Phase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma.

BACKGROUND: A phase II randomised discontinuation trial assessed cabozantinib (XL184), an orally bioavailable inhibitor of tyrosine kinases including VEGF receptors, MET, and AXL, in a cohort of patients with metastatic melanoma. METHODS: Patients received cabozantinib 100 mg daily during a 12-week lead-in. Patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumours (RECIST) at week 12 were randomised to cabozantinib or placebo. Primary endpoints were objective response rate (ORR) at week 12 and postrandomisation progression-free survival (PFS). RESULTS: Seventy-seven patients were enroled (62% cutaneous, 30% uveal, and 8% mucosal). At week 12, the ORR was 5%; 39% of patients had SD. During the lead-in phase, reduction in target lesions from baseline was seen in 55% of evaluable patients overall and in 59% of evaluable patients with uveal melanoma. Median PFS after randomisation was 4.1 months with cabozantinib and 2.8 months with placebo (hazard ratio of 0.59; P=0.284). Median PFS from study day 1 was 3.8 months, 6-month PFS was 33%, and median overall survival was 9.4 months. The most common grade 3/4 adverse events were fatigue (14%), hypertension (10%), and abdominal pain (8%). One treatment-related death was reported from peritonitis due to diverticular perforation. CONCLUSIONS: Cabozantinib has clinical activity in patients with metastatic melanoma, including uveal melanoma. Further clinical investigation is warranted.

Deregulation of apoptotic factors Bcl-xL and Bax confers apoptotic resistance to myeloid-derived suppressor cells and contributes to their persistence in cancer.

Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that accumulate in response to tumor progression. Compelling data from mouse models and human cancer patients showed that tumor-induced inflammatory mediators induce MDSC differentiation. However, the mechanisms underlying MDSC persistence is largely unknown. Here, we demonstrated that tumor-induced MDSCs exhibit significantly decreased spontaneous apoptosis as compared with myeloid cells with the same phenotypes from tumor-free mice. Consistent with the decreased apoptosis, cell surface Fas receptor decreased significantly in tumor-induced MDSCs. Screening for changes of key apoptosis mediators downstream the Fas receptor revealed that expression levels of IRF8 and Bax are diminished, whereas expression of Bcl-xL is increased in tumor-induced MDSCs. We further determined that IRF8 binds directly to Bax and Bcl-x promoter in primary myeloid cells in vivo, and IRF8-deficient MDSC-like cells also exhibit increased Bcl-xL and decreased Bax expression. Analysis of CD69 and CD25 levels revealed that cytotoxic T lymphocytes (CTLs) are partially activated in tumor-bearing hosts. Strikingly, FasL but not perforin and granzymes were selectively activated in CTLs in the tumor-bearing host. ABT-737 significantly increased the sensitivity of MDSCs to Fas-mediated apoptosis in vitro. More importantly, ABT-737 therapy increased MDSC spontaneous apoptosis and decreased MDSC accumulation in tumor-bearing mice. Our data thus determined that MDSCs use down-regulation of IRF8 to alter Bax and Bcl-xL expression to deregulate the Fas-mediated apoptosis pathway to evade elimination by host CTLs. Therefore, targeting Bcl-xL is potentially effective in suppression of MDSC persistence in cancer therapy.

Clinical and Demographic Factors, Treatment Patterns, and Overall Survival Associated With Rare Triple-Negative Breast Carcinomas in the US.

