Impact of androgen receptor expression in fluoxymesterone-treated estrogen receptor-positive metastatic breast cancer refractory to contemporary hormonal therapy.

PURPOSE: The purpose of this study is to evaluate survival outcome in patients with hormone receptor (HR)-positive (+) metastatic breast cancer (MBC) who received fluoxymesterone after disease progression while receiving contemporary hormonal therapy, as well as the association between estrogen receptor (ER)/androgen receptor (AR) status and survival outcome in these patients. METHODS: We retrospectively identified 103 patients treated with fluoxymesterone for HR + MBC from 2000 to 2014 and with at least one previous hormonal therapy in a metastatic setting. RESULTS: A median of 3 (range 1-10) hormonal therapies (aromatase inhibitors, tamoxifen, and/or fulvestrant) were received before fluoxymesterone; 33 patients discontinued fluoxymesterone before progression because of physician decision or adverse events including toxicity in 14 patients. Of the remaining 70 patients, 2 (3 %) had complete response, 7 (10 %) partial response, and 21 (30 %) stable disease for at least 6 months, yielding a clinical benefit rate of 43 %. The median PFS was 3.9 months (95 % CI 3.2-5.3 months). Multivariate analysis revealed no significant association between PFS and the type or number of prior systemic treatments. All 39 patients who had archived tumor slides available for AR staining had ER + carcinoma; 10 had ≥1 % but <10 %, 18 had ≥10 %, and 11 had no AR nuclear expression. AR positivity with various cutoffs (i.e. any AR + cells, ≥1 % AR + cells, or ≥10 % AR + cells) was not significantly associated with survival outcome. CONCLUSIONS: Fluoxymesterone can be considered for patients whose ER + MBC progresses on contemporary hormonal therapy, regardless of the level of AR expression.

[Assessment of risk factors for adverse events due to pemetrexed in patients with reduced renal function].

Pemetrexedis a key drug in the first and second -line therapy for non-small-cell lung cancer. It exhibits an increased area under the plasma drug concentration-time curve, and it has a prolonged half -life when administered to patients with reduced renal function, resulting in a high frequency of neutropenia. Accordingly, pemetrexed is administered to these patients with caution. Herein, we retrospectively investigated the background characteristics of patients with a creatinine clearance rate (Ccr) of<45 mL/min, who experienced severe adverse events due to pemetrexed. Thirty-eight patients with a Ccr of <45 mL/min were administered pemetrexed. Of these patients, 13 (34%) developed severe adverse events (≥Grade 3) such as neutropenia, thrombocytopenia, and nausea. Multiple logistic regression analysis revealed that a Ccr of <30 mL/min (p= 0.033) and the concomitant use of non-steroidal anti-inflammatory drugs (p=0.012) were significant risk factors for adverse events. Therefore, whenever possible, pemetrexed administration should be avoided in patients with a Ccr of <30 mL/ min and in those receiving concomitant non-steroidal anti-inflammatory drugs.

Obesity Measured via Body Mass Index May Be Associated with Increased Incidence but Not Worse Outcomes of Immune-Mediated Diarrhea and Colitis.

Obesity defined by high body mass index (BMI) has traditionally been associated with gastrointestinal inflammatory processes but has recently been correlated with better survival in patients receiving immune checkpoint inhibitors (ICI). We sought to investigate the association between BMI and immune-mediated diarrhea and colitis (IMDC) outcomes and whether BMI reflects body fat content on abdominal imaging. This retrospective, single-center study included cancer patients with ICI exposure who developed IMDC and had BMI and abdominal computed tomography (CT) obtained within 30 days before initiating ICI from April 2011 to December 2019. BMI was categorized as <25, ≥25 but <30, and ≥30. Visceral fat area (VFA), subcutaneous fat area (SFA), total fat area (TFA: VFA+SFA), and visceral to subcutaneous fat (V/S) ratio were obtained from CT at the umbilical level. Our sample comprised 202 patients; 127 patients (62.9%) received CTLA-4 monotherapy or a combination, and 75 (37.1%) received PD-1/PD-L1 monotherapy. Higher BMIs ≥ 30 were associated with a higher incidence of IMDC than BMIs ≤ 25 (11.4% vs. 7.9%, respectively; p = 0.029). Higher grades of colitis (grade 3-4) correlated with lower BMI (p = 0.03). BMI level was not associated with other IMDC characteristics or did not influence overall survival (p = 0.83). BMI is strongly correlated with VFA, SFA, and TFA (p < 0.0001). Higher BMI at ICI initiation was linked to a higher incidence of IMDC but did not appear to affect outcomes. BMI strongly correlated with body fat parameters measured by abdominal imaging, suggesting its reliability as an obesity index.

