44% of patients were classified as HT responsive (HER2-positive and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT responsive patients, CEF was superior to CMF with improved RFS (adjusted HR, 0.64; 95% CI, 0.42 to 0.98) and a borderline-significant improvement in OS (adjusted HR, 0.66; 95% CI, 0.42 to 1.04). A significant HT profile versus treatment interaction was detected for OS (P=0.03). In 2T responsive patients, CEF was superior to CMF with borderline significant improvement in RFS (adjusted HR, 0.67; 95% CI, 0.43 to 1.03), and with improvement in OS (adjusted HR, 0.58; 95% CI, 0.36 to 0.93). A significant 2T profile versus treatment interaction was detected for OS (P=0.01). Conclusion: In the MA.5 trial, we have validated the HT and 2T profiles as predictors of incremental benefit from anthracycline-containing chemotherapy. The proportion of patients categorized as anthracycline responsive increases from 18–27% using individual markers to 37–44% when combining TIMP-1 with either HER2 or TOP2A. Patients with responsive profiles had a 34–42% relative reduction in mortality when treated with CEF. In contrast, patients with non-responsive profiles (56-63% of patients) had no incremental benefit from CEF compared with CMF. All 3 biomarkers are easily applied in the pathology lab and as such could be used in daily clinical practice to select patients for anthracycline or non-anthracycline containing adjuvant chemotherapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-07.

Prediction of late recurrences by breast cancer index in the NCIC CTG MA.17 cohort.

2 Background: The MA.17 trial demonstrated that extended adjuvant endocrine therapy with letrozole after 5-y of tamoxifen markedly reduced the risk of recurrence in women with ER+ early stage breast cancer. This trial provides an opportunity to assess the ability of biomarkers to predict late recurrences in ER+ breast cancer. The Breast Cancer Index (BCI), a continuous risk index based on the combination of HOXB13:IL17BR (H:I) and the molecular grade index (MGI), estimates the individual risk of recurrence in ER+ breast cancer patients. In this study, the prognostic utility of BCI to predict late recurrences was examined. Methods: FFPE tumor blocks were collected from patients who experienced a breast cancer recurrence up to unblinding of MA.17. Controls were matched 2:1 for age, tumor size, nodal status and prior chemotherapy, and were disease free for longer than cases. All cases were reviewed for standard histopathology and evaluated using the real-time RT-PCR BCI assay. Results: Patient characteristics for the case-control study were similar to that from the overall study. Characteristics for cases (N=83) and controls (N=166) were not significantly different except for treatment. A higher percentage of controls compared to cases tended to be categorized as low risk by BCI (58% vs 43%), while a lower percentage of controls than cases tended to be categorized as high risk by BCI (34% vs 24%). In univariate analysis, treatment, BCI, H:I and HOXB13, but not tumor grade or MGI, were significant predictors of late recurrence. After adjusting for standard variables (age, tumor grade and treatment), BCI (OR 2.37; P=0.03), H:I (OR 2.55; P=0.04) and HOXB13 (OR 1.35; P=0.02) remained significant predictors of recurrence. HOXB13 expression at diagnosis predicted patient benefit from extended endocrine therapy with letrozole. Conclusions: In this case-controlled study, the data demonstrate that BCI is a significant predictor of late recurrences in ER+ patients following 5-y of tamoxifen. The prognostic performance of BCI to predict late recurrences was largely dependent on HOXB13 expression. The integration of H:I and MGI within BCI provides prognostic utility for both early and late recurrences.

Randomized Trial of Tamoxifen Versus Combined Tamoxifen and Octreotide LAR Therapy in the Adjuvant Treatment of Early-Stage Breast Cancer in Postmenopausal Women: NCIC CTG MA.14

