Citations

Abstract Background: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium. Methods: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression. Results: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08–1.14, P = 7 × 10−18) for invasive breast cancer and 1.10 (95% CI = 1.01–1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99–1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR = 1.16, 95% CI = 1.12–1.20, P = 1 × 10−18 vs. OR = 1.03, 95% CI = 0.99–1.07, P = 0.2 for PR-negative disease; Pheterogeneity = 2 × 10−7); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14–1.25), 1.13 (1.09–1.16), and 1.04 (0.99–1.08) for grade 1, 2, and 3/4, respectively; Ptrend = 5 × 10−7]. Conclusion: 5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer. Impact: Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants. Cancer Epidemiol Biomarkers Prev; 20(10); 2222–31. ©2011 AACR.

Abstract Purpose: To investigate the associations between baseline and posttreatment circulating tumor cell (CTC) gene expression and outcome of patients enrolled in four North Central Cancer Treatment Group metastatic breast cancer (MBC) trials in which specimens were shipped (at 4°C) from community-based sites to a reference laboratory (Mayo Clinic, Rochester, MN). Experimental Design: Blood was collected at treating sites from MBC patients before (baseline), during, and at the end of treatment with erlotinib + gemcitabine (N0234), sorafenib (N0336), irinotecan + cetuximab (N0436), or paclitaxel-poliglumex + capecitabine (N0437). CTCs from 10 mL of EDTA blood were enriched with CD45 depletion, 24 to 30 hours postblood collection. Reverse transcription/quantitative PCR was used to determine cytokeratin-19 (CK19) and mammaglobin (MGB1) mRNA levels in CTCs from up to 13 (N0234), 16 (N0336), 18 (N0436), and 39 (N0437) patients. The gene expressions were normalized to β2-microglobulin and calibrated to healthy blood using the 2–ΔΔCq algorithm; positivity was defined as 2 or more. Results: CK19+mRNA cells were detected in 56% to 75% and MGB1+mRNA cells in 23% to 38% of 86 patients at baseline. CK19+mRNA cells were detected in 30% to 67% and MGB1+mRNA cells in 14% to 64% of 110 postbaseline serial samples. The presence of baseline CK19+mRNA cells (P = 0.01) but not MGB1+mRNA cells (P = 0.14) was significantly associated with shorter overall survival. A decrease in MGB1+mRNA levels (baseline-week 8) seemed to be associated with clinical response (P = 0.05). Conclusions: CTC gene expression analysis conducted by a reference laboratory is feasible when blood is collected from treating sites and processed 24 to 30 hours postcollection. The presence of baseline CK19+mRNA CTCs was associated with poor prognosis; a decrease in MGB1+mRNA CTCs may help predict response to therapy of MBC patients. Clin Cancer Res; 17(22); 7183–93. ©2011 AACR.

Abstract Purpose: To conduct an exploratory analysis of the relationship between gene expression and recurrence in patients with operable triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin-containing chemotherapy. Experimental Design: RNA was extracted from archived tumor samples derived from 246 patients with stage I-III TNBC treated with adjuvant doxorubicin-containing chemotherapy, and was analyzed by quantitative reverse transcriptase PCR for a panel of 374 genes. The relationship between gene expression and recurrence was evaluated using weighted Cox proportional hazards model score tests. Results: Growth factor receptor bound protein 7 (GRB7) was the only gene for which higher expression was significantly associated with increased recurrence in TNBC (Korn's adjusted P value = 0.04). In a Cox proportional hazards model adjusted for clinicopathologic features, higher GRB7 expression was associated with an increased recurrence risk (HR = 2.31; P = 0.04 using the median as the split). The 5-year recurrence rates were 10.5% [95% confidence intervals (CI), 7.8–14.1] in the low and 20.4% (95% CI, 16.5–25.0) in the high GRB7 groups. External validation in other datasets indicated that GRB7 expression was not prognostic in two adjuvant trials including variable systemic therapy, but in two other trials showed that high GBR7 expression was associated with resistance to neoadjuvant doxorubicin and taxane therapy. Conclusions: GRB7 was associated with an increased risk of recurrence in TNBC, suggesting that GRB7 or GRB7-dependent pathways may serve as potential biomarkers for therapeutic targets. Therapeutic targeting of one or more factors identified which function as interaction nodes or effectors should also be considered. Clin Cancer Res; 17(22); 7194–203. ©2011 AACR.

