Trastuzumab for the treatment of salivary duct carcinoma.

OBJECTIVE: Salivary duct carcinoma (SDC) is a rare and aggressive malignancy with high mortality and poor response to treatment. A significant fraction of SDCs are HER2 positive. This retrospective review examines HER2 testing in SDC and the outcome of trastuzumab-based therapy in adjuvant and palliative settings. METHODS: A total of 13 patients with SDC and HER2/neu expression by immunohistochemistry of 1-3+ were treated with trastuzumab in adjuvant (n = 8) or palliative (n = 5) setting. Adjuvant therapy consisted of concurrent radiation and chemotherapy with weekly paclitaxel, carboplatin, and trastuzumab (TCH) for 6 weeks followed by TCH for 12 weeks and trastuzumab alone for 1 year. Palliative treatment for metastatic disease consisted of TCH every 3 weeks for 6 cycles followed by trastuzumab for variable time periods with or without second-line chemotherapy for progression. All patients had fluorescence in situ hybridization testing for HER2/neu gene amplification. RESULTS: The median duration of follow-up was 27 months (range: 8-48 months). In all, 62% of adjuvant patients (5/8) had no evidence of disease more than 2 years from completion of therapy. All patients with metastatic disease (5/5 patients) responded to treatment with TCH. One patient achieved a complete response and remains with no evidence of disease 52 months after initiation of TCH. The median duration of response was 18 months (range: 8-52 months). CONCLUSION: HER2/neu positivity and treatment with trastuzumab correlated well with long-term survival and response in our patients. Based on this data, we propose that HER2/neu status be examined routinely in all patients with SDCs and the treatment be directed accordingly.

Phase II Study of Afatinib in Patients With Tumors With Human Epidermal Growth Factor Receptor 2-Activating Mutations: Results From the National Cancer Institute-Molecular Analysis for Therapy Choice ECOG-ACRIN Trial (EAY131) Subprotocol EAY131-B.

PURPOSE: National Cancer Institute-Molecular Analysis for Therapy Choice is a multicohort trial that assigns patients with advanced cancers to targeted therapies on the basis of central tumor genomic testing. Arm B evaluated afatinib, an ErbB family tyrosine kinase inhibitor, in patients with ERBB2-activating mutations. METHODS: Eligible patients had selected ERBB2 single-nucleotide variants or insertions/deletions detected by the National Cancer Institute-Molecular Analysis for Therapy Choice next-generation sequencing assay. Patients had performance status ≤ 1, left ventricular ejection fraction > 50%, grade ≤ 1 diarrhea, and no prior human epidermal growth factor receptor 2 (HER2) therapy. Patients received afatinib 40 mg once daily in 28-day cycles. The primary end point was objective response rate (ORR). Secondary end points were 6-month progression-free survival, overall survival, toxicity, and molecular correlates. RESULTS: A total of 59 patients were assigned and 40 were enrolled. The median age was 62 years, 78% were female, 68% had performance status = 1, and 58% had received > 3 prior therapies. The confirmed ORR was 2.7% (n = 1 of 37; 90% CI, 0.14 to 12.2), and 6-month progression-free survival was 12.0% (90% CI, 5.6 to 25.8). A confirmed partial response occurred in a patient with adenocarcinoma of extra-mammary Paget disease of skin who progressed after cycle 6. Two unconfirmed partial responses were observed (low-grade serous gynecological tract and estrogen receptor-positive/HER2-negative immunohistochemistry breast ductal carcinoma). Of 12 patients with breast cancer, 1 additional patient with lobular carcinoma (estrogen receptor-positive/HER2 fluorescent in situ hybridization) had a 51% reduction in target lesions but progressed because of a new lesion at cycle 6. The most common (> 20%) treatment-related adverse events were diarrhea (68%), mucositis (43%), fatigue (40%), acneiform rash (30%), dehydration (27%), vomiting (27%), nausea (27%), anemia (27%), and anorexia (22%). Four patients (11%) discontinued because of adverse events. CONCLUSION: Although afatinib did not meet the prespecified threshold for antitumor activity in this heavily pretreated cohort, the response in a rare tumor type is notable. The safety profile of afatinib was consistent with prior studies.

Genomic Correlates of Response to Everolimus in Aggressive Radioiodine-refractory Thyroid Cancer: A Phase II Study.

Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine-refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included.Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis.Results: Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3-18.5) with a 2-year PFS of 23.6% (95% CI, 10.5-39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8-85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt-mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.Conclusions: Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine. Clin Cancer Res; 24(7); 1546-53. ©2018 AACR.

Patterns of failure after reirradiation with intensity-modulated radiation therapy and the competing risk of out-of-field recurrences.