Importance: Triple-negative breast cancers are known collectively to demonstrate a more aggressive clinical course and earlier recurrence than cancers of other histological subtypes. However, the literature on rare triple-negative breast cancers and the association of histological type with survival and risk of metastasis is sparse. Objective: To present the clinical and demographic characteristics, treatment patterns, and overall survival (OS) for histologically rare (<10% of breast cancers) triple-negative breast cancer types: medullary carcinoma, adenoid cystic carcinoma, and metaplastic breast carcinoma. Design, Setting, and Participants: This cohort study was performed in the US using data reported by the National Cancer Database between 2010 and 2016. Confirmed cases of medullary carcinoma, adenoid cystic carcinoma, and metaplastic breast cancer were analyzed. Univariable analyses and multivariable Cox regression models were performed. Data analysis was performed from April to May 2020. Main Outcomes and Measures: The primary outcome was 5-year OS. Secondary outcomes included site of metastasis, effect of immunohistochemistry, management, and 2-year mortality. Results: A total of 8479 patients with breast cancer (mean [SD] age; 62.6 [14.3] years; 8435 women [99.48%]) were analyzed. Metaplastic carcinoma was the most commonly diagnosed histological type in this cohort, with 6867 patients (81%), followed by 1357 (16%) with adenoid cystic carcinoma and only 255 (3%) with medullary carcinoma. Medullary carcinoma presented earlier in life, at a median (interquartile range) age of 53 (45-62) years, compared with 62 (53-72) years for patients with adenoid cystic carcinoma and 63 (52-74) years for patients with metaplastic carcinoma. The proportion of tumors with triple-negative immunohistochemistry varied by histological type for medullary carcinoma (57 patients [22.4%]), adenoid cystic carcinoma (653 patients [48.1%]), and metaplastic carcinoma (3637 patients [53.0%]). Patients with adenoid cystic carcinoma were less likely to receive radiotherapy (711 patients [52.4%]) and chemotherapy (175 patients [12.9%]) compared with patients with medullary carcinoma (radiotherapy, 156 patients [61.2%]; chemotherapy, 190 patients [74.5%]) and metaplastic carcinoma (radiotherapy, 3416 patients [49.7%]; chemotherapy, 4709 patients [68.6%]). The 5-year OS rate was superior for patients with medullary (91.7%) and adenoid cystic carcinoma (88.4%) compared with patients with metaplastic carcinoma (63.1%). The 5-year mortality rate for adenoid cystic carcinoma was 8.33% vs 36.91% for metaplastic carcinoma. Conclusions and Relevance: Nationally, over the course of 7 years, medullary carcinoma was most common and metaplastic carcinoma had the worst 5-year OS among the rare histological breast cancer subtypes analyzed. Factors associated with a poor prognosis for metaplastic carcinoma included advanced stage, lung metastasis, older age, and not receiving chemotherapy or radiation therapy. Future research focusing on rare subtypes of breast cancer is desirable and could inform the optimal management of these relatively understudied carcinomas.

National Institute on Aging /Alzheimer's Association criteria for Mild Cognitive Impairment applied to chemotherapy treated breast cancer survivors.

BACKGROUND: In this analysis we use the National Institute on Aging/Alzheimer's Association (NIA/AA) criteria to identify Mild Cognitive Impairment (MCI) in a sample of breast cancer survivors treated with chemotherapy. METHODS: Sixty women ages 39-79 on a prospective clinical trial of donepezil were assessed at baseline using a battery of standardized/validated neurocognitive measures. Cognitive status was adjudicated to identify MCI by a panel of dementia experts. RESULTS: Fifty percent were not cognitively impaired, 43% met the NIA/AA criteria for MCI, 2% had dementia, and 5% could not be classified. DISCUSSION: In this sample, nearly half of breast cancer survivors met the NIA/AA criteria for MCI. We propose these criteria be used to define cancer-related Mild Cognitive Impairment (cMCI), providing a framework for conducting additional studies to further characterize cMCI and identify clinical, imaging, and genetic factors associated with the progression of cMCI to more advanced stages of cognitive impairment.

Management of cancer pain.

There are four basic approaches to cancer pain control: modify the source of pain, alter central perception of pain, modulate transmission of pain to the central nervous system, and block transmission of pain to the central nervous system. Systemic pharmacologic management aimed at the first three of these approaches is the cornerstone of the treatment of most cancer patients with moderate to severe pain. Optimal pharmacologic management of cancer pain requires selection of the appropriate analgesic drug; prescription of the appropriate dose; administration of the analgesic by the appropriate route; scheduling of the appropriate dosing interval; prevention of persistent pain and relief of breakthrough pain; aggressive titration of the dose of the analgesic; prevention, anticipation, and management of analgesic side effects; consideration of sequential trials of opioid analgesics; and use of appropriate co-analgesic drugs for specific pain syndromes. Most clinicians should be able to control most of the pain in most of their cancer patients. Collaboration with pain and hospice/palliative care experts should help the rest. No cancer patient should live or die with unrelieved pain.