Somatostatin analogs act directly on breast cancer cells and indirectly on insulin and insulin-like growth factor 1 (IGF-1) levels. This trial was undertaken to assess whether octreotide would lower insulin and IGF-1 levels and reduce risk of breast cancer recurrence. The NCIC CTG MA.14 (NCIC Clinical Trials Group MA.14) trial randomly assigned postmenopausal women to 5 years of tamoxifen 20 mg daily (TAM) or TAM plus 2 years of octreotide 90 mg depot intramuscular injections monthly (TAM-OCT) as adjuvant therapy. The primary end point was event-free survival (EFS). Secondary end points were relapse-free survival (RFS), overall survival (OS), toxicity, and effects of treatment on IGF physiology. Among 667 women with a median follow-up of 7.9 years, 220 events occurred-108 with TAM-OCT and 112 with TAM. Adjusted hazard ratios (HRs; TAM-OCT to TAM) were 0.93 for EFS (95% CI, 0.71 to 1.22; P = .62), 0.84 for RFS (95% CI, 0.59 to 1.18; P = .31), and 0.97 for OS (95% CI, 0.69 to 1.37; P = .86). Among patients with normal baseline gallbladder imaging, cholecystectomy was required in 23.0% of those receiving TAM-OCT but in only 1.4% of those receiving TAM (P < .001). At 4 months, TAM-OCT had significantly (P < .001) lowered IGF-1, IGF binding protein 3, and C-peptide levels. Older age (P = .02), tumor size (P = .001), nodal status (P = .01), high C-peptide levels (P < .001), and higher body mass index (BMI) in models excluding C-peptide (P < .001) were associated with poorer EFS in multivariate analysis. Octreotide-related changes in circulating IGF-1 and C-peptide levels were statistically significant. Octreotide did not add significant clinical benefit. High C-peptide levels (surrogate for insulin secretion rate) and high BMI were associated with poor outcome.

Elevated Bone Turnover Predicts for Bone Metastasis in Postmenopausal Breast Cancer: Results of NCIC CTG MA.14

We investigated the association of bone-only relapse with a pretreatment marker of bone resorption: serum beta C-terminal telopeptide (B-CTx) of type I collagen. Pretreatment serum B-CTx concentrations were determined from 621 of 667 patients with primary breast cancer enrolled onto the NCIC CTG MA.14 phase III adjuvant trial of tamoxifen with or without octreotide. Recurrence-free survival (RFS) was a secondary end point; the focus here was bone-only relapse. We analyzed continuous or categorical (.71 ng/mL cut point) serum B-CTx in stepwise forward multivariate Cox regression, adjusted for trial stratification factors. We also examined B-CTx and bone relapse by pretrial chemotherapy status. At median 7.9 years follow-up, 123 of 621 patients experienced recurrence; 19 (3.1%) of 621 had bone-only recurrence, and 47 (7.5%) of 621 had bone plus other sites of recurrence. Larger pathologic tumor size (P = .001) and elevated continuous and categorical serum B-CTx were associated with shorter bone-only RFS (both P = .02) when added to a model with factors significant in the main trial analyses (hazard ratio [HR], 3.43 and 3.50, respectively; 95% CI, 1.20 to 9.77 and 1.26 to 9.75, respectively). The univariate HR for B-CTx was 2.80 (95% CI, 1.05 to 7.48; P = .03). Elevated serum B-CTx was also associated with shorter bone-only RFS (P = .02) when added to a model with factors significant in the main trial analyses. Serum B-CTx level was not associated with any other type of recurrence. Serum B-CTx was not significantly different for patients who underwent pretrial chemotherapy, compared with those who did not (P = .27), nor did pretrial chemotherapy affect bone relapse (P = .48 for bone only; P = .76 for bone with other relapse). Higher pretreatment serum B-CTx was a significant predictor of shorter RFS for bone-only metastasis. Increased bone resorption creates an environment that promotes growth of breast cancer cells.

NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer.