PURPOSE: To describe patterns of failure (POF) after reirradiation (reRT) with intensity modulated radiation therapy (IMRT) for recurrent/second primary squamous cell carcinoma of the head and neck. METHODS: From 08/2004-02/2013, 75 consecutive patients received reRT with IMRT. Gross tumor was generally treated with a 5mm planning target volume (PTV) margin. For postoperative cases, a 5mm PTV was added to the clinical target volume which included the postoperative bed. Elective neck coverage was not standard. POF were characterized by correlating the recurrent tumor location on CT-imaging with the reRT IMRT plan. RESULTS: Patients received definitive reRT (55%) or postoperative reRT (45%) to a median 60Gy (range, 59.4-70Gy). Most patients (88%) received concurrent chemotherapy including induction (16%). The median overall survival was 1.8years. Isolated local-regional recurrence (LRR) was the most common failure-type (2-year cumulative incidence [CI] 22.5% [95% C.I. 13.6-32.7%]), but concurrent LRR and distant-failure occurred frequently (2-year CI LRR+distant-failure 19.6% [95% C.I. 11.3-29.5%]); isolated distant-failure was rare (2-year CI 5.7% [95% C.I. 1.8-12.8%]). The 2-year in-field control was 65% (95% C.I. 52-81%) reflecting encouraging control within the irradiated target. Patients with gross disease were more likely to recur in-field (p=0.02), whereas postoperative patients were more likely to recur out-of-field/marginally than in-field (p=0.02). CONCLUSIONS: POF after reRT differ when treating gross disease or postoperatively and should be considered when delineating reRT targets. Aggressive local therapy resulted in favorable in-field control, yet there remains a high competing risk of regional and distant micrometastatic disease. Better systemic agents are needed to control clinically occult local-regional and distant disease.

Human papillomavirus and induction chemotherapy versus concurrent chemoradiotherapy in locally advanced oropharyngeal cancer: The Dana Farber Experience.

BACKGROUND: Human papillomavirus (HPV) infection indicates favorable prognosis in oropharyngeal squamous cell carcinoma (SCC). The purpose of this study was for us to assess the impact of HPV in patients treated with sequential therapy versus concomitant chemoradiotherapy (CRT). METHODS: Patients with stage III and IVA and B oropharyngeal SCC were reviewed spanning 10 years. RESULTS: Among 500 cases, 291 (58%) received CRT versus 209 (42%) sequential therapy. HPV status was known in 279 of patients (56%) and positive in 77% (determined by polymerase chain reaction [PCR; 91%], p16 immunohistochemical [IHC], or both). Median follow-up was 2.8 years. Overall survival (OS) did not differ for sequential therapy versus CRT overall (hazard ratio [HR] = 0.90; p = .66; 3-year OS = 86% and 87%) or within HPV-positive patients (HR = 0.89; p = .81; 3-year OS = 91% and 91%) or within HPV-negative patients (HR = 0.55; p = .32; 3-year OS = 85% and 75%). CONCLUSION: Survival for all patients was high and notable for HPV-negative patients treated with sequential therapy. Further studies in this patient population are warranted. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1618-E1624, 2016.

A combination of rituximab, cyclophosphamide and dexamethasone effectively treats immune cytopenias of chronic lymphocytic leukemia.

Auto-immune hemolytic anemia (AIHA) and idiopathic thrombocytopenic purpura (ITP) are known complications of chronic lymphocytic leukemia (CLL). Rituximab, cyclophosphamide and dexamethasone (RCD) effectively target lymphocytes and inhibit autoimmune processes. We reviewed 21 patients with CLL treated for AIHA alone (n = 18), ITP alone (n = 1) or both (n = 2) with the following RCD regimen: rituximab 375 mg/m(2) i.v. infusion given on day 1, cyclophosphamide 750-1000 mg/m(2) i.v. on day 2 and dexamethasone 12 mg day 1-7 given every 3 weeks. Response to treatment was seen in all 20 patients with CLL with AIHA. Median hemoglobin pre-treatment was 8 g/dL. The median change in hemoglobin was 5.2 g/dL and the median post-treatment hemoglobin level was noted to be 13.1 g/dL. Median duration of response was 22 months. Nine relapsed patients responded as well. Fifty percent of evaluable patients converted to Coombs negative with median duration of response of 41 months vs. 10 months for those who did not convert. This difference was not statistically significant (p = 0.0674). Steroid-refractory immune thrombocytopenia was present in three patients and all responded to RCD. There were no hospitalisations or infections directly related to RCD. RCD is a safe and effective regimen in the treatment of immune cytopenias associated with CLL.