Predicting pathological complete response to neoadjuvant systemic therapy for triple-negative breast cancers using deep learning on multiparametric MRIs.

We trained and validated a deep learning model that can predict the treatment response to neoadjuvant systemic therapy (NAST) for patients with triple negative breast cancer (TNBC). Dynamic contrast enhanced (DCE) MRI and diffusion-weighted imaging (DWI) of the pre-treatment (baseline) and after four cycles (C4) of doxorubicin/cyclophosphamide treatment were used as inputs to the model for prediction of pathologic complete response (pCR). Based on the standard pCR definition that includes disease status in either breast or axilla, the model achieved areas under the receiver operating characteristic curves (AUCs) of 0.96 ± 0.05, 0.78 ± 0.09, 0.88 ± 0.02, and 0.76 ± 0.03, for the training, validation, testing, and prospective testing groups, respectively. For the pCR status of breast only, the retrained model achieved prediction AUCs of 0.97 ± 0.04, 0.82 ± 0.10, 0.86 ± 0.03, and 0.83 ± 0.02, for the training, validation, testing, and prospective testing groups, respectively. Thus, the developed deep learning model is highly promising for predicting the treatment response to NAST of TNBC.Clinical Relevance- Deep learning based on serial and multiparametric MRIs can potentially distinguish TNBC patients with pCR from non-pCR at the early stage of neoadjuvant systemic therapy, potentially enabling more personalized treatment of TNBC patients.

Distinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy.

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8+ T cell axis in both blood and inflamed joints. CX3CR1hi CD8+ T cells in blood and CXCR3hi CD8+ T cells in synovial fluid, the most clonally expanded T cells, significantly share TCR repertoires. The migration of blood CX3CR1hi CD8+ T cells into joints is possibly mediated by CXCL9/10/11/16 expressed by myeloid cells. Furthermore, arthritis after combined CTLA-4 and PD-1 inhibitor therapy preferentially has enhanced Th17 and transient Th1/Th17 cell signatures. Our data provide insights into the mechanisms, predictive biomarkers, and therapeutic targets for arthritis-irAE.

Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors.

PURPOSE: This study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition. METHODS: This was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD. RESULTS: Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses). CONCLUSIONS: Continuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested.

Ecological momentary assessment of sleep, symptoms, and mood during chemotherapy for breast cancer.

OBJECTIVE: This study examined the association of sleep before and during a chemotherapy (CT) cycle for breast cancer with symptoms and mood during a CT cycle. METHODS: Twenty women undergoing CT for breast cancer completed the Pittsburgh Sleep Quality Index (PSQI) 1 h prior to a CT infusion. For 3 weeks following infusion, participants estimated sleep efficiency, minutes to sleep (sleep latency), number of nocturnal awakenings (sleep fragmentation (SF)), and sleep quality (SQ) each morning and rated symptoms (nausea, fatigue, numbness, and difficulty thinking) and mood three times daily (morning, afternoon, and evening) via ecological momentary assessments using automated handheld computers. RESULTS: The results showed that disturbed sleep (PSQI score > 5) prior to CT infusion was associated with greater fatigue, and more negative and anxious mood throughout the 3-week CT cycle, and good pre-CT infusion sleep (PSQI score < 5) buffered anxious mood in the first days following infusion. Time-lagged analyses controlling for mood/symptom ratings reported the previous evening revealed that longer sleep latency and greater SF were associated with greater daytime fatigue; poorer SQ and greater SF were antecedents of worse morning negative mood, and greater SF was associated with feeling more passive and drowsy. No evening symptom or mood ratings were related to subsequent SQ. CONCLUSIONS: These findings suggest that disturbed sleep before and after a CT infusion exacerbates fatigue, and negative, anxious, and drowsy mood during a CT cycle. Reducing sleep disturbance may be an important way to improve quality of life during CT.

Residual risk of breast cancer recurrence 5 years after adjuvant therapy.

There is limited prognostic information to identify breast cancer patients who are at risk for late recurrences after adjuvant or neoadjuvant systemic therapy (AST). We evaluated the residual risk of recurrence and prognostic factors of 2838 patients with stage I-III breast cancer who were treated with AST between January 1, 1985, and November 1, 2001, and remained disease free for 5 years. Residual recurrence-free survival was estimated from the landmark of 5 years after AST to date of first recurrence or last follow-up using the Kaplan-Meier method. The log-rank test (two-sided) was used to compare groups. Residual recurrence-free survival rates at 5 and 10 years were 89% and 80%, respectively, and 216 patients developed a recurrence event. The 5-year residual risks of recurrence for patients with stage I, II, and III cancers were 7% (95% confidence interval [CI] = 3% to 15%), 11% (95% CI = 9% to 13%), and 13% (95% CI = 10% to 17%), respectively (P = .02). In multivariable analysis, stage, grade, hormone receptor status, and endocrine therapy were associated with late recurrences. Breast cancer patients have a substantial residual risk of recurrence, and selected tumor characteristics are associated with late recurrences.

