Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer

BRCA; Cáncer de mama triple negativo: Antígeno 2 de la superficie celular del trofoblastoBRCA; Càncer de mama triple negatiu; Antigen 2 de la superfície cel·lular del trofoblastBRCA; Triple-negative breast cancer; Trophoblast cell-surface antigen 2Background The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician’s choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes. Patients and methods Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline. Results Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations. Conclusions SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.This work was supported by Immunomedics, Inc., a subsidiary of Gilead Sciences, Inc. (no grant number)

Formal change impact analyses for emulated control software

Processor emulators are a software tool for allowing legacy computer programs to be executed on a modern processor. In the past emulators have been used in trivial applications such as maintenance of video games. Now, however, processor emulation is being applied to safety-critical control systems, including military avionics. These applications demand utmost guarantees of correctness, but no verification techniques exist for proving that an emulated system preserves the original system’s functional and timing properties. Here we show how this can be done by combining concepts previously used for reasoning about real-time program compilation, coupled with an understanding of the new and old software architectures. In particular, we show how both the old and new systems can be given a common semantics, thus allowing their behaviours to be compared directly

Total hemoglobin reduction in the tumor volume correlates with response to breast cancer neoadjuvant chemotherapy within two weeks of treatment

Optical imaging techniques have emerged as a possible alternative to predict pathological complete response (pCR) in breast cancer patients undergoing neoadjuvant chemotherapy (NAC). Our team developed a so-called diffuse optical tomographic breast imaging system (DOTBIS) which does not require the use of contrast agents or compression, and enables imaging of the whole breast volume using low intensity near infrared light capable to measure tissue concentration of oxy-hemoglobin (ctO2Hb), deoxy-hemoglobin (ctHHb) and water percentage. In this retrospective study, ctTHb changes in the tumor region of 16 breast cancer patients were analyzed across NAC. Both breasts of all patients have been scanned simultaneously with our DOTBIS system, Figure 1, which employs four wavelengths and gathers data from a total of 64 sources and 128 detectors per breast. A PDE-constrained multispectral image reconstruction code creates 3D image maps of total hemoglobin (ctHbT = ctO2Hb+ ctHHb). Tumor volume is selected by entering radiologic information such as tumor side, clock position and distance from the nipple (FN). An automated code was designed to select the highest value from the distance FN and the quadrant referent to the clock position. Subsequently, a region-based image segmentation method is implemented to examine neighboring pixels of the highest value point considering a mask of 90%. After tumor volume segmentation, we calculate the mean ctHbT extracted from the region of interest. An independent-samples t-test was run to determine if there were differences in ctTHb reduction in the tumor region before the third cycle of taxane between responders (n=4) and non-responders (n=12). ctTHb reduction was greater to pCR (45.71 ± 25.16 mM) than non-pCR tumors (-9.67 ± 25.65 mM), a statistically significant difference of 55.38 mM (95% CI, 23.74 to 87), t(14) = 3.755, p = .002, in Figure 2 we can see an example. From the ROC plot results, we can observe that ctTHb reduction in the tumor region after 2 cycles of Taxane is a good indicator to anticipate pCR status. With an area under the curve of 0.958, the best cut-off that maximizes sensitivity and specificity is 16.86mM. At this reduction level, the sensitivity is 100% and specificity is 91.7%. In conclusion, our findings indicate that DOTBIS-measured total hemoglobin in the tumor region may be a strong and independent predictor of treatment response to NAC. Please click Additional Files below to see the full abstract

Case-based review and olinical guidance on the use of genomic assays for early-stage breast cancer: Breast Cancer Therapy Expert Group (BCTEG)

