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Abstract Background: Pathological complete response (pCR) is accepted by FDA as a surrogate endpoint for accelerated approval of targeted agents in combination with chemotherapy based on better long-term outcomes compared to residual disease (Cortazar 2014). Methods: The multi-center, adaptively-randomized I-SPY2 platform trial uses pCR as the primary endpoint to identify investigational agents that will improve outcomes in women with stage 2/3 breast cancer with high risk of early recurrence, across all signatures, based on hormone receptor (HR), HER2, and 70-gene (MammaPrint) status. For patients with HR+ HER2- tumors, only 70-gene (Mammaprint) high-risk patients are enrolled. To date, 1200+ patients have been randomized to one of 14 arms: control (paclitaxel followed by AC); veliparib/carboplatin; neratinib; MK2206; trebananib; trastuzumab/pertuzumab; ado-trastuzumab emtansine/pertuzumab; pembrolizumabx4; ganitumab/metformin; ganetespib; PLX-3397. 7 agents graduated in at least one signature (> 85% probability of success in a 300-patient phase III confirmatory trial); 2 did not graduate; 1 stopped for toxicity, and 3 are enrolling (patritumab/trastuzumab, talazoparib/irinotecan, pembrolizumabx8). Local pathologists were centrally trained using the Residual Cancer Burden (RCB) assessment to ensure uniform evaluation and response classification; RCB 0 = pCR. Results: We evaluated the relationship between pCR and event free (EFS) and distant disease free survival (DDFS) in the first 522 pts (median follow-up:2.5 years). 180 pts achieved pCR (36%) while 338 did not (RCB=1-3). There were 82 EFS and 65 DRFS events. Over the entire group (including all arms), pCR was highly associated with 3-year EFS (p<0.001 for both). Pts achieving pCR had a 3% recurrence risk (RR) at 3 years; those with non-pCR had 24% RR over this time period. For distant recurrence, the 3-year RR with pCR was 2%, compared to 20% in pts with non-pCR. As expected, pCR rates varied by breast cancer subtype (HR+/HER2: 18% (35/196), HR+/HER2+: 40% (33/82), HR-/HER2+:68% (34/50), HR-/HER2-:41% (76/188)). The relationship between pCR and EFS was significant and clinically impactful within each subtype. 3-year survival (pCR group)Hazard Ratio OverallOverallHR+/HER2-HER2+TNBCEFS97%0.08 (0.03-0.23)0.14 (0.02-1.04)0 (NA)0.11 (0.03-0.37)DDFS98%0.08 (0.03-0.26)0.17 (0.01-1.23)0 (NA)0.09 (0.02-0.40) Conclusions: The first long-term efficacy results from the I-SPY2 TRIAL demonstrate that achieving pCR is a very strong surrogate endpoint for improved EFS and DDFS in a high-risk population, across all treatment arms, regardless of subtype. I-SPY2 shows substantially lower estimated EFS hazards for patients achieving pCR, compared to the 5 yr EFS hazard ratio for pCR vs not in Cortazar (hazard ratio 0.49), demonstrating important differences between a metaanalysis compared to a platform trial with uniform high-risk eligibility, standardized pathology assessment, and multiple targeted therapies. Our data support the use of pCR as a primary endpoint for accelerated approval of new drugs if EFS is evaluated in the same population. Based on these findings, the I-SPY2 TRIAL will test whether therapy can be deescalated or escalated for individual patients with the goal of achieving pCR for all. Citation Format: Yee D, DeMichele A, Isaacs C, Symmans F, Yau C, Albain KS, Hylton NM, Forero-Torres A, van't Veer LJ, Perlmutter J, Rugo HS, Melisko M, Chen Y-Y, Balassanian R, Krings G, Datnow B, Hasteh F, Tipps A, Weidner N, Zhang H, Tickman R, Thornton S, Ritter J, Amin K, Klein M, Chen B, Keeney G, Ocal T, Feldman M, Klipfel N, Sattar H, Mueller J, Gwin K, Baker G, Kallakury B, Zeck J, Duan X, Ersahin C, Gamez R, Troxell M, Mansoor A, Grasso LeBeau L, Sams S, Wisell J, Wei S, Harada S, Vinh T, Stamatakos MD, Tawfik O, Fan F, Adams A, Rendi M, Minton S, Magliocco A, Sahoo S, Fang Y, Hirst G, Singhrao R, Asare SM, Wallace AM, Chien AJ, Ellis ED, Han HS, Clark AS, Boughey JC, Elias AD, Nanda R, Korde L, Murthy R, Lang J, Northfelt D, Khan Q, Edmiston KK, Viscusi R, Haley B, Kemmer K, Zelnak A, Berry DA, Esserman LJ. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-08.

