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ASCO believes that high-quality observational studies can advance evidence-based practice for cancer care and are complementary to randomized controlled trials (RCTs). Observational studies can generate hypotheses by evaluating novel exposures or biomarkers and by revealing patterns of care and relationships that might not otherwise be discovered. Researchers can then test these hypotheses in RCTs. Observational studies can also answer or inform questions that either have not been or cannot be answered by RCTs. In addition, observational studies can be used for postmarketing surveillance of new cancer treatments, particularly in vulnerable populations. The incorporation of observational research as part of clinical decision making is consistent with the position of many leading institutions. ASCO identified five overarching recommendations to enhance the role of observational research in clinical decision making: (1) improve the quality of electronic health data available for research, (2) improve interoperability and the exchange of electronic health information, (3) ensure the use of rigorous observational research methodologies, (4) promote transparent reporting of observational research studies, and (5) protect patient privacy.

675 Background: Recent retrospective analysis of CALGB/SWOG 80405 showed that left-sided colon cancers (LCC) respond differently to biological therapy compared with right-sided tumors. However, differences between rectal cancers (RC) and LCC remain undefined. Herein, we report our exploration of differences between these two groups. Methods: Individual patient data from 4182 patients (pts) with metastatic colorectal cancers, enrolled onto 8 first-line randomized trials, were pooled. Only pts with tumor locations that were clearly defined as LCC (splenic flexure to sigmoid) or RC were included in this analysis. Differences in pt characteristics and disease factors according to LCC vs. RC were identified. The prognostic effect of primary tumor location on OS and PFS was quantified via multivariable Cox proportional hazards modeling stratified by treatment arm within each study and adjusting for age, sex, performance status, and prior surgery. Results: In total, 2,479 (59%) pts with LCC and 1,703 (41%) pts with RC were identified. Pts with RC, compared with LCC, were more likely to be male (68% vs. 62%, p < 0.001), have lung metastases (mets) (56% vs. 37%, p < 0.001), and have 2 or more metastatic sites (64% vs. 60%, p < 0.02), whereas pts with LCC were more likely to have liver mets (84% vs. 76%, p < 0.001). RC had a greater frequency of KRAS mutations (41% vs. 37%, p = 0.04) than LCC but there were no differences in the frequency of BRAF mutations (5% vs. 4%, p = 0.2). In multivariable analysis, no differences in OS or PFS were observed between pts with LCC vs. RC. While risk of death did not differ by primary tumor location, across all pts with LCC or RC, those with liver mets had a 17% increased risk of death compared to those with lung mets (HR = 1.17, p = 0.03) after adjusting for effects of other variables. Forthcoming prognostic analysis of LCC vs. RC within grouped backbone treatments (e.g., FOLFOX and FOLFIRI) is underway. Conclusions: Tumors arising in the rectum may carry clinical and molecular features that are distinct from LCC. Further investigations are warranted to determine whether RC should be treated with the same chemo backbone and biological therapy as LCC.

LBA1000 Background: The primary aims were to determine whether adjuvant DD AC→PG will be superior to DD AC→P as well as to TAC in DFS and to compare the relative DFS of TAC and DD AC→P. Secondary endpoints include survival and toxicity. Methods: From Nov 3, 2004 to May 3, 2007, 4894 women were randomized; 1630 to TAC (docetaxel [T] 75 mg/m2, doxorubicin [A] 50 mg/m2, cyclophosphamide [C] 500 mg/m2 q3 wks x 6), 1634 to DD AC→P (A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 followed by P 175 mg/m2 q2 wks x 4), and 1630 to DD AC→PG (A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 → P 175 mg/m2 + G 2000 mg/m2q2 wks x 4). Primary G-CSF support was required and erythropoiesis-stimulating agents (ESA) were used at investigator discretion. 52% were postmenopausal, 65% had 1 - 3 positive nodes, and 80% had HR+ breast cancer. Log-rank tests were used for pair-wise comparisons of the primary (DFS) and secondary (OS) endpoints among the three treatment arms. Results: With 64 months median follow-up, 5-year DFS in DD AC→PG group was 80.6% compared with 82.2% in DD AC→P group (HR=1.1; p=0.27) and 80.1 % (HR=0.97; p=0.71) in TAC group. 5-year OS was 90.8% in DD AC→PG group as compared with 89.1% (HR=.89; p=0.25) in DD AC→P group and 89.6 % (HR=0.90; p=0.32) in TAC group. HR for DFS and OS of DD AC→P vs. TAC were 0.89 (p=0.14) and 1.01 (p=0.92) respectively. Toxicities for TAC, DD AC→P, DD AC→PG, respectively: febrile neutropenia (Gr 3/4: 9%, 4%, 4% [p<0.001]), sensory neuropathy (Gr 3/4: <1%, 7%, 6% [p<0.001]), diarrhea (Gr 3/4: 8 %, 2%, 2% [p<0.001]). Hgb was <10 in 12%, 26%, 33% with ESA use in 35.2%, 47%, 51.6% and transfusions in 3.7%, 6.3%, 9.4%. Deaths on treatment: N=13, 5, 7 (p=0.2). AML/MDS: N=5, 8, 11. All cycles completed in 91% for TAC and 88% for DD regimens. Conclusions: Addition of G to DD AC→P did not improve outcomes. No significant differences in efficacy endpoints were identified between DD AC→P and TAC, though toxicity profiles differed. Funding: NCI PHS U10-CA-37377, -69974, -12027, -69651 and NCCTG U10-CA25224, with additional funding from Eli Lilly & Company, and Amgen, Inc.