Characteristics, treatment, and outcome of diverticulitis after immune checkpoint inhibitor treatment in patients with malignancies.

PURPOSE: Immune checkpoint inhibitors (ICIs) are efficacious for treating various malignancies. In addition to immune-related adverse events (irAEs), growing evidence suggests that ICIs might also be associated with diverticulitis. We aim to assess the clinical presentations and management of colonic diverticulitis among cancer patients after ICI treatment. METHODS: A retrospective study was conducted on ICI-treated adult cancer patients between 01/2010 and 06/2020. Patients were grouped based on when diverticulitis developed relative to ICI treatment, either before (controls) or after (cases). Patient clinical characters, treatment, and outcomes were compared between both groups. RESULTS: 77 eligible patients were included: 63 patients developed diverticulitis after ICI exposure (46 had initial episode after ICI exposure, 17 had a history of diverticulitis prior then recurred after ICI exposure), and 14 had diverticulitis before ICI exposure. Diverticulitis occurred after a median of 129 days after ICI initiation. Clinical characteristics overlapped with traditional diverticulitis. 93% of patients had symptom resolution after treatment, while 23.8% experienced complications. These patients exhibited higher rates of hospitalization (87% vs 48%, P = 0.015) and surgery/interventional radiology procedures (27% vs 0, P = 0.002), and worse overall survival (P = 0.022). History of diverticulitis was not associated with a more severe disease course. Immunosuppressants (e.g., corticosteroids) were rarely required unless for concurrent ICI-mediated colitis. CONCLUSION: Colonic diverticulitis can occur after ICI therapy at very low incidence (0.5%). Its clinical presentation, evaluation, and management are similar to traditional diverticulitis, but associated with higher complication rates requiring surgical intervention and has lower overall survival.

Immune checkpoint inhibitor-related gastrointestinal toxicity in patients with malignancy involving the luminal gastrointestinal tract and its impact on cancer outcomes.

Background: Immune checkpoint inhibitors (ICI) are known to cause immune-related adverse events (irAE) with the gastrointestinal (GI) tract among the most affected. Our knowledge of GI irAE in patients with luminal GI malignancies is poor. We aimed to characterize the incidence, clinical features, treatment, and outcomes of these GI irAEs. Methods: This was a retrospective study of patients with malignancies involving the luminal GI tract and GI irAEs at MD Anderson Cancer Center from January 2010 to June 2020. Clinical data were collected and analyzed. Results: Eighteen patients with luminal GI tract malignancies treated with ICIs had evidence of GI irAEs based on clinical symptoms and/or histology. The predominant GI irAE symptom was diarrhea (78%). Ten had non-ulcerative inflammation (56%) and 5 had ulcerative inflammation (28%) on endoscopy. Histologically, 3 patients (17%) had evidence of acute inflammation, 4 (22%) had chronic inflammation, and 9 (50%) had both. Ten patients (56%) received immunosuppressant treatment, which included steroids alone (n=2, 20%), steroids with biologics (infliximab or vedolizumab) (n=7, 70%), or biologics alone (n=1, 10%), with clinical remission in all cases. Of the 6 patients who previously had stable or ICI-responsive cancer and received immunosuppressants, none developed progression of GI luminal malignancy during the study period. Conclusions: GI irAEs occurred in 2.4% of patients treated with ICI for cancer involving the luminal GI tract. Immunosuppressant therapies (e.g., vedolizumab) appear to be effective for GI irAEs, showing no association with further GI luminal cancer progression, recurrence, or a subsequent poor response to ICI therapy.