Circulating tumor cells in metastatic breast cancer: biologic staging beyond tumor burden.

BACKGROUND: The detection of circulating tumor cells (CTCs) predicts overall survival in patients with metastatic breast cancer (MBC). However, it is unknown whether CTCs have superior value compared with other standard prognostic factors. We compared the prognostic significance of CTCs with clinical and laboratory measures of tumor burden and phenotypic subtype of disease. PATIENTS AND METHODS: One hundred fifty-one patients with MBC evaluated between 2000 and 2006 were included in this retrospective analysis. Circulating tumor cells were isolated and enumerated in whole blood using an immunomagnetic bead system (CellSearch System). Overall survival was evaluated according to the level of CTCs (negative: <5 CTCs per 7.5 mL of blood; positive: >or=5 CTCs per 7.5 mL of blood), Swenerton score, cancer antigen 27-29 level, age (<50 years vs. >or=50 years), hormone-receptor status and HER2 status, metastatic site, and type and line of therapy. RESULTS: The median age of patients was 53 years (range, 24-88 years), and 44% of the patients had >5 CTCs. The median overall survival for negative versus positive CTCs were 29.3 months and 13.5 months, respectively (P<0.0001). In the multivariable Cox model, the detection of>or=5 CTCs demonstrated the highest hazard ratio with 2.2 times the risk of death (P=0.003). The prognostic value was independent of measure of tumor burden and type and line of therapy, and phenotypic subtype of the disease. CONCLUSION: Circulating tumor cells have superior and independent prognostic value of tumor burden and disease phenotype and might represent an important marker of tumor biology in MBC. Detection of CTCs should be considered for new staging stratification of patients with MBC.

Clinical outcome of patients with lymph node-negative breast carcinoma who have sentinel lymph node micrometastases detected by immunohistochemistry.

BACKGROUND: The ideal pathologic assessment of sentinel lymph nodes (SLNs) in patients with breast carcinoma remains controversial. The authors evaluated how detailed assessment of SLNs using immunohistochemistry (IHC) and serial sectioning would affect treatment decisions and outcomes in patients with breast carcinoma who had negative SLNs on standard hematoxylin and eosin staining. METHODS: The SLNs from patients who were treated between June 1998 and June, 1999 and who had negative lymph node status determined by hematoxylin and eosin staining (n = 84 patients) were evaluated further with serial sectioning and cytokeratin IHC. Patients were offered adjuvant therapy based on primary tumor factors. RESULTS: The median patient age was 57 years, and the median tumor size was 1.2 cm. At a median follow-up of 40.2 months, 81 patients (96%) were alive with no evidence of disease, 1 patient was alive with disease, 1 patient had died of disease, and 1 patient had died of other causes. Fifteen patients (18%) had micrometastases identified on IHC. Of the total 84 patients, information regarding adjuvant therapy was not available for 5 patients. Of the remaining 79 patients, 10 patients (13%) were not offered adjuvant chemotherapy but had positive SLN status determined by IHC. SLN status based on IHC evaluation did not correlate with age (P = 0.077), tumor size (P = 0.717), grade (P = 0.148), estrogen receptor status (P = 1.000), or lymphovascular invasion (P = 0.274). Furthermore, IHC-detected positive SLN status did not correlate with distant metastasis (P = 0.372) or overall or distant metastasis-free survival (P = 0.543 and P = 0.540, respectively). CONCLUSIONS: Although the finding of SLN micrometastases by IHC may change management in > 12% of patients, preliminary results suggested that such micrometastases do not affect outcomes significantly.

Automated quantification of apoptosis after neoadjuvant chemotherapy for breast cancer: early assessment predicts clinical response.

PURPOSE: A large body of evidence implicates apoptosis in the effects of cancer chemotherapeutic agents on tumor cells in vitro and tumor xenografts in vivo, but the predictive value of apoptosis as an early marker for clinical response in cancer patients remains unclear. EXPERIMENTAL DESIGN: We developed an automated, laser scanning cytometer-based method to quantify the percentage of tumor cells containing DNA fragmentation characteristic of apoptosis in tumor sections. We measured levels of apoptosis in a panel of 15 matched, 18-gauge core breast cancer biopsies obtained before and 48 h after neoadjuvant therapy with docetaxel plus doxorubicin or paclitaxel as part of two prospective clinical trials. RESULTS: The results revealed a strongly significant (P = 0.0023) association between chemotherapy-induced apoptosis and pathological response. CONCLUSIONS: If the results can be validated in a larger patient cohort, the method could be used to "tailor" therapy to optimize benefit in a patient-specific fashion.