LBA1003 Background: Randomized trials have demonstrated that locoregional radiation after mastectomy reduces locoregional recurrence and improves overall survival (OS) in women with node positive breast cancer treated with adjuvant systemic therapy. MA.20 evaluated the addition of regional nodal irradiation (RNI) to whole breast irradiation (WBI) following breast conserving surgery (BCS). Methods: Women with high risk node-negative or node-positive breast cancer treated with BCS and adjuvant chemotherapy and/or endocrine therapy were stratified by positive nodes, axillary nodes removed, chemo- and endocrine therapy and randomized to WBI (50Gy in 25 fractions +/- boost irradiation) or WBI plus RNI (45Gy in 25 fractions) to the internal mammary, supraclavicular, and high axillary lymph nodes. The primary outcome was OS. The Data Safety Monitoring Committee approved the analysis plan for the protocol specified interim analysis of relapse patterns, survival and toxicity at 5 years. Upon review of the data, they recommended release of the results. Results: Between March 2000 to March 2007, 1,832 women were randomly assigned to WBI+RNI (916) or WBI (916). Median follow-up was 62 months. Characteristics of the study population were: mean age, 53.3 years; node negative, 10%; 1-3 positive nodes, 85%; &gt; 4 positive nodes, 5%; adjuvant chemotherapy, 91%; and adjuvant endocrine therapy, 71%. WBI+RNI in comparison to WBI alone was associated with an improvement in isolated locoregional disease free survival (DFS; HR=.59, p=.02, 5 year risk: 96.8% and 94.5% respectively), distant DFS (HR=.64, p=.002, 5 year risk: 92.4% and 87.0% respectively), DFS (HR=.68, p=.003, 5 year risk: 89.7% and 84.0% respectively) and OS (HR=.76, p=.07, 5 year risk: 92.3% and 90.7% respectively). WBI+RNI in comparison to WBI was associated with an increase in grade 2 or greater pneumonitis (1.3% and 0.2% respectively, p=.01), and lymphedema (7.3% and 4.1% respectively, p=.004). Conclusions: The majority of women with node positive breast cancer are now managed by BCS followed by WBI and adjuvant systemic therapy. Results from MA.20 demonstrate that additional RNI reduces the risk of locoregional and distant recurrence, and improves DFS with a trend in improved OS.

Measurement of baseline serum SDF-1 levels as a predictive biomarker for outcomes in the NCIC CTG MA.14 trial of octreotide, a somatostatin analogue in postmenopausal breast cancer.

577 Background: Stromal cell derived-factor 1 (SDF-1) is a chemokine implicated in breast tumor growth and metastasis. Blood SDF-1 levels have a significant prognostic value in primary breast cancers. We have reported that 4 month serum SDF-1 levels had a significant EFS predictive value in the adjuvant breast cancer population of MA.14 (ASCO 2010). Here, we sought to confirm the association with baseline assessments of SDF-1. Methods: NCIC CTG MA.14 is a randomized phase III trial in postmenopausal women of tam 20 mg daily for 5 yr +/- octreotide LAR for 2 yr. Stratification factors were adjuvant chemo, axillary nodal status, and ER status. The primary endpoint was event-free survival (EFS) defined as time from randomization to recurrence, second malignancy, or death due to any cause. Serum was collected at various timepoints throughout the trial. Baseline SDF-1 serum levels were measured with an ELISA kit (R&D). To assess the effect of SDF-1 on EFS in the context of factors considered in the main trial, we used step-wise forward multivariate adjusted Cox modeling, adjusting by the stratification factors, and adding a factor if the likelihood ratio criterion was significant, p ≤ 0.05. Events for the analysis were those reported at ASCO 2008. Results: 667 women were accrued (333 to tam, 334 to tam + oct), and followed for a median 7.9 years. We successfully measured the baseline levels of SDF-1 in 469 (70%) patients, 241 on tamoxifen arm, of whom 80 (33%) experienced an EFS event; and for 228 on tamoxifen and octreotide LAR arm, of whom 70 (31%) had an EFS event.Consistent with our previous findings, we found that in a step-wise multivariate analysis, higher log (SDF-1) (p < 0.0001) was significantly associated with worse EFS. Also, the interaction of treatment and SDF-1 split at median was significantly (p < 0.0001) associated with EFS with inclusion of the significant main trial factors. Conclusions: We have confirmed that baseline SDF-1 levels have a predictive value in the breast cancer population of MA.14 treated with octreotide LAR. Further validation of SDF-1 and investigation of a possible pharmacogenetic effect with octreotide therapy is warranted.

Measurement of Pax2, TC21, CCND1, and RFS1 as predictive biomarkers for outcomes in the NCIC CTG MA.12 trial of tamoxifen after adjuvant chemotherapy in premenopausal women with early breast cancer.

