Evaluation of methylated DCR1 as a biomarker for response to adjuvant irinotecan-based therapy in stage III colon cancer: cancer and leukaemia Group B 89803 (Alliance).

Aberrantly methylated genes contribute to the landscape of epigenetic alterations in colorectal adenocarcinoma. The global CpG Island methylator phenotype (CIMP) and individually methylated genes are potential prognostic/predictive biomarkers. Research suggests an association between methylated DCR1 (mDCR1) and lack of benefit with irinotecan (IFL) treatment. We assessed the association between DCR1 methylation status and survival in patients receiving adjuvant fluorouracil/ leucovorin (5-FU/LV) or IFL. We analysed data from patients with stage III colon adenocarcinoma randomly assigned to adjuvant 5-FU/LV or IFL in CALGB 89803 (Alliance). The primary endpoint was overall survival (OS), and the secondary endpoint was disease-free survival (DFS). Using tumour sample DNA, we evaluated the association between survival, DCR1 methylation status, and molecular subgroups (BRAF, KRAS, mismatch repair status, CIMP status) using Kaplan-Meier estimator and Cox proportional hazard model. mDCR1 was observed in 221/400 (55%) colon cancers. Histopathologic features were similar between mDCR1 and unmethylated DCR1 (unDCR1) colon cancers. There was no difference in OS (p = 0.83) or DFS (p = 0.85) based on DCR1 methylation status. There was no association between methylation status and response to IFL . In patients with unDCR1 and KRAS-wildtype tumours, those who received IFL had a nearly two-fold worse DFS compared to patients who received 5-FU/LV (HR = 1.85, 95% CI (0.97-3.53, p = 0.06). This relationship was not notable among other subgroups. In stage III colon cancer patients, mDCR1 status did not associate with response to irinotecan. Larger studies may suggest an association between the iridocene response and molecular subgroups.

A Phase II Study Evaluating the Safety and Efficacy of Sunitinib Malate in Combination With Weekly Paclitaxel Followed by Doxorubicin and Daily Oral Cyclophosphamide Plus G-CSF as Neoadjuvant Chemotherapy for Locally Advanced or Inflammatory Breast Cancer.

INTRODUCTION: Neoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC. METHODS: We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m2 IV weekly ×12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor [ER] and grade). RESULTS: Seventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER+ disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue. CONCLUSIONS: Neoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR; however, 47% were responders using pCR and/or CPS + EG score ≤2. ER positive patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for patients with ER positive LABC.

When cardiomyopathy, cancer, and COVID-19 collide: A case report.

Malignancy has historically prohibited solid organ transplant; however, patients with effectively treated, favorable-risk cancers should not necessarily be eliminated as transplant candidates. These cases require careful review by a multidisciplinary team. Here, we report the case of a woman with end-stage heart failure undergoing heart transplant evaluation during the COVID pandemic who was found to have early-stage, hormone receptor-positive breast cancer. Given her favorable cancer-related prognosis, a multidisciplinary committee recommended lumpectomy, accelerated partial breast irradiation, and adjuvant aromatase inhibitor therapy for definitive treatment to allow for consideration of orthotopic heart transplant.

Use of perioperative chemotherapy in colorectal cancer metastatic to the liver.

A curative-intent approach may improve survival in carefully selected patients with oligometastatic colorectal cancer. Aggressive treatments are most frequently administered to patients with isolated liver metastasis, though they may be judiciously considered for other sites of metastasis. To be considered for curative intent with surgery, patients must have disease that can be definitively treated while leaving a sufficient functional liver remnant. Neoadjuvant chemotherapy may be used for upfront resectable disease as a test of tumor biology and/or for upfront unresectable disease to increase the likelihood of resectability (so-called 'conversion' chemotherapy). While conversion chemotherapy in this setting aims to improve survival, the choice of a regimen remains a complex and highly individualized decision. In this review, we discuss the role of RAS status, primary site, sidedness, and other clinical features that affect chemotherapy treatment selection as well as key factors of patients that guide individualized patient-treatment recommendations for colorectal-cancer patients being considered for definitive treatment with metastasectomy.

Combined Targeted Therapies for First-line Treatment of Metastatic Triple Negative Breast Cancer-A Phase II Trial of Weekly Nab-Paclitaxel and Bevacizumab Followed by Maintenance Targeted Therapy With Bevacizumab and Erlotinib.

