Objective. DNA sequencing tests are enabling physicians to interrogate the molecular profiles of patients' tumors, but most oncologists have not been trained in advanced genomics. We initiated a molecular tumor board to provide expert multidisciplinary input for these patients. Materials and Methods. A team that included clinicians, basic scientists, geneticists, and bioinformatics/pathway scientists with expertise in various cancer types attended. Molecular tests were performed in a Clinical Laboratory Improvement Amendments environment. Results. Patients (n 5 34, since December 2012) had received a median of three prior therapies. The median time from physician order to receipt of molecular diagnostic test results was 27 days (range: 14-77 days). Patients had a median of 4 molecular abnormalities (range: 1-14 abnormalities) found by next-generation sequencing (182-or 236-gene panels).Seventy-four genes were involved, with 123 distinct abnormalities. Importantly, no two patients had the same aberrations, and 107 distinct abnormalities were seen only once. Among the 11 evaluable patients whose treatment had been informed by molecular diagnostics, 3 achieved partial responses (progression-free survival of 3.4 months, $6.5 months, and 7.6 months).The most common reasons for being unable to act on the molecular diagnostic results were that patients were ineligible for or could not travel to an appropriately targeted clinical trial and/or that insurance would not cover the cognate agents. Conclusion. Genomic sequencing is revealing complex molecular profiles that differ by patient. Multidisciplinary molecular tumor boards may help optimize management. Barriers to personalized therapy include access to appropriately targeted drugs. The Oncologist 2014;19:631-636Implications for Practice: Our study relates our experience with the initiation of molecular tumor board meetings, which are a new vehicle for managing patients with complex malignancies on whom molecular diagnostics have been performed. This experience could be of significant importance to oncologists who are increasingly faced with advanced molecular diagnostic data, yet have minimal training in genomics. Our article should help clinicians to handle practical issues related to setting up and efficiently utilizing molecular tumor board meetings. We also aim at helping oncologists and health care systems understand and address practical, logistical, and scientific issues, such as the challenges associated with interpretation of molecular testing for patients with advanced cancer. INTRODUCTIONTechnological developments in genomic sequencing are advancing at a breathtaking rate. These tests are rapidly being made available in the clinic, potentially facilitating a personalized treatment strategy [1][2][3][4]. The collaboration between biologists who interpret and confirm the functional relevance of molecular abnormalities and clinicians who assess relationships to cancer prognosis and response to therapy has led to the discovery of the activity of molecu...

The p27 tumor suppressor negatively regulates G 1 cell cycle progression. However, human malignancies rarely select for deletion/inactivation of p27, a hallmark of tumor suppressor genes. Instead, p27 is degraded or relocalized to the cytoplasm in aggressive malignancies, supporting the notion that p27 sequestration from its nuclear cyclin:cyclin-dependent kinase (cdk) targets is critical. However, emerging cell biology data suggest a novel cdk-independent cytoplasmic function of p27 in cell migration. Here, we find cytoplasmic p27 in 70% of invasive and metastatic melanomas. In contrast, no cytoplasmic p27 was detected in noninvasive, basement membraneconfined melanoma in situ, suggesting a late oncogenic role for cytoplasmic p27 in metastasis. Targeted cytoplasmic expression of wild-type or non-cdk-binding p27 at subphysiologic levels induced melanoma motility and resulted in numerous metastases to lymph node, lung, and peritoneum. These observations point to a prominent role of cytoplasmic p27 in metastatic disease that is independent of cyclin:cdk regulation or mere nuclear loss. [Cancer Res 2007;67(19):9238-43]

Background Previous studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings. MethodsIn this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, from patients (aged ≥18 years) with primary stage I-III breast cancer treated with neoadjuvant chemotherapy followed by surgery. We assessed the association between the continuous RCB score and the primary study outcome, event-free survival, using mixed-effects Cox models with the incorporation of random RCB and cohort effects to account for betweenstudy heterogeneity, and stratification to account for differences in baseline hazard across cancer subtypes defined by hormone receptor status and HER2 status. The association was further evaluated within each breast cancer subtype in multivariable analyses incorporating random RCB and cohort effects and adjustments for age and pretreatment clinical T category, nodal status, and tumour grade. Kaplan-Meier estimates of event-free survival at 3, 5, and 10 years were computed for each RCB class within each subtype. FindingsWe analysed participant-level data from 5161 patients treated with neoadjuvant chemotherapy between Sept 12, 1994, and Feb 11, 2019. Median age was 49 years (IQR 20-80). 1164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0-186]). RCB score was prognostic within each breast cancer subtype, with higher RCB score significantly associated with worse event-free survival. The univariable hazard ratio (HR) associated with one unit increase in RCB ranged from 1•55 (95% CI 1•41-1•71) for hormone receptor-positive, HER2-negative patients to 2•16 (1•79-2•61) for the hormone receptor-negative, HER2-positive group (with or without HER2-targeted therapy; p<0•0001 for all subtypes). RCB score remained prognostic for eventfree survival in multivariable models adjusted for age, grade, T category, and nodal status at baseline: the adjusted HR ranged from 1•52 (1•36-1•69) in the hormone receptor-positive, HER2-negative group to 2•09 (1•73-2•53) in the hormone receptor-negative, HER2-positive group (p<0•0001 for all subtypes).Interpretation RCB score and class were independently prognostic in all subtypes of breast cancer, and generalisable to multiple practice settings. Although variability in hormone receptor subtype definitions and treatment across patients are likely to affect prognostic performance, the association we observed between RCB and a patient's residual risk suggests that prospective evaluation of RCB could be c...

The prognostic and predictive value of Her2/neu and the hormone receptors in patient with primary or metastatic breast cancer is essential for a favorable outcome of treatment. We have been experiencing increasing requests to test cytologic specimens for these markers in patients with metastatic breast carcinoma. A recent study threw some doubts on the validity of such testing using cell blocks. In this study we compared our immunohistochemical Her2/neu, ER and PR testing performed on 42 formalin-fixed, paraffin-embedded cell blocks from 27 fine needle aspirations (FNA) and 15 serous effusions of 42 patients with metastatic (n = 38) and primary (n = 4) breast carcinoma to the test results obtained on tissue sections. In seven cases the Her2/neu immunohistochemistry (IHC) results on cell blocks were also compared with Her2/neu fluorescence in situ hybridization (FISH) on tissue or cell block. The study revealed 100% correlation for positive and negative Her2/neu results. For ER testing the results showed 85.7% sensitivity, 100% specificity, 100% positive predictive value (PPV), and 85.7% negative predictive value (NPV). For PR testing the results showed 80% sensitivity, 100% specificity, 100% PPV, and 88.8% NPV respectively. In conclusion, IHC for Her2/neu, ER and PR performed on formalin-fixed, paraffin-embedded cell blocks prepared from fresh FNA and serous fluid is reliable in predicting the expression of these markers when correlated with IHC and FISH performed on the corresponding tumor tissue.

I-SPY2 Trial ConsortiumIMPORTANCE Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial.OBJECTIVE To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence-free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents. DESIGN, SETTING, AND PARTICIPANTSMulticenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019.INTERVENTIONS Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide.MAIN OUTCOMES AND MEASURES Pathologic complete response and 3-year EFS and DRFS. RESULTSOf the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS. CONCLUSIONS AND RELEVANCEThe 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study.