560 Background: Several molecular factors have been associated with the sensitivity of breast cancers to tamoxifen (T). Pax2 can mediate the repression of ERBB2 expression by the tamoxifen-ER compl...

NCIC CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer.

LBA1003 The full, final text of this abstract will be available in Part II of the 2011 Annual Meeting Proceedings, distributed onsite at the Meeting on June 4, 2011, and as a supplement to the June 20, 2011, issue of Journal of Clinical Oncology.

Relationship of treatment-emergent symptoms and recurrence-free survival in the NCIC CTG MA.27 adjuvant aromatase inhibitor trial.

525 Background: New vasomotor or joint symptoms within 3 months of initiating either tamoxifen or anastrozole in the ATAC trial predicted superior recurrence-free survival (RFS). We hypothesized that women treated with anastrozole (A) or exemestane (E) in NCIC CTG Trial MA.27 who developed new or worsening vasomotor or joint symptoms would have improved RFS. There was no evidence of this correlation at the second interim analysis. We now report results by treatment arm from the final analysis. Methods: 7,576 ER+ postmenopausal women with early breast cancer were accrued to MA.27. Final analysis revealed no significant differences between A and E in the primary endpoints, event free or overall survival. We examined the effect of emergent vasomotor and joint symptoms 3 and 12 months following treatment initiation with A and E on subsequent RFS events excluding non-breast cancer deaths. We examined associations of symptoms with patient characteristics using chi-square tests, and associations of early symptoms and disease outcomes using stratified log-rank and stratified univariate and multivariate Cox modeling. Results: Of 4,812 women who were asymptomatic at baseline, 53% experienced new symptoms at 12 months; the RFS stratified univariate Cox hazard ratio (HR) for new symptoms was 0.84 (95% CI, 0.652-1.093). With all 7,246 evaluable women included, 53% of women developed new or worsening symptoms at 12 months and RFS was not statistically significant between women with or without new or worsening symptoms (HR 0.928, 95% CI, 0.755-1.142). Higher T stage (p<0.001) and more fractures prior to allocation (p=0.01) were associated with worse RFS. Only 5% of women reported new or worsening symptoms at 3 months, which were not associated with outcome. Drug assignment did not influence new or worsening symptoms. Conclusions: In contrast to findings in the ATAC trial, we did not observe an association between emergence of symptoms at either 3 or 12 months with improved RFS. Until prospective data are available, clinicians should not use treatment-emergent symptoms to counsel their patient whether to continue, or change, their prescribed adjuvant AI. PG is supported in part by the Avon Foundation NY.

Effects of adjuvant exemestane versus anastrozole on bone mineral density: Two-year results of the NCIC CTG MA.27 bone companion study.

518 Background: In MA.27 [Exemestane (EX) vs Anastrozole (AN) for 5 years], we hypothesized EX, an irreversible steroidal aromatase inhibitor (SAI), would affect bone turnover and risk of OP less than the non-SAI AN. Methods: MA.27 B recruited 497 patients (pts) from the main study into 2 cohorts: pts without OP (n=300; Group A) and pts with OP (n=197; Group B). Both groups received 800 IU Vit. D and 1000mg Calcium daily and Group B had additional bisphosphonate. Total hip and L1-L4 (postero-anterior) spine BMD were measured yearly for 5 years, with censoring of Group A if OP developed. Where possible, centrally reviewed BMD, and left hip data were used. Lunar data in g/cm2was converted to hologic equivalent. The co-primary objectives for Groups A and B were to determine differences in hip and spine BMD at 2 years. Two-sided Bonferroni adjusted Mann-Whitney tests were used to examine per person + change in BMD from baseline to 2 years (below, p<=0.025 for 5+ significance) and -t-tests, for treatment arm 6 and 12 month differences from baseline in serum P1NP and N-telopeptide. Results: Group A (n=287 eligible pts) and Group B (n=184 eligible pts) had the following results (shown in the table). There were no significant changes in bone turnover markers at 6 and 12 months. For women without OP, the group mean spine BMD change was 0.79+ on EX compared to −3.72+ on AN (p=0.05). Conclusions: In women without OP and not on bisphosphonate therapy, there is less early bone loss at the hip with adjuvant EX than with AN at year 1. For women with OP, bisphosphonate, calcium and vitamin D increased BMD despite AI therapy at one and two years. Percent change in patient BMD g/cm2. Exemestane Anastrozole N Mean % (95% CI) N Mean % (95% CI) P value At 1 year Hip Group A 99 -0.62 (-1.48; 0.23) 114 -1.66 (-2.73; -0.54) 0.007 Group B 64 0.61 (-1.81; 3.04) 66 0.83 (-0.16; 1.82) 0.23 L spine Group A 102 -0.59 (-1.73; 0.54) 116 -1.88 (-3.06; -0.7) 0.32 Group B 69 3.75 (2.13; 5.36) 66 2.6 (1.24; 3.96) 0.67 At 2 years Hip Group A 83 -1.93 (-2.93; -0.93) 79 -2.47 (-4.02; -0.92) 0.13 Group B 61 2.09 (-1.45; 5.63) 54 0.09 (-3.64; 3.82) 0.35 L spine Group A 87 -0.92 (-2.35; 0.5) 77 -2.39 (-3.77; -1.01) 0.08 Group B 63 2.11 (-0.84; 5.06) 57 3.72 (1.54; 5.89) 0.26