INTRODUCTION: Angiogenesis and epidermal growth factor receptor signaling are potential therapeutic targets in triple negative breast cancer (TNBC). We hypothesized that targeting these critical pathways would prolong progression-free survival with first-line therapy for metastatic TNBC. PATIENTS AND METHODS: We conducted a phase II trial of nab-paclitaxel and bevacizumab, followed by maintenance therapy with bevacizumab and erlotinib, for patients with metastatic TNBC. During induction, the patients received nab-paclitaxel 100 mg/m2 intravenously (days 1, 8, and 15) and bevacizumab 10 mg/kg intravenously (days 1 and 15) every 28 days for 6 cycles. Patients free of progression at 24 weeks received maintenance therapy with bevacizumab 10 mg/kg intravenously every 2 weeks and oral erlotinib 150 mg/d until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints were best overall response, overall survival (OS), and adverse events. We explored the measurement of circulating tumor cells as a prognostic marker. RESULTS: A total of 55 evaluable patients were enrolled. The median PFS and OS for the cohort was 9.1 months (95% confidence interval, 7.2-11.1) and 18.1 months (95% confidence interval, 15.6-21.7), respectively. Of the 53 patients with measurable disease, 39 (74%) had experienced a partial response and 10 (19%) had stable disease using the Response Evaluation Criteria In Solid Tumors. The most common toxicities were uncomplicated neutropenia, fatigue, and neuropathy. Decreased circulating tumor cells from baseline to the first assessment correlated with longer PFS and OS. CONCLUSION: Nab-paclitaxel and bevacizumab, followed by maintenance targeted therapy with bevacizumab and erlotinib, resulted in PFS similar to that of other trials. Most patients experienced a partial response (74%). Most patients received maintenance therapy (55%), providing a break from cytotoxic chemotherapy.

The PI3K/mTOR dual inhibitor P7170 demonstrates potent activity against endocrine-sensitive and endocrine-resistant ER+ breast cancer.

Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway has been implicated in anti-estrogen resistance in breast cancer. We tested the therapeutic potential of the novel PI3K/mTOR dual inhibitor P7170 in a panel of anti-estrogen-sensitive and anti-estrogen-resistant models of ER+ breast cancer. Estrogen receptor-positive (ER+) breast cancer cells were treated ±P7170. Fresh cores from primary ER+/HER2- tumors from two patients were treated ±P7170 ex vivo. Mice bearing breast cancer xenografts were randomized to treatment with vehicle, fulvestrant, P7170, or combinations, and tumor volumes were measured. Tissues and cells were analyzed for markers of pathway activity, cell viability, and apoptosis. In cell lines, P7170 exhibited IC50 values in the range of 0.9-7 nM and induced apoptosis. P7170 potently inhibited mTOR activity (≤ 25 nM) and inhibited PI3K at higher concentrations (≥ 200 nM). P7170 completely inhibited MCF-7 tumor growth, significantly inhibited growth of fulvestrant-resistant T47D tumors, and suppressed tumor cell proliferation but did not induce apoptosis. While P7170 inhibits PI3K and mTOR in ER+/HER2- human breast cancer cells and tumors ex vivo, in vivo data indicate that the primary mechanism of P7170 anti-tumor action is inhibition of mTOR and cell proliferation. P7170 is a novel agent worthy of further investigation for the treatment of ER+ breast cancer.

A genetic mouse model of invasive endometrial cancer driven by concurrent loss of Pten and Lkb1 Is highly responsive to mTOR inhibition.

Signals from the tumor suppressors PTEN and LKB1 converge on mTOR to negatively regulate its function in cancer cells. Notably, both of these suppressors are attenuated in a significant fraction of human endometrial tumors. In this study, we generated a genetic mouse model of endometrial cancer driven by concomitant loss of these suppressors to gain pathophysiological insight into this disease. Dual loss of Pten and Lkb1 in the endometrial epithelium led to rapid development of advanced endometrioid endometrial tumors with 100% penetrance and short host survival. The tumors displayed dysregulated phosphatidylinositol 3-kinase (PI3K)/Akt and Lkb1/Ampk signaling with hyperactivation of mTOR signaling. Treatment with a dual PI3K/mTOR inhibitor, BEZ235, extended the time before tumor onset and prolonged overall survival. The PI3K inhibitor GDC-0941 used as a single agent reduced the growth rate of primary tumor implants in Pten/Lkb1-deficient mice, and the mTOR inhibitor RAD001 was unexpectedly as effective as BEZ235 in triggering tumor regression. In parallel, we also found that ectopic expression of LKB1 in PTEN/LKB1-deficient human endometrial cancer cells increased their sensitivity to PI3K inhibition. Together, our results demonstrated that Pten/Lkb1-deficient endometrial tumors rely strongly on deregulated mTOR signaling, and they provided evidence that LKB1 status may modulate the response of PTEN-deficient tumors to PI3K or mTOR inhibitors.