Purpose Trastuzumab is a humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). The clinical benefits of adjuvant trastuzumab have been demonstrated in interim analyses of four large trials. Initial data of the combined analysis of the North Central Cancer Treatment Group (NCCTG) N9831 Intergroup trial and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial were reported in 2005. Long-term follow-up results on disease-free survival (DFS) and overall survival (OS) have been awaited. Patients and Methods Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab in the NCCTG N9831 and NSABP B-31 trials. The similar design of both trials allowed data from the control and trastuzumab-containing arms to be combined in a joint analysis. Results At 3.9 years of median follow-up, there continues to be a highly statistically significant reduction in DFS event rate in favor of the trastuzumab-containing arm (P < .001). Similarly, there continues to be a statistically significant 39% reduction in death rate in favor of the trastuzumab-containing arm (P < .001). Conclusion These data demonstrate consistent DFS and OS advantages of adjuvant trastuzumab over time, with the longest follow-up reported to date. The clinical benefits continue to outweigh the risks of adverse effects.

Background Acute lung injury (ALI) is a serious postoperative complication with limited treatment options. A preoperative risk-prediction model would assist clinicians and scientists interested in ALI. The objective of this investigation was to develop a surgical lung injury prediction (SLIP) model to predict risk of postoperative ALI based on readily available preoperative risk factors. Methods Secondary analysis of a prospective cohort investigation including adult patients undergoing high-risk surgery. Preoperative risk factors for postoperative ALI were identified and evaluated for inclusion in the SLIP model. Multivariate logistic regression was used to develop the model. Model performance was assessed with the area under the receiver operating characteristic curve and the Hosmer-Lemeshow goodness-of-fit test. Results Out of 4,366 patients, 113 (2.6%) developed early postoperative ALI. Predictors of postoperative ALI in multivariate analysis that were maintained in the final SLIP model included high-risk cardiac, vascular, or thoracic surgery, diabetes mellitus, chronic obstructive pulmonary disease, gastroesophageal reflux disease, and alcohol abuse. The SLIP score distinguished patients who developed early postoperative ALI from those who did not with an area under the receiver operating characteristic curve (95% CI) of 0.82 (0.78-0.86). The model was well calibrated (Hosmer-Lemeshow, P = 0.55). Internal validation using 10-fold cross-validation noted minimal loss of diagnostic accuracy with a mean ± SD area under the receiver operating characteristic curve of 0.79 ± 0.08. Conclusions Using readily available preoperative risk factors, we developed the SLIP scoring system to predict risk of early postoperative ALI.

AbstractApproximately 60% of patients with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) are curable with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemoimmunotherapy. Epratuzumab (E) is an unlabeled anti-CD22 monoclonal antibody with efficacy in relapsed DLBCL. This phase 2 trial tested the safety and efficacy of combining E with R-CHOP (ER-CHOP) in untreated DLBCL. A secondary aim was to assess the efficacy of interim positron emission tomography (PET) to predict outcome in DLBCL. Standard R-CHOP with the addition of E 360 mg/m2 intravenously was administered for 6 cycles. A total of 107 patients were enrolled in the study. Toxicity was similar to standard R-CHOP. Overall response rate in the 81 eligible patients was 96% (74% CR/CRu) by computed tomography scan and 88% by PET. By intention to treat analysis, at a median follow-up of 43 months, the event-free survival (EFS) and overall survival (OS) at 3 years in all 107 patients were 70% and 80%, respectively. Interim PET was not associated with EFS or OS. Comparison with a cohort of 215 patients who were treated with R-CHOP showed an improved EFS in the ER-CHOP patients. ER-CHOP is well tolerated and results appear promising as a combination therapy. This study was registered at www.clinicaltrials.gov as #NCT00301821.

