Videssa Breast can effectively detect BC when used in conjunction with imaging and can substantially reduce unnecessary medical procedures, as well as provide assurance to women that they likely do not have BC.
Discovery of the JAK2 V617F mutation in the myeloproliferative neoplasms (MPNs) essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) has stimulated great interest in the underlying molecular mechanisms and treatment of these diseases. Along with acceleration of technologies, novel mutations in genes such as MPL, LNK, and CBL have been discovered that converge on the JAK-STAT pathway. Several additional novel mutations in genes involved in epigenetic regulation of the genome, including TET2, ASXL1, DNMT3A, and IDH1/2, have emerged, in addition to several mutations in cellular splicing machinery. While understanding of the pathogenetic mechanisms of these novel mutations in MPNs has improved, it is still lagging behind the pace of mutation discovery. Concurrent with molecular discoveries, especially with regard to JAK-STAT signaling, therapeutic development has accelerated in recent years. More than ten JAK kinase inhibitors have been advanced into clinical trials. Recently the first JAK2 inhibitor was approved for use in patients with PMF. Most JAK-targeting agents share similar characteristics with regard to clinical benefit, consisting of improvements in splenomegaly, constitutional symptoms, and cytopenias, for example. It remains to be determined if JAK2 inhibitors can considerably impact disease progression and bone marrow histologic features (e.g., fibrosis) or significantly impact the JAK2 allele burden. While JAK2 inhibitors appear to be promising in PV and ET, they need to be compared with standard therapies, such as hydroxyurea or interferon-based therapies. Future clinical development will focus on optimal combination partners and agents that target alternative mechanisms, deepen the response, and achieve molecular remissions.
31 Background: An approach to detection that relies on biochemical markers of breast cancer would significantly contribute to more accurate detection in women with suspicious lesions. The combination of imaging, which identifies anatomical anomalies consistent with cancer with proteomic approaches promises to provide a powerful detection paradigm. A proteomic detection approach would provide a powerful tool for the detection of breast cancer in women with dense breast, a diagnosis that is difficult utilizing imaging alone. While protein signatures for the presence of breast cancer have remained elusive, we have developed a novel approach that combines serum protein biomarkers with tumor-associated autoantibodies. We utilized prospectively collected serum samples to develop novel algorithms for use in conjunction with imaging. We tested whether the assay was able to distinguish benign from invasive breast cancers in a prospective, randomized setting. Methods: Provista-002 enrolled 509 patients from multiple sites across the US and followed for 6 months after the first blood draw under IRB approval. Patients were consented after assessment of a BIRADS 3 or 4 and considered eligible if they were between 25 and 75 years of age, no history of cancer, no prior breast biopsy within the last six months, and were assessed as BIRADS 3 or 4 within 28 days. Upon enrollment, patients were randomized to either training or validation groups. Clinical truth was considered equal to or greater than 80% sensitivity and/or specificity. Serum protein biomarkers and tumor-associated autoantibodies identified in prior proteomic screens were measured prior to biopsy in a blinded and randomized fashion. Individual biomarker concentrations, together with specific patient data were evaluated using various logistic regression models developed from prior studies. Results: Provista-002 demonstrated a clear difference between women under the age of 50 from over the age of 50 in both markers required for early detection and the algorithm (models) used to distinguish benign from invasive breast cancer/DCIS. This is the first study that demonstrates clearly that modeling of proteomic patterns differs significantly in the BIRADS 3/4 setting and in the detection of early breast cancer lesions. As demonstrated in Provista – 001, we did not observe a statistical difference between early detection in women with dense breast and those with mostly fatty breast. The ability of the Videssa assay to distinguish between invasive breast cancer/DCIS from benign breast conditions was demonstrated as 85.7% sensitivity and 82.4% specificity for women under the age of 50 (although, unfortunately all lesions were pathologically confirmed to be CIS) and in women over the age of 50, the sensitivity was 86.4% and specificity was 83%. Conclusions: As above, both age groups of women needed distinct marker sets and linear regressions to distinguish benign (non-clinically significant) lesions from those that needed further evaluation (DCIS and IBC). Clinical trial information: NCT02078570.
27 Background: Clinicians often experience difficulty in differentiating benign lesions from invasive breast cancers in patients designated as dense breast. A major limitation of radiological breast cancer screening methods involves a decrease in sensitivity and specificity in women with dense breast. Thus, we sought to test whether Klarify Breast, a combinatorial protein-based biomarker panel could improve early detection of significant breast lesions in a controlled fashion. Clearly, a diagnostic assay that would provide biochemical evidence in the patient’s clinical course is greatly needed. Methods: We have conducted two independent, multi-center, prospective clinical trials to establish the clinical validity of Klarify Breast – an assay that uses multiple Serum Protein Biomarkers (SPBs), Tumor-Associated Autoantibodies (TAAbs), patient specific clinical data and develop a score to differentiate patients with benign breast disease from those with invasive breast cancer. Independent panels of biomarkers and associated algorithms were developed using prospectively collected samples from women under age 50 (n = 351) and from women ages 25-75 (n = 500). Here, we present the benefit of integrating the results of Klarify Breast test with patient imaging to best assess risk in women with dense breast. Results: While performance of the assay was somewhat age dependent (women under the age of 50 demonstrated a higher sensitivity and specificity than women over the age of 50). Here we present data that both groups of women clearly benefit from the addition of a biomarker assay combined with standard of care imaging in identifying invasive breast lesions. Conclusions: Clearly, in women with dense breast, where radiologic studies alone do not permit full assessment in women with a dense breast finding. The biomarker test here, comprised of TAAbs and SPBs, offers a clear advantage in terms of NPV, PPV, Sensitivity and specificity. The results argue strongly for the use of appropriate biomarkers to augment imaging based breast cancer screening in women with dense breast or those who are at high risk. Clinical trial information: NCT01839045, NCT02078570.
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