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Zardavas D.,Breast International Group BIG | Piccart-Gebhart M.,Free University of Colombia
Cancer Biology and Medicine

The implementation of molecular profiling technologies in oncology deepens our knowledge for the molecular landscapes of cancer diagnoses, identifying aberrations that could be linked with specific therapeutic vulnerabilities. In particular, there is an increasing list of molecularly targeted anticancer agents undergoing clinical development that aim to block specific molecular aberrations. This leads to a paradigm shift, with an increasing list of specific aberrations dictating the treatment of patients with cancer. This paradigm shift impacts the field of clinical trials, since the classical approach of having clinico-pathological disease characteristics dictating the patients' enrolment in oncology trials shifts towards the implementation of molecular profiling as prescreening step. In order to facilitate the successful clinical development of these new anticancer drugs within specific molecular niches of cancer diagnoses, there have been developed new, innovative trial designs that could be classified as follows: i) longitudinal cohort studies that implement (or not) "nested" downstream trials, 2) studies that assess the clinical utility of molecular profiling, 3) "master" protocol trials, iv) "basket" trials, v) trials following an adaptive design. In the present article, we review these innovative study designs, providing representative examples from each category and we discuss the challenges that still need to be addressed in this era of new generation oncology trials implementing molecular profiling. Emphasis is put on the field of breast cancer clinical trials. Copyright © 2016 by Cancer Biology & Medicine Source

Zardavas D.,Breast International Group BIG | Fouad T.M.,Breast European Adjuvant Studies Team BrEAST | Piccart M.,Free University of Colombia

The introduction of trastuzumab as adjuvant treatment for patients with HER2-positive breast cancer changed the natural course of early-stage disease. Currently, one year of trastuzumab given concurrently with a taxane and following an anthracycline regimen is the preferred standard of care in Europe. The first attempt to escalate this approach, though the implementation of dual HER2 blockade with lapatinib added to trastuzumab, as assessed by the ALTTO trial, failed to improve further clinical outcomes; clinical assessment of the adjuvant trastuzumab/pertuzumab regimen is still ongoing in the APHINITY trial. Negative results were also reported for the addition of bevacizumab to adjuvant trastuzumab treatment within the context of the BETH study. Similarly, efforts to de-escalate through shortening the duration of adjuvant trastuzumab treatment failed (the PHARE trial), whereas others are still ongoing. Of note, evidence supports the use of lighter chemotherapy regimens with one year of adjuvant trastuzumab as backbone, for women with small HER2-positive breast tumors, where the omission of anthracyclines did not compromise the clinical outcome. Despite the successes achieved so far, a proportion of women with early-stage HER2-positive breast cancer, will still experience disease recurrence. The identification of these women is urgently needed, as well as the identification of predictive biomarkers to dictate the optimal treatment strategy. So far, HER2 expression status has been the only validated predictive biomarker for this patient population. Despite the clear association of pCR achieved through neoadjuvant trastuzumab-based chemotherapy with clinical outcome, results from neoadjuvant trials have not been always consistent with what was seen in the adjuvant setting. Similarly, inconsistent results have been reported for the predictive ability of alterations affecting the PI3K signaling pathway or the quantification of tumor infiltrating lymphocytes. In the era of personalized oncology, rigorous translational and clinical collaborative efforts are needed to further advance the field of treatment of patients with HER2-positive breast cancer. © 2015 Elsevier Ltd. Source

Saini K.S.,Breast International Group BIG | Saini K.S.,Free University of Colombia | Azim Jr H.A.,Institute Jules Bordet | Metzger-Filho O.,Free University of Colombia | And 5 more authors.

Summary: HER2-positive tumors comprise 15% to 20% of all breast cancers (BC) and are associated with worse clinical outcomes [Slamon et al., Science 1987;235:177-82]. Trastuzumab is a humanized monoclonal antibody designed to target the extracellular domain of the HER2 receptor, and is the foundation of care of women with early and advanced HER2-positive BC. However, a significant proportion of patients with this type of BC display either primary or secondary resistance to trastuzumab. Therefore, in an effort to overcome such resistance and further improve the outcome of patients with HER2-positive disease, several new anti-HER2 agents are currently being developed. These include small molecules that inhibit the HER2 tyrosine kinase activity (lapatinib, neratinib), monoclonal antibodies directed at other epitopes of the HER2 extracellular domain (pertuzumab), antibody-drug conjugates (trastuzumab-DMl), and heat shock protein 90 inhibitors (tanespimycin).A great deal of interest has been generated by recent data from the randomized neo-adjuvant studies NeoALTTO and NeoSphere, which have shown that dual blockade of the HER2 receptor with anti-HER2 agents is significantly superior to using one agent alone. If these results are validated in larger ongoing and planned phase III studies in early BC, they could lead to a paradigm shift in treatment strategy. Therefore, to avoid unnecessary toxicities and costs, it is critical to intensify the research for biomarkers that can identify those patients most likely to benefit from specific targeted therapies. © 2011 Elsevier Ltd. Source

Michiels S.,Unit of Biostatistics and Epidemiology | Michiels S.,University Paris - Sud | Michiels S.,Free University of Colombia | Pugliano L.,Free University of Colombia | And 20 more authors.
Annals of Oncology

Background: The gold standard end point in randomized clinical trials in metastatic breast cancer (MBC) is overall survival (OS). Although therapeutics have been approved based on progression-free survival (PFS), its use as a primary end point is controversial. We aimed to assess to what extent PFS may be used as a surrogate for OS in randomized trials of anti-HER2 agents in HER2+ MBC. Methods: Eligible trials accrued HER2+ MBC patients in 1992-2008. A correlation approach was used: at the individual level, to estimate the association between investigator-assessed PFS and OS using a bivariate model and at the trial level, to estimate the association between treatment effects on PFS and OS. Correlation values close to 1.0 would indicate strong surrogacy. Results: We identified 2545 eligible patients in 13 randomized trials testing trastuzumab or lapatinib. We collected individual patient data from 1963 patients and retained 1839 patients from 9 trials for analysis (7 first-line trials). During follow-up, 1072 deaths and 1462 progression or deaths occurred. The median survival time was 22 months [95% confidence interval (CI) 21-23 months] and the median PFS was 5.7 months (95% CI 5.5-6.1 months). At the individual level, the Spearman correlation was equal to ρ = 0.67 (95% CI 0.66-0.67) corresponding to a squared correlation value of 0.45. At the trial level, the squared correlation between treatment effects (log hazard ratios) on PFS and OS was provided by R2 = 0.51 (95% CI 0.22-0.81). Conclusions: In trials of HER2-targeted agents in HER2+ MBC, PFS moderately correlates with OS at the individual level and treatment effects on PFS correlate moderately with those on overall mortality, providing only modest support for considering PFS as a surrogate. PFS does not completely substitute for OS in this setting. © The Author 2016. Source

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