Abstract P3-10-26: Quantitative Protein and Gene Expression Biomarkers of Tamoxifen and Letrozole Recurrence in the NCIC CTG MA.17 Cohort

Abstract Background: The MA.17 study showed that extended adjuvant endocrine therapy with letrozole (LET) after completing 5 years of tamoxifen (TAM) markedly reduced the risk of recurrence in women with ER+ early stage breast cancer and improved overall survival in women presenting with node +ve disease. The HOXB 13:IL17BR gene expression ratio (signature) has been shown to predict outcome in breast cancer patients treated with adjuvant tamoxifen monotherapy and provides additional information beyond that from known positive (ER and PR) and negative (Her-1 and Her-2) predictors of responsiveness to tamoxifen in node-ve women. We report a case control evaluation of the Breast Cancer Index (BCI; bioTheranostics, Inc.), which combines the HOXB13 and IL17BR twogene and the molecular grade index (MGI) gene expression signatures, with respect to distinguishing which patients are at risk of late recurrences and who would respond to extended endocrine therapy with LET. The prognostic and predictive utility of quantitative immunofluorescence of ER, PR, Her-2, tumor aromatase, COX-2, GATA3 and Nat1 in the TAM-PLACEBO and the TAM-LET cohorts will also be evaluated and compared to results derived by standard immunohistochemistry. Methods: FFPE tumor blocks were collected from patients who experienced a breast cancer recurrence up to unblinding of MA.17. Controls were matched 2:1 for age, tumor size, lymph node status, and prior chemotherapy, and were all disease free for longer than cases. All cases were reviewed for standard histopathology by two independent pathologists. RNA was extracted, amplified, converted to cDNA and subjected to RT-PCR with primers and probes to HOXB13, IL17BR, BUB1A, CENPA, NEK2, RACGAP1 and RRM2. ER, PR HER1, HER2, COX2, Aromatase, GATA3 and NAT1 will be analyzed by routine IHC techniques and by immunoflourescent Automated Quantitative Analysis (AQuA). Results: 105 cases and 210 matched controls are available for evaluation. All sections are under review and tissue microarrays have been performed on all cases and controls. Detailed results on the BCI and ER, PR, Her-2 will be available at the SABCS. Discussion: MA.17 has shown that extended adjuvant endocrine therapy after tamoxifen is effective at preventing disease recurrence given for an additional 5 years. Numerous clinical trials are exploring whether extending AIs will show this benefit, and there is an increasing need to improve the therapeutic index by distinguishing those at risk from those who are not. It is also important to determine which patients will benefit from the therapy and which will recur without benefit. The latter patients could be triaged to clinical trials of novel therapies to overcome endocrine resistance. This study will help to define these issues and pave the way for more effective selection of specific patients for adjuvant endocrine strategies. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-26.