BACKGROUNDThe Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ) was developed as the first spine oncology‐specific health‐related quality of life (HRQOL) measure. This study evaluated the psychometric properties and clinical validity of the SOSGOQ in a diverse cohort of patients with spinal metastases.METHODSAn international, multicenter, prospective observational cohort study including patients with spinal metastases who underwent surgery and/or radiotherapy was conducted by the AOSpine Knowledge Forum Tumor. Demographic, tumor, and treatment data were collected. HRQOL was evaluated using the SOSGOQ and Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF‐36) at baseline and fixed follow‐up times. Construct validity was assessed using multitrait scaling analyses, confirmatory factor analyses, and correlation with the SF‐36 and NRS pain score. Test‐retest reliability was assessed in a subgroup of patients between 12 weeks after treatment and the retest 4 to 9 days later.RESULTSA total of 238 patients were enrolled at 9 centers across North America; 153 of these patients had HRQOL data available at 12 weeks after treatment. Multitrait scaling analyses and confirmatory factor analyses resulted in a refined version of the SOSGOQ with 4 domains and 4 single items. The revised SOSGOQ (SOSGOQ2.0) demonstrated strong correlations with SF‐36 and the ability to discriminate between clinically distinct patient groups. Reliability of the SOSGOQ2.0 was demonstrated to be good, with an intraclass correlation coefficient ranging from 0.58 to 0.92 for the different domains.CONCLUSIONSThe SOSGOQ2.0 is a reliable and valid measure with which to evaluate HRQOL in patients with spinal metastases. It is recommended to use the SOSGOQ2.0 together with a generic HRQOL outcome measure to comprehensively assess HRQOL and increase sensitivity and specificity. Cancer 2018;124:1828‐38. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

Tamoxifen is biotransformed by CYP2D6 to 4‐hydroxytamoxifen and 4‐hydroxy N‐desmethyl tamoxifen (endoxifen), both with greater antiestrogenic potency than the parent drug. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer. We summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype.

Abstract BACKGROUND Several hypotheses have been proposed for the pathophysiology of suprascapular nerve (SSN) palsy, including compression, traction, and nerve inflammation. OBJECTIVE To provide insight into the pathophysiology of isolated nontraumatic SSN palsy by performing critical reinterpretations of electrodiagnostic (EDX) studies and magnetic resonance (MR) images of patients with such diagnosis. METHODS We retrospectively reviewed all patients referred to our institution for the past 20 yr with a diagnosis of nontraumatic isolated suprascapular neuropathy who had an upper extremity EDX study and a shoulder or brachial plexus MR scan. Patient charts were reviewed to analyze their initial clinical examination, and their original EDX study and MR images were reinterpreted by an experienced neurologist and a musculoskeletal radiologist, respectively, both blinded from the authors’ hypothesis and from each other's findings. RESULTS Fifty-nine patients were included. Fifty of them (85%) presented with at least 1 finding that was inconsistent with an isolated SSN palsy. Forty patients (68%) had signs on physical examination beyond the SSN distribution. Thirty-one patients (53%) had abnormalities on their EDX studies not related to the SSN. Twenty-two patients (37%) had denervation atrophy in other muscles than the spinati, or neural hyperintensity in other nerves than the SSN on their MR scans, without any evidence of SSN extrinsic compression. CONCLUSION The great majority of patients with presumed isolated SSN palsy had clinical, electrophysiological, and/or imaging evidence of a more diffuse pattern of neuromuscular involvement. These data strongly support an inflammatory pathophysiology in many cases of “isolated” SSN palsy.

Vascular protection using gene therapy can reduce the late toxicities of radiotherapy.