Identifying biomarkers of differential chemotherapy response in TNBC patient-derived xenografts with a CTD/WGCNA approach.

Although systemic chemotherapy remains the standard of care for TNBC, even combination chemotherapy is often ineffective. The identification of biomarkers for differential chemotherapy response would allow for the selection of responsive patients, thus maximizing efficacy and minimizing toxicities. Here, we leverage TNBC PDXs to identify biomarkers of response. To demonstrate their ability to function as a preclinical cohort, PDXs were characterized using DNA sequencing, transcriptomics, and proteomics to show consistency with clinical samples. We then developed a network-based approach (CTD/WGCNA) to identify biomarkers of response to carboplatin (MSI1, TMSB15A, ARHGDIB, GGT1, SV2A, SEC14L2, SERPINI1, ADAMTS20, DGKQ) and docetaxel (c, MAGED4, CERS1, ST8SIA2, KIF24, PARPBP). CTD/WGCNA multigene biomarkers are predictive in PDX datasets (RNAseq and Affymetrix) for both taxane- (docetaxel or paclitaxel) and platinum-based (carboplatin or cisplatin) response, thereby demonstrating cross-expression platform and cross-drug class robustness. These biomarkers were also predictive in clinical datasets, thus demonstrating translational potential.

Breast Cancer Treatment Delay in SafetyNet Health Systems, Houston Versus Southeast Brazil.

BACKGROUND: Breast cancer outcomes among patients who use safety-net hospitals in the highly populated Harris County, Texas and Southeast Brazil are poor. It is unknown whether treatment delay contributes to these outcomes. METHODS: We conducted a retrospective cohort analysis of patients with non-metastatic breast cancer diagnosed between January 1, 2009 and December 31, 2011 at Harris Health Texas and Unicamp's Women's Hospital, Barretos Hospital, and Brazilian National Institute of Cancer, Brazil. We used Cox proportional hazards regression to evaluate association of time to treatment and risk of recurrence (ROR) or death. RESULTS: One thousand one hundred ninety-one patients were included. Women in Brazil were more frequently diagnosed with stage III disease (32.3% vs. 21.1% Texas; P = .002). Majority of patients in both populations had symptom-detected disease (63% in Brazil vs. 59% in Texas). Recurrence within 5 years from diagnosis was similar 21% versus 23%. Median time from diagnosis to first treatment defined as either systemic therapy (chemotherapy or endocrine therapy) or surgery, were comparable, 9.9 weeks versus 9.4 weeks. Treatment delay was not associated with increased ROR or death. Higher stage at diagnosis was associated with both increased ROR and death. CONCLUSION: Time from symptoms to treatment was considerably long in both populations. Treatment delay did not affect outcomes. IMPACT: Access to timely screening and diagnosis of breast cancer are priorities in these populations.

Concurrent Chemo-radiation As a Means of Achieving Pathologic Complete Response in Triple Negative Breast Cancer.

Management of triple negative breast cancer (TNBC) that is resistant to chemotherapy remains a challenge. Many studies have investigated the unconventional approach of concurrent chemotherapy with radiation in management of TNBC that is resistant to neoadjuvant anthracycline and taxane containing chemotherapy. Various chemotherapies have been used as radiosensitizers. In this report we summarize the published literature and highlight clinical trials that pertain to management of TNBC.

Neurofibromin Is an Estrogen Receptor-α Transcriptional Co-repressor in Breast Cancer.

We report that neurofibromin, a tumor suppressor and Ras-GAP (GTPase-activating protein), is also an estrogen receptor-α (ER) transcriptional co-repressor through leucine/isoleucine-rich motifs that are functionally independent of GAP activity. GAP activity, in turn, does not affect ER binding. Consequently, neurofibromin depletion causes estradiol hypersensitivity and tamoxifen agonism, explaining the poor prognosis associated with neurofibromin loss in endocrine therapy-treated ER+ breast cancer. Neurofibromin-deficient ER+ breast cancer cells initially retain sensitivity to selective ER degraders (SERDs). However, Ras activation does play a role in acquired SERD resistance, which can be reversed upon MEK inhibitor addition, and SERD/MEK inhibitor combinations induce tumor regression. Thus, neurofibromin is a dual repressor for both Ras and ER signaling, and co-targeting may treat neurofibromin-deficient ER+ breast tumors.