In addition to classical clinicopathologic factors, such as hormone receptor positivity, human epidermal growth factor receptor 2 (HER2) status, and tumor size, grade, and lymph node status, a number of commercially available genomic tests may be used to help inform treatment decisions for early breast cancer patients. Although these tests improve our understanding of breast cancer and help to individualize treatment decisions, clinicians face challenges when deciding on the most appropriate test to order, and the advantages, if any, of one test over another. The Breast Cancer Therapy Expert Group (BCTEG) recently convened a roundtable meeting to discuss issues surrounding the use of genomic testing in early breast cancer, with the goal of providing practical guidance on the use of these tests by the community oncologist, for whom breast cancer may be only one of many tumor types they treat. The group recognizes that genomic testing can provide important prognostic (eg, risk for recurrence), and in some cases predictive, information (eg, benefit of chemotherapy, or extended adjuvant endocrine therapy), which can be used to help guide treatment decisions in breast cancer. The available tests differ in the types of information they provide, and in the patient populations and clinical trials that were conducted to validate them. We summarize the discussion of the BCTEG on this topic, and we also consider several patient cases and clinical scenarios in which genomic testing may, or may not, be useful to guide treatment decisions for the practicing community oncologist

The role of neuroplasticity in the psychoemotional disorders formation in the chronic tension-type headache

The study was devoted to investigation of relationship between level of the brain-derived neurotrophic factor (BDNF) in the peripheral blood and pain, psychoemotioal state in patients with chronic tension-type headache (CTTH). The chronic form of TTH had a well-marked anxiety and depressive and asthenic symptoms, which leads to a significant deficiency of BDNF in the peripheral blood.Исследование посвящено изучению взаимосвязи уровня нейротрофического фактора головного мозга (BDNF) в периферической крови с показателями болевого и психоэмоционального статуса у пациентов с хронической головной болью напряжения (ХГБН). В ходе проведенного исследования выявлено, что хроническая форма ГБН имеет в своей клинической картине отчетливую тревожно-депрессивную и астеническую симптоматику, при этом в сыворотке периферической крови выявляется выраженный дефицит BDNF

Can phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibition ERase them all?

Seventy percent of breast tumors are estrogen receptor (ER) positive. Although endocrine therapy is successful for the majority of patients with ER-positive tumors, approximately 30% show de novo or acquired resistance and the underlying molecular mechanisms and biomarkers that predict such resistance remain elusive. Two recent papers report that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway produces resistance to tamoxifen. This raises the possibility that combining endocrine therapy and PI3K inhibition may be more effective than monotherapy for treating ER-positive breast tumors, either as first-line therapy for tumors with high PI3K activity or after the development of resistance to endocrine therapy

Markers for the identification of late breast cancer recurrence

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited

Use of cyclin-dependent kinase (CDK) 4/6 inhibitors for hormone receptor-positive, human epidermal growth factor receptor 2-negative, metastatic breast cancer: a roundtable discussion by The Breast Cancer Therapy Expert Group (BCTEG)

Purpose: To provide an overview of clinical data supporting the use of cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), metastatic breast cancer (mBC), from the perspective of the practicing oncologist community. Methods: A recent roundtable discussion was convened by The Breast Cancer Therapy Expert Group (BCTEG) to review existing data on this topic and its impact on their current practice. Results: Level 1 evidence now supports use of a CDK 4/6 inhibitor in combination with endocrine therapy for patients with HR+, HER2−, mBC. Currently, there are no biomarkers that reliably define patients who will, or will not, benefit from the addition of a CDK 4/6 inhibitor to their endocrine therapy. Additional research is needed to identify the optimal sequencing of CDK 4/6 inhibitors in relation to other therapies as well as the optimal duration of therapy; at present, evidence suggests that use in the upfront setting is better than waiting for a later line of therapy, or adding after endocrine therapy has started. Conclusions: Thus far, three CDK 4/6 inhibitors—palbociclib, ribociclib, and more recently, abemaciclib—have been approved for use in the setting of HR+, HER2−, mBC. The degrees to which these agents differ in terms of CDK4/6 affinity, side-effect profiles, dosing, degree of central nervous system (CNS) penetration, optimal use in combination with antiestrogen therapy, and across other subsets of breast cancer, remain an active area of investigation