LBA4 Background: WBRT significantly improves tumor control in the brain after SRS, yet the role of adjuvant WBRT remains undefined due to concerns regarding neurocognitive risks. Methods: Patients with 1-3 brain metastases, each < 3 cm by contrast MRI, were randomized to SRS alone or SRS + WBRT and underwent cognitive testing before and after treatment. The primary endpoint was cognitive progression (CP) defined as decline > 1 SD from baseline in any of the 6 cognitive tests at 3 months. Time to CP was estimated using cumulative incidence adjusting for survival as a competing risk. Results: 213 patients were enrolled with 2 ineligible and 3 cancels prior to receiving treatment. Baseline characteristics were well-balanced between study arms. The median age was 60 and lung primary the most common (68%). CP at 3 months was more frequent after WBRT + SRS vs. SRS alone (88.0% vs. 61.9% respectively, p = 0.002). There was more deterioration in the WBRT + SRS arm in immediate recall (31% vs. 8%, p = 0.007), delayed recall (51% vs. 20%, p = 0.002), and verbal fluency (19% vs. 2%, p = 0.02). Intracranial tumor control at 6 and 12 months were 66.1% and 50.5% with SRS alone vs. 88.3% and 84.9% with SRS+WBRT (p < 0.001). Median OS was 10.7 for SRS alone vs. 7.5 months for SRS+WBRT respectively (HR = 1.02, p = 0.93). Conclusions: Decline in cognitive function, specifically immediate recall, memory and verbal fluency, was more frequent with the addition of WBRT to SRS. Adjuvant WBRT did not improve OS despite better brain control. Initial treatment with SRS and close monitoring is recommended to better preserve cognitive function in patients with newly diagnosed brain metastases that are amenable to SRS. Clinical trial information: NCT00377156.

BACKGROUND. No laboratory test can predict the risk of nonrelapse mortality (NRM) or severe graft-versus-host disease (GVHD) after hematopoietic cellular transplantation (HCT) prior to the onset of GVHD symptoms. METHODS. Patient blood samples on day 7 after HCT were obtained from a multicenter set of 1,287 patients, and 620 samples were assigned to a training set. We measured the concentrations of 4 GVHD biomarkers (ST2, REG3α, TNFR1, and IL-2Rα) and used them to model 6-month NRM using rigorous cross-validation strategies to identify the best algorithm that defined 2 distinct risk groups. We then applied the final algorithm in an independent test set ( n = 309) and validation set ( n = 358). RESULTS. A 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month NRM of 28% in the high-risk group and 7% in the low-risk group ( P < 0.001). The algorithm performed equally well in the test set (33% vs. 7%, P < 0.001) and the multicenter validation set (26% vs. 10%, P < 0.001). Sixteen percent, 17%, and 20% of patients were at high risk in the training, test, and validation sets, respectively. GVHD-related mortality was greater in high-risk patients (18% vs. 4%, P < 0.001), as was severe gastrointestinal GVHD (17% vs. 8%, P < 0.001). The same algorithm can be successfully adapted to define 3 distinct risk groups at GVHD onset. CONCLUSION. A biomarker algorithm based on a blood sample taken 7 days after HCT can consistently identify a group of patients at high risk for lethal GVHD and NRM. FUNDING. The National Cancer Institute, American Cancer Society, and the Doris Duke Charitable Foundation.