Somatic mutations, clinicopathologic characteristics, and survival in patients with untreated breast cancer with bone-only and non-bone sites of first metastasis.

Background: Bone is the most common site of metastasis of breast cancer. Biological mechanisms of metastasis to bone may be different from mechanisms of metastasis to non-bone sites, and identification of distinct signaling pathways and somatic mutations may provide insights on biology and rational targets for treatment and prevention of bone metastasis. The aims of this study were to compare and contrast somatic mutations, clinicopathologic characteristics, and survival in breast cancer patients with bone-only versus non-bone sites of first metastasis. Methods: Primary tumor samples were collected before treatment from 389 patients with untreated primary breast cancer and distant metastasis at diagnosis. In each sample, 46 or 50 cancer-related genes were analyzed for mutations by AmpliSeq Ion Torrent next-generation sequencing. Fisher's exact test was used to identify somatic mutations associated with bone-only first metastasis. Logistic regression models were used to identify differences in detected somatic mutations, clinicopathologic characteristics, and survival between patients with bone-only first metastasis and patients with first metastasis in non-bone sites only ("other-only first metastasis"). Results: Among the 389 patients, 72 (18.5%) had bone-only first metastasis, 223 (57.3%) had other-only first metastasis, and 94 (24.2%) had first metastasis in both bone and non-bone sites. The most commonly mutated genes were TP53 (N=103), PIK3CA (N=79), AKT (N=13), and PTEN (N=2). Compared to patients with other-only first metastasis, patients with bone-only first metastasis had higher rates of hormone-receptor-positive disease, non-triple-negative subtype, and lower grade (grade 1 or 2; Nottingham grading system) (all three comparisons, p<0.001); had a lower ratio of cases of invasive ductal carcinoma to cases of invasive lobular carcinoma (p=0.002); and tended to have a higher 5-year overall survival (OS) rate (78.2% [95% confidence interval (CI), 68.6%-89.0%] vs 55.0% [95% CI, 48.1%-62.9%]; p=0.051). However, in the subgroup of patients with TP53 mutation and in the subgroup of patients with PIK3CA mutation, OS did not differ between patients with bone-only and other-only first metastasis (p=0.49 and p=0.68, respectively). In univariate analysis, the rate of TP53 mutation tended to be lower in patients with bone-only first metastasis than in those with other-only first metastasis (15.3% vs 29.1%; p=0.051). In multivariate analysis, TP53 mutation was not significantly associated with site of first metastasis (p=0.54) but was significantly associated with hormone-receptor-negative disease (p<0.001). Conclusions: We did not find associations between somatic mutations and bone-only first metastasis in patients with untreated breast cancer. Patients with bone-only first metastasis tend to have longer OS than patients with other-only first metastasis. More comprehensive molecular analysis may be needed to further understand the factors associated with bone-only metastatic disease in breast cancer.

Prior systemic treatment increased the incidence of somatic mutations in metastatic breast cancer.

BACKGROUND: Understanding the biology of breast cancer is important for guiding treatment strategies and revealing resistance mechanisms. Our objectives were to investigate the relationship between previous systemic therapy exposure and mutational spectrum in metastatic breast cancer and to identify clinicopathological factors associated with identified frequent somatic mutations. METHODS: Archival tissues of patients with metastatic breast cancer were subjected to hotspot molecular testing by next-generation sequencing. The variables that significantly differed (P < 0.05) in univariate analysis were selected to fit multivariate models. Logistic models were fit to estimate the association between mutation status and clinical variables of interest. Five-fold cross-validation was performed to estimate the prediction error of each model. RESULTS: A total of 922 patients were included in the analysis. In multivariate analysis, previous systemic treatment before molecular testing (N = 186) was associated with a significantly higher rate of TP53 and PIK3CA mutations compared with the lack of systemic treatment (P < 0.001 for both). CONCLUSION: Systemic treatment exposure is an independent risk factor for high rates of TP53 and PIK3CA mutation, which suggests the importance of testing samples after systemic therapy to accurately assess mutations. It is worth testing the gene profile when tumours become resistant to systemic treatments.