Abstract Identification of HER2 as an important cellular marker in the biology and treatment of breast cancer has highlighted the importance of reliable testing methodology. Controversy exists regarding type of test, reliability, definition of positivity, and which test may best predict for patient (pt) efficacy to anti-HER2 therapies. Purpose: To determine the concordance between HER2 results by 3 central laboratories, impact of round-robin adjudication of discordant cases, and heterogeneity in HER2 results using specimens from 3 adjuvant trials where HER2 testing was performed by local and central laboratories for enrollment. Methods: We performed a blinded round-robin exchange of randomly sampled, HER2-normal (IHC-& FISH-) and HER2-positive breast tumors among 3 central laboratories (NCCTG, BCIRG and NSABP) for confirmatory HER2 testing. The 3 laboratories performed immunohistochemistry (IHC) for HER2 using the HercepTest kit (Dako, Carpenteria, CA) and fluorescence in situ hybridization (FISH) for HER2 using the PathVysion HER2 DNA probe kit/HER2/CEN17 probe mixture (Abbott Molecular, Des Plaines, IL) on 389 tumor specimens obtained from N9831/BCIRG006 (37 IHC+/FISH+, 33 IHC+/FISH-, 36 IHC-/FISH+, 62 IHC-& FISH-) and BCIRG005 (96 IHC-& FISH-); 123 cases had ≥2 blocks examined from the same pt. HER2 positivity was defined according to FDA-approved guidelines used in the clinical trials (IHC+: 3+ complete membrane staining in &gt;10% cells; FISH+: HER2/CEN17 ratio ≥2.0). The HER2 status (IHC: 3+ vs 0-2+; FISH: amplified vs not) for each block was independently determined at each site; discordant IHC and FISH cases were adjudicated at a face-to-face meeting. Results: Independent reads were concordant across pathologists in IHC status in 351/381 (92%) cases and in FISH status in 343/373 (92%) cases. Upon adjudication, a consensus was reached on 16 and 18 of the discordant IHC and FISH cases, respectively. Among 96 BCIRG005 cases, IHC-and FISH-were confirmed in the primary block in all 96 cases. Among 59 evaluable N9831 HER2-normal cases, IHC-and FISH-were confirmed in the primary block in 57 (97%) cases (but another block tested HER2+ for 4 cases). Among 102 N9831/BCIRG006 HER2+ cases, HER2 positivity was confirmed in the primary block in 73 (72%) cases. Among 118 cases with IHC results for &gt; 1 block, the adjudicated IHC result agreed across blocks in 106 (90%) cases. Among 113 cases with FISH results for &gt;1 block, the adjudicated FISH result agreed in 107 (95%) cases. Among 53 N9831 HER2-normal cases adjudicated as IHC-& FISH-(although they all had a previous local HER2+ test), there was significant improvement in disease-free survival associated with trastuzumab given concurrently with paclitaxel after doxorubicin and cyclophosphamide compared to chemotherapy alone (HR=0.31, 95% CI 0.11-0.91; A 23 pts, 10 events; C 30 pts, 5 events). Conclusions: Excellent agreement (96%) was observed among the pathologists at adjudication, suggesting that standardized methods improve assay proficiency. HER2 heterogeneity across blocks was observed more at the protein than at the gene level. In the small subset of N9831 pts adjudicated as HER2-normal trastuzumab benefit was observed. This work was supported by NCI and Genentech. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD10-02.

Abstract Background: NKTR-102, a topoisomerase 1 inhibitor-polymer conjugate with reduced peak concentrations and a continuous concentration profile, demonstrated evidence of anti-tumor activity in a broad range of tumors in phase 1 (Von Hoff; EORTC-NCI-AACR 2008, abstract #595), including three patients (pts) with triple negative breast cancer (one confirmed PR by RECIST, one 20% reduction in tumor burden and one 50%+ reduction in CA 27.29). We now report data of a randomized phase 2 study in pts with MBC following progression to taxane-based therapy. Methods: This open-label, phase 2 study enrolled pts to receive NKTR-102 intravenously (IV) at a target dose of 145 mg/m2. Eligible patients had progressive MBC following taxane therapy, ECOG PS 0-1, adequate renal, hepatic, and marrow function. The study randomized pts to receive NKTR-102 q14d or q21d; each schedule followed a two-stage Simon design to ensure adequate response rate prior to proceeding to full enrollment. The primary endpoint was objective response rate (ORR) by RECIST v1.0; secondary endpoints were safety and PFS. Results: 70 pts were randomized from Feb09 to Apr10 and treated (35 on each schedule); 20 patients remain active on study as of 14Jun2010. Median age was 55 (range 33-83); all but 1 pt was female. ECOG PS 0/1 equaled 40%/60%. Prior neo-adjuvant and adjuvant therapy had been administered in 15 and 39 patients respectively; 23 pts had received prior hormonal therapy. Median number of prior non-hormonal regimens for metastatic disease was 2 (range 0-4). All pts had received prior taxane therapy; 11 in the adjuvant setting and 60 in the metastatic setting). 45 pts had received only prior anthracycline/taxane therapy (“AT”); an additional 14 pts had received prior AT/capecitabine therapy (“ATC”). 42 were estrogen or progesterone receptor positive and 20 pts had triple negative disease. Best RECIST response rate (confirmed and unconfirmed) equaled 27% (9 pts; 2 awaiting confirmation) and 24% (8 pts; 4 awaiting confirmation) for the q14d and q21d schedules (n=33 and 34, respectively; 3 patients had not undergone first on-study CT exam). As ORR results were similar for each schedule, the combined best RECIST ORR for in AT/ATC pts equaled 23%/29%, respectively and in pts with triple negative disease, this equaled 25%. Common related Grade 3/4 toxicities (q14d/q21d schedules; n=67 pts with AE data available): diarrhea (15%/12%), neutropenia (15%/9%),fatigue (12%/3%), and dehydration (6%/3%). One pt in each schedule died due to septic shock and acute renal failure secondary to hypovolemia. Conclusion: Single-agent NKTR-102 demonstrates significant anti-tumor activity in pts with MBC, including pts having tumor progression after ATC-based therapy and pts with triple negative disease, with a tolerable toxicity profile. Mature ORR and median PFS will be available by December 2010. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-01.