FDG PET/CT in evaluation of unusual cutaneous manifestations of breast cancer.

Cutaneous metastases of primary internal malignancies are rare, with an incidence of 0.7% to 10.4%. Cutaneous manifestations due to breast cancer are the most common metastases dermatologists observe, with a prevalence of 2.4% and an incidence of 23.9%. Presence of cutaneous metastases is usually a late event in disease progression, indicating grave prognosis. Recognition of cutaneous breast cancer metastases significantly alters therapeutic plans, especially when the disease was thought to be successfully cured. F-FDG PET CT imaging can detect cutaneous metastasis and sites of distant metastases and monitor response to therapy. We report 3 patients with cutaneous-predominant breast carcinoma seen by FDG PET/CT.

Is the era of HER2 over? Pertuzumab in the neoadjuvant treatment of early HER2-positive breast cancer.

At the ASCO Breast Cancer Symposium in San Francisco last year, the keynote speaker, Dr George Sledge, chief of oncology at Stanford University School of Medicine and a preeminent breast cancer researcher, gave his 5 predictions for the state of breast cancer care in 10 years. One of his more startling predictions was that in 10 years, he believed that the era of HER2/neu would be over. He predicted that 3-year disease-free survival for patients with HER2/neu-positive disease would more than 92%, approximating outcomes in other good prognosis malignancies such as testicular cancer. In view of that expectation, he believed that the main research questions regarding HER2- positive disease would eventually involve decreasing toxicity and costs rather than the improving efficacy of HER2-targeted therapy. Essentially, HER2/neu-positive disease would cease to be a public health issue. In view of this remarkable but likely prescient statement, we note the recent publication of 2 trials (NeoSphere and TRPHAENA) that examined the efficacy and safety of the use of pertuzumab in combination with trastuzumab and chemotherapy in the neoadjuvant treatment of early-stage HER2-positive breast cancer.

Recurrent adult choroid plexus carcinoma treated with high-dose chemotherapy and syngeneic stem cell (bone marrow) transplant.

Choroid plexus carcinomas (CPCs) are rare epithelial central nervous system tumors. CPC occurs mainly in infants and young children, comprising ≈ 1 to 4% of all pediatric brain neoplasms. There is very limited information available regarding tumor biology and CPC treatment due to its rarity. There have been various case reports and meta-analyses of reported cases with CPC. Surgical resection is often challenging but remains a well-established treatment option. Chemotherapy is often reserved for recurrent or refractory cases, but the goal of treatment is usually palliative. We present a case of recurrent, adult CPC with disseminated leptomeningeal involvement treated with salvage chemotherapy including high-dose ifosfamide, carboplatin, and etoposide; once a remission was achieved, this response was consolidated with a syngeneic stem cell (bone marrow) transplant after a preparative regimen of high-dose chemotherapy with carboplatin, etoposide, and thiotepa. Although the patient tolerated the transplant well and remained disease-free for 12 months, she subsequently succumbed to relapsed disease 18 months posttransplant. We believe that this is the first report of using syngeneic stem cell transplant in CPC to consolidate a remission achieved by salvage chemotherapy.

First-in-human phase I dose-escalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors.

PURPOSE: A phase I study was conducted with the primary objective of determining the maximum tolerated dose (MTD) of AUY922 in patients with advanced solid tumors. Secondary objectives included characterization of the safety, pharmacokinetic, and pharmacodynamic profiles. PATIENTS AND METHODS: Patients with advanced solid tumors received 1-hour i.v. infusions of AUY922 once a week in a 28-day cycle. An adaptive Bayesian logistic regression model that employed observed dose-limiting toxicities (DLT) in the first treatment cycle was used to guide dose-escalation decisions, with the established MTD to be used in phase II studies. RESULTS: One hundred and one patients were enrolled and explored at doses in the range of 2 to 70 mg/m(2). DLTs occurred in 8 patients (22-70 mg/m(2)) and included diarrhea, asthenia/fatigue, anorexia, atrial flutter, and visual symptoms. At 70 mg/m(2), the AUY922 concentration achieved was consistent with active concentrations in a range of xenograft models. There was evidence of target inhibition in peripheral blood mononuclear cells (HSP70 induction) and tumor (client protein depletion and reduction of metabolic activity by (18)F-FDG PET). The recommended phase II dose (RP2D) of 70 mg/m(2) was proposed on the basis of toxicity and pharmacokinetic and pharmacodynamic profiles. CONCLUSIONS: At the RP2D of 70 mg/m(2), AUY922 exhibited acceptable tolerability, and phase II single-agent and combination studies have been initiated in patients with HER2-positive breast, gastric, and non-small cell lung cancers.