Androgen Receptor Function and Androgen Receptor-Targeted Therapies in Breast Cancer: A Review.

IMPORTANCE: The androgen receptor (AR) pathway is emerging as a potential therapeutic target in breast cancer. To date, AR-targeted drugs have been approved only for treatment of prostate cancer; however, AR-targeted treatment for breast cancer is an area of active investigation. Through review of preclinical studies, retrospective clinical studies, and clinical trials, we examined the biology of AR and AR-related pathways, the potential for AR-targeted therapies in breast cancer, and potential biomarkers for AR-targeted treatments. OBSERVATIONS: The rate of AR positivity in breast cancer is about 60% to 80%. Biologically, the AR pathway has cross-talk with several other key signaling pathways, including the PI3K/Akt/mTOR and MAPK pathways, and with other receptors, including estrogen receptor and human epidermal growth factor receptor-2. The value of AR positivity as a prognostic marker has not yet been defined. Androgen receptor-targeted therapies, including AR agonists, AR antagonists, and PI3K inhibitors, have shown promising results in clinical trials in patients with breast cancer, and combinations of AR-targeted therapies with other agents have been investigated for overcoming resistance to AR-targeted therapies. Biomarkers to stratify patients according to the likelihood of response to AR-targeted drugs are yet to be established. Potential biomarkers of response to AR inhibitors include AR phosphorylation and AR gene expression. CONCLUSIONS AND RELEVANCE: Androgen receptor-targeted treatments for breast cancer are in development and have shown promising preliminary results. In-depth understanding of AR and AR-related signaling pathways would improve the treatment strategies for AR-positive breast cancer. Further preclinical and clinical studies of AR-targeted drugs alone and in combination with other drugs are justified and warranted to clarify the biology of AR and inform the development of AR-targeted therapies to improve survival outcome in patients with breast cancer.

Incidence of Second Malignancy after Successful Treatment of Limited-Stage Small-Cell Lung Cancer and Its Effects on Survival.

INTRODUCTION: Extended survival outcomes from improved treatments for patients with cancer come with an increased risk for development of a metachronous second malignancy (MSM). We evaluated the incidence of MSM after successful treatment of SCLC and compared survival between patients with SCLC in whom MSM developed and those in whom it did not. METHODS: Selection criteria were a diagnosis of limited-stage SCLC and receipt of at least 45 Gy of radiotherapy and chemotherapy at a single institution in 1985-2012. MSM was defined as a tumor of a different histologic type than the primary that appeared more than 2 years after the diagnosis of SCLC. RESULTS: Of 704 patients identified, 32 were excluded for lack of follow-up, 48 for having SCLC as MSM after treatment of another type of cancer, 37 for nonmelanoma skin cancer as MSM, and 46 for MSM within 2 years after SCLC diagnosis. Of the remaining 541 patients, 346 had recurrent SCLC, 180 had no second malignancy and no recurrence, and 15 (2.8%) had MSM (13 in a lung [eight adenocarcinomas and five squamous cell carcinomas], one sarcoma, and one acute myeloid leukemia). All 15 patients with MSM achieved complete response to the SCLC treatment. Overall survival was longer for patients with MSM than for patients with no other malignancies and no recurrence, with 10-year rates of 61.9% (95% confidence interval: 30.0%-82.6%) and 29.9% (95% confidence interval: 21.5%-38.6%), respectively (p = 0.03). CONCLUSIONS: Long-term survivors after treatment for SCLC should be made aware of the risk for MSM and the necessity of follow-up.