Abstract S1-1: Final Analysis of NCIC CTG MA.27: A Randomized Phase III Trial of Exemestane Versus Anastrozole in Postmenopausal Women with Hormone Receptor Positive Primary Breast Cancer

Abstract Background: The non-steroidal reversible aromatase inhibitor (AI), anastrozole (A) is approved as adjuvant monotherapy in hormone receptor (HR) positive early breast cancer (EBC). The steroidal irreversible AI exemestane (E) is approved in sequence after an initial 2-3 years of tamoxifen. MA27 tested the hypothesis that exemestane would have greater efficacy and better end-organ safety than anastrozole for several reasons: E is an irreversible and more potent AI than A; unlike A, E does not induce intra-tumoral aromatase and; through its mild androgenic activity E may exert a second anti-tumor effect and a more favorable bone and lipid metabolism profile than A. Initially the study also tested the role of a cyclooxygenase-2 inhibitor, celecoxib, used in combination with an AI. However, celecoxib was discontinued early in MA27 following identification of cardiovascular toxicity with COX-2 inhibitors. Methods: Postmenopausal women with hormone receptor positive primary breast cancer were randomized after adequate local treatment to 5 years of adjuvant A (1mg/day) or E (25mg/day) with or without celecoxib/placebo (400mg/plac twice daily for 3 years). The primary objective is the comparison of event free survival (EFS) between women treated with A or E. Secondary objectives include overall survival (OS), distant recurrence (DDFS), incidence of contralateral breast cancer (CBC) and safety. Quality of Life in a subset of women has been evaluated, and a very extensive tissue bank created. Stratification included: prior chemotherapy; lymph node status, celecoxib (during use), aspirin use (during randomization to celecoxib), and trastuzumab use (since November 2005). The primary endpoint (EFS) will look for an improvement from 87.5% to 89.9%; HR 0.80, 2-sided 5% level and 80% power, with 644 events required. Results: 7576 women were randomized between June 2003 and July 2008. Celecoxib/placebo, was discontinued 2 years into the trial in December 2004 after 1635 patients had received celecoxib. The number of events required for final analysis was reached April 2010. Patient characteristics were balanced for age (median 64.1yrs); race; ECOG PS; mastectomy; TNM staging and; prior adjuvant chemotherapy. EFS, OS, DDFS, and CBC as well as clinical fractures, cardiovascular events and adverse events will be presented by arm in the final analysis. Conclusions: NCIC CTG MA.27 is the first definitive EBC trial comparing a non-steroidal and steroidal AI as initial adjuvant therapy. Exemestane is not currently approved as initial adjuvant treatment and superiority or equivalence will lead to its inclusion as a first-line option for EBC in postmenopausal HR positive breast cancer. Efficacy, clinical fractures, cardiovascular events and AI related symptoms will help to define the cost-benefit ratios of these two AIs. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-1.

Abstract PD03-04: Effects of Diabetes (DM), Hypertension (HTN) and Coronary Artery Disease (CAD) on Prognosis after 5 Years of Adjuvant Tamoxifen (TAM) and on Treatment Outcomes with the Use of Extended Letrozole (LET): NCIC CTG MA.17