Dural-based metastatic carcinomas mimicking primary CNS neoplasia: report of 7 cases emphasizing the role of timely surgery and accurate pathologic evaluation.

Clinical presentation with dural-based metastasis mimicking meningiomas is rare. We aimed to evaluate the role of frozen section in guiding surgery and histopathologic diagnosis in determining primary sites of dural-based metastatic carcinomas. Following the receipt of HAC approval, we retrospectively reviewed 7cases presenting with dural-based masses clinically suspected to be primary brain tumors (6 meningiomas and 1 superficial glioblastoma), but diagnosed to be metastatic carcinomas on subsequent resection. Pertinent clinical records and follow-up data were reviewed. Patient's age ranged from 59 to 80 years. Imaging showed extra-axial dural-based masses with contiguous but not primary brain involvement. On intra-operative frozen section (not performed in case 7), differential diagnoses included metastatic carcinoma in all cases, and surgery modified accordingly. Nesting, cribriform, and "picket-fence" like glands were among useful histologic diagnostic patterns. Immunoprofile supported histologic diagnosis in all cases. Subsequent clinical and radiologic evaluation confirmed coexistent sites of origin in all cases. The metastases were solitary in all cases; except multiple dural-based tumors in case 1, in which interestingly no systemic metastasis were identified. Dural-based metastatic carcinomas mimicking meningiomas may be solitary, of unknown primary, or without concomitant systemic spread on imaging. Frozen section evaluation is helpful in modifying surgery. Although high-grade, these are typically differentiated enough to allow accurate histopathologic diagnosis, and reasonable determination of primary tumor site, especially with a judicious panel of cytokeratins, transcription factors, hormone receptors and relatively organ-specific markers. Clinicians and pathologists need to be aware of the occurrence, spectrum, need for timely intervention, and accurate diagnosis of dural-based metastatic carcinomas.

Race as an independent risk factor for breast cancer survival: breast cancer outcomes from the medical college of georgia tumor registry.

BACKGROUND: Causes of racial disparities in breast cancer survival remain unclear. This study assesses overall survival (OS) after diagnosis between black and white women and examines factors that might correlate with this disparity. PATIENTS AND METHODS: Data were obtained from the Medical College of Georgia Tumor Registry. Cases included those diagnosed between 1990 and 2005. We analyzed race, stage, age of diagnosis, and treatment received: chemotherapy, radiation, surgery, and hormonal therapy. A Cox proportional hazards model was used to determine differences in OS. RESULTS: Compared with 670 white women, 489 black women were more likely to be younger, have later-stage disease at diagnosis, and were less likely to have received hormonal therapy. Both groups received similar rates of radiation, surgery, and chemotherapy. Black women had significantly poorer OS (adjusted hazard ratio, 1.35; 95% CI, 1.12-1.63). White women had a 5-year OS of 54% compared with 45% in black women (P = .0031). Having received radiation, surgery, or chemotherapy was not associated with OS. White women were more likely to have received hormonal therapy, which had a significant protective effect. However, a stratified analysis (between those who received hormonal therapy and those who did not) showed similar results, whereas black women experienced poorer OS in both strata. CONCLUSION: Black women with breast cancer had a significantly poorer OS compared with white women. White women received more hormonal therapy, which had a protective effect. There were no differences in treatment received regarding radiation, surgery, or chemotherapy, and these treatments were not associated with OS. The reasons for racial disparities in breast cancer OS remain complex.