Dose-reduced trastuzumab deruxtecan can be safely used in liver failure and active leptomeningeal metastases.

Trastuzumab deruxtecan has been shown to have responses in heavily pretreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. However, the safety of this medication in patients with severe liver dysfunction and untreated or symptomatic central nervous system metastases is unknown. We describe a patient with metastatic HER2-positive breast cancer with liver failure and leptomeningeal metastases who was treated with dose-reduced trastuzumab deruxtecan. With treatment, the patient's hyperbilirubinemia resolved and she demonstrated a response on imaging. She was dose-escalated to full dose with minimal adverse events.

Endocrine therapy for ER-positive/HER2-negative metastatic breast cancer.

The estrogen receptor (ER) has been targeted for breast cancer treatment for over a century, but many challenges persist. ER-positivity identifies the largest breast cancer subgroup, and ER-directed therapies prolong survival and improve symptoms in the advanced setting with a very favorable side effect profile. Treatment strategies have included decreasing estrogen synthesis and modulating or degrading the ER. However, ER+ breast cancer once diagnosed in the advanced setting still represents an incurable condition. Many efforts are ongoing to circumvent resistance mechanisms with a few strategies already incorporated into clinical practice such as the combination of endocrine agents with drugs that interfere with other signaling pathways and cell-cycle progression. Important questions remain as how best to select each available strategy, how to sequence them and ultimately how to extend benefits to the largest number of patients in need.

Fulvestrant in management of hormone receptor-positive metastatic breast cancer.

Fulvestrant is a steroidal selective estrogen receptor degrader that was approved by the US FDA in 2002 for treatment of ER-positive metastatic breast cancer (ER + MBC) post-progression on aromatase inhibitors. In 2017, the label was updated to include endocrine therapy naive ER + MBC. While initially fulvestrant was thought to be equivalent to aromatase inhibitors with monthly dose of 250 mg intramuscular injection, several postmarketing trials challenged this understanding. Subsequently, the recommended dose changed to 500 mg monthly plus loading dose, and this was proven to be superior to anastrozole in efficacy. Most recently the results of FALCON trial have further challenged the way fulvestrant is viewed and used. This report provides a historical perspective on this compound, its evolving role in management of ER + MBC and what the future may hold for this drug.

Surgery for CNS Tumors in the Brazilian National Health Care System.

PURPOSE: Resource limitations in low- and middle-income countries make the management of CNS tumors challenging, particularly in Brazil, a country with major disparities in socioeconomic status and access to health care. We aimed to evaluate cancer-related neurosurgical procedures in the public health care system. METHODS: On the basis of Brazil's public health system database, we collected data for neurosurgical procedures related to CNS tumors performed between January 2008 and November 2013. Information about the number of procedures, costs, length of stay, and number of inpatient deaths were analyzed for each state and then correlated to the state-specific population, gross domestic product per capita, and number of procedures. RESULTS: In all, 57,361 procedures were performed, the majority of them in the Southeast region. The mean length of hospital stay was 14.4 days, but longer hospital stay was reported for patients treated in the North. The inpatient mortality rate was 7.11%. Mortality rates decreased as the number of procedures (P < .001), gross domestic product per capita (P < .001), or state population increased (P < .001). On multivariate analysis, only the number of procedures (odds ratio, 0.93; 95% CI, 0.91 to 0.96; P < .001) and state population (odds ratio, 1.25; 95% CI, 1.13 to 1.38; P < .001) had an independent association with mortality. CONCLUSION: To the best of our knowledge, this is the first study to evaluate disparities in CNS tumor surgery in a middle-income country, confirming that regional disparities exist and that clinical and economic outcomes correlate with income level, number of procedures, and state population.