Abstract Background: Women with early stage breast cancer and DM have poorer survival compared to non-DM women (Lipscombe 2008). Mechanisms include insulin dysregulation and/or DM related comorbidities such as HTN and CAD. MA.17 showed that adjuvant LET after five yrs of TAM reduced the risk of recurrence in women with ER+ early stage breast cancer and improved survival in node +ve disease. We evaluated the impact of DM, HTN, or CAD on prognosis after 5 yrs of TAM and the efficacy of LET in MA.17. Methods: All 5170 women randomized to MA.17 were included. Four year disease free survival (DFS), distant disease free survival (DDFS) and overall survival (OS) were compared using Cox regression model adjusting for other prognostic factors: a) in women treated with placebo (PLAC) based on the presence or absence of baseline DM (n=462), HTN (n=1627), CAD (n=604) or any one of these comorbidities (n=2049), and b) between LET and PLAC groups in each comorbidity. Analyses based on nodal status were also performed. Test for interaction assessed for differential treatment effects in comorbidity groups. Results: Women with DM on PLAC had non-significant lower DFS (89.7 vs. 89.9%, p=0.68), DDFS (92.1 vs 93.9%, p=0.85), and OS (92.1 vs 95.2, p=0.37) than those without DM on PLAC. Treatment effect outcomes were similar between those with and without DM. Women with HTN on PLAC trended toward lower DDFS (92.2 vs 94.4%, HR=1.50, 95%CI: 0.98-2.3, p=0.06) and OS (93.7 vs. 95.5%, HR=1.61, 95%CI: 0.95-2.72, p=0.08) than non-HTN women on PLAC. The interaction between treatment and HTN status was significant for DDFS (p=0.004) with HTN women having significantly better outcome on LET vs PLAC (HR=0.27, 95%CI: 0.13 to 0.54; p=0.0002) compared to non-HTN women on LET vs PLAC (HR=0.82, 95%CI: 0.56-1.20; p=0.31). Women with CAD on PLAC did not have worse outcome, nor did CAD status have a treatment related effect. Women with at least one co-morbidity on PLAC had significantly lower OS (93.6 vs. 95.8%, HR=2.10, 95%CI:1.26-3.51, p=0.004) than those free of comorbidity. For node +ve women, the difference between LET and PLAC in DDFS was greater among women with at least one co-morbidity (HR=0.30, 95%CI:0.15-0.60, p=0.001) compared to those without any co-morbidity (HR=0.72, 95%CI:0.45-1.16, p=0.17) with interaction p=0.04. Conclusions: Having at least one comorbidity was a negative prognostic indicator for OS after 5 yrs of TAM and led to improved DDFS for node +ve women taking LET. DM was not prognostic nor did it predict treatment outcomes. Explanations include not controlling for DM medications; as well, MA.17 enrolled women 5 yrs after TAM with evidence suggesting hyperinsulinemia being a risk for early rather than late recurrence. HTN was a potential risk factor with a trend for worse DDFS and OS. HTN also predicted for treatment benefit: HTN women on LET had improved DDFS compared to non-HTN women on LET. Hypothesis include antihypertensive agents slowing the metabolism of LET; alternatively there may be variations in VEGF levels between groups. HTN predictive effects will be further explored in MA.27 with potential to correlate with VEGF levels. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD03-04.

Abstract P4-09-09: Serum SDF-1: Biomarker of Bone Relapse in the NCIC MA.14 Adjuvant Breast Cancer Trial

Abstract Background: Massague et al have shown that breast cancer cell line subpopulations with elevated bone metastatic activity overexpress chemokine receptor 4 (CXCR4), interleukin 11 (IL11), osteopontin (OPN) and connective tissue growth factor (CTGF) (Cancer Cell 3:537, 2003). CXCR4 overexpression results in bone-homing and extravasation of tumor cells in bone. In MA.14, we found that serum β-CTx was associated with bone-only relapse while Basik et.al showed that higher serum stromal cell-derived factor 1 (SDF-1) (ligand for CXCR-4) levels were associated with worse overall event-free survival (EFS) (ASCO 2010). In this study, we examined concurrently the association of both β-CTx and serum SDF-1 with bone relapse. Methods: Serum β-CTx (Serum CrossLaps, Nordic Biosciences, Copenhagen, DN) was determined in pretreatment sera from 621 of 667 NCIC CTG MA.14 patients. SDF-1 (CXCL12) (R&amp;D Systems, Minneapolis, MN) levels were successfully determined in the 4 month post-treatment serum (SDF-1) for 508 (76%) of the patients. Trial stratification was by administration of adjuvant chemotherapy, axillary lymph node status, and ER and/or PR status. Recurrence-free survival (RFS) was defined as the time from randomization to the time of recurrence of the primary disease. Adjusted and unadjusted Cox step-wise forward multivariate analyses were used to assess the effects of β-CTx, SDF-1, trial therapy and baseline patient characteristics on non-bone, all bone and bone-only RFS; a factor was added if p&amp;lt;=0.05. Results: Joint assessment of β-CTx and SDF-1 was possible for 493 (74%) of the 667 patients. Imbalances in who was, or was not, included in this subset led to the trial arm of Tamoxifen + Octreotide LAR having a significant longer unadjusted ITT non-bone RFS (p=0.03-0.06). There was shorter time to bone metastasis of any type with higher lymph node involvement (p=0.001), larger T (p=0.02), and higher log SDF-1 (p=0.03). Meanwhile, high categorical and continuous β-CTx was associated multivariately with shorter bone-only RFS (p=0.04 and 0.01, respectively); higher log SDF-1 was only associated with shorter bone-only RFS (p=0.02) when the number of strata were reduced to 2 categories per factor. Conclusions: Higher serum SDF-1 level may be associated with bone metastasis, although there is less evidence of its relevance in bone-only relapse than there is for the biomarker β-CTx. Serum SDF-1 deserves further study as a promising predictive factor of bone relapse in breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-09.

Metabolic Syndrome, Insulin Resistance, and Inflammation in Breast Cancer: Impact on Prognosis and Adjuvant Interventions

The metabolic syndrome, a clinical syndrome that includes central obesity, dyslipidemia, hypertension and glucose intolerance, has been associated with diabetes and cardiovascular disease. Recent evidence links it to breast cancer risk and outcome and suggests that existing adjuvant therapies may exacerbate the syndrome and have reduced efficacy when the syndrome is present. Potential mediators of effects of the syndrome on cancer include insulin/insulin-like growth factor, adipocytokines such as leptin, and markers of inflammation such as interleukins, C-reactive protein, and serum amyloid A. Growing epidemiologic, clinical, and preclinical evidence suggests insulin may be a key mediator. Potential interventions include changes in lifestyle (weight loss, increased physical activity) or pharmacologic approaches. Metformin, a drug commonly used to treat diabetes that reduces the hyperinsulinemia and hyperglycemia associated with the metabolic syndrome, shows promise in epidemiologic, preclinical, and clinical work. Interventions trials involving metformin are underway, including a large adjuvant study by the National Cancer Institute of Canada known as NCIC CTG MA.32.

Prognostic and predictive impact of biologic classification by qRT-PCR with a 50-gene subtype predictor (PAM50) for adjuvant tamoxifen in premenopausal breast cancer: Results from the NCIC CTG MA.12 randomized trial.

508 Background: Gene expression profiling has reclassified breast cancer into intrinsic subtypes based on the biology of the underlying disease pathways. We have utilized material from a prospective randomized trial of tamoxifen versus placebo in premenopausal women with primary breast cancer who have completed adjuvant chemotherapy (NCIC CTG MA.12) in order to evaluate the prognostic and predictive significance of intrinsic subtypes as classified by both the PAM50 gene set and an IHC panel of biomarkers. Methods: Total RNA from 399/672 (59%) patients were available for intrinsic subtyping with a 50 gene predictor (PAM50) by qRT-PCR for luminal A, luminal B, HER-2 enriched and basal like subtypes. A tissue microarray (TMA) was also constructed from 492/672 (72%) of the study population to assess a panel of six IHC antibodies (ER, PR, HER2, EGFR, CK 5/6 and Ki67), with established cut-offs, to define the same intrinsic subtypes. Results: There were no apparent differences in baseline characteristics between all patients randomized to the trial and patients with either PAM50 or IHC datasets. PAM50 by qRT- PCR classified 35% as luminal A, 21% luminal B, 18% HER2-enriched and 21% basal-like. Intrinsic subtypes as classified by the PAM50 assay was clearly prognostic for both RFS (p = 0.0003) and OS (p = 0.0002), whereas classification by the IHC panel was not (p = 0.63 and 0.11 for RFS and OS respectively). Luminal subtypes by PAM50 was predictive of tamoxifen benefit (RFS: HR 0.56; 95% CI 0.35-0.90 vs HR 0.80; 95% CI 0.49-1.30 for non-luminal subtypes), though the interaction test was not significant (p = 0.35), whereas neither subtyping by central IHC panel (HR 0.75; 95% CI 0.51-1.09) nor by local ER status was predictive of tamoxifen benefit. Risk of relapse (ROR) modeling with the PAM50 assay will be presented. Conclusions: In the MA.12 study, intrinsic biological classification by qRT-PCR with the PAM50 assay is superior to IHC profiling for both prognosis, and prediction of benefit from hormone therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration University Genomics Bioclassifier LLC