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Total amount of cfDNA extracted from each patient sample

Available therapies and clinical trials

Allelic fractions for all variants detected in tDNA and ctDNA* in patients for whom both plasma and tissue samples were obtained (n=50)

Summary of driver and resistance mutations in EGFR and ALK detected in ctDNA, tDNA, and both ctDNA and tDNA

Tissue next-generation sequencing gene coverage. A: Illumina TruSeq panel (47 genes), and B: Penn Precision Panel (20 genes)

Analysis of discordant EGFR driver and resistance mutations detected in tDNA or ctDNA

All mutations detected in patient ctDNA (n=102)

Circulating tumor DNA next-generation sequencing gene coverage

Purpose: The expanding number of targeted therapeutics for non–small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS.Experimental Design: A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible.Results: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible.Conclusions: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772–82. ©2016 AACR.

The phase 4 ABOUND.70+ trial assessed the safety and efficacy of nab-paclitaxel/carboplatin continuously or with a 1-week break between cycles in elderly patients with advanced non-small cell lung cancer (NSCLC). Patients ≥70 years with locally advanced/metastatic NSCLC were randomized 1:1 to first-line nab-paclitaxel days 1, 8, 15 plus carboplatin day 1 of a 21-day cycle (21d) or the same nab-paclitaxel/carboplatin regimen with a 1-week break between cycles (21d + break; 28d). The primary endpoint was the percentage of patients with grade ≥ 2 peripheral neuropathy (PN) or grade ≥ 3 myelosuppression. Other key endpoints included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). A total of 143 patients were randomized (71 to 21d, 72 to 21d + break). The percentage of patients with grade ≥ 2 PN or grade ≥ 3 myelosuppression was similar between the 21d and 21d + break arms (76.5 and 77.1%; P = 0.9258). Treatment exposure was lower in the 21d arm compared with the 21d + break arm. Median OS was 15.2 and 16.2 months [hazard ratio (HR) 0.72, 95% CI 0.44–1.19; P = 0.1966], median PFS was 3.6 and 7.0 months (HR 0.48, 95% CI 0.30–0.76; P

The combination of cisplatin, 5-fluorouracil, and cetuximab is a standard treatment for patients with recurrent/metastatic head and neck cancer, with a high rate of toxicity. Identifying less toxic, equally effective regimens is imperative. Therefore, in the current study, the authors investigated first-line treatment with an all-oral regimen of capecitabine and lapatinib.Patients were required to have incurable head and neck cancer of any primary site other than the nasopharynx, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2, and no prior exposure to capecitabine or lapatinib. Subjects were treated with capecitabine at a dose of 1000 mg/m(2) twice daily and lapatinib at a dose of 1250 mg daily. Capecitabine was administered for 14 days of each 21-day cycle for 4 cycles. Lapatinib was administered daily until disease progression. The primary outcome was overall survival.A total of 44 subjects were accrued between November 13, 2009 and April 29, 2014. Approximately 38.6% of the sample had an ECOG PS of 0, 52.3% had an ECOG PS of 1, and 9.1% had an ECOG PS of 2. Approximately 81.8% were male and the median age of the patients was 62 years. Prior attempts at curative treatment with chemotherapy had been used in 68.2% of patients (platinum was used in 55.8%). There was no grade 5 toxicity noted (toxicity was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]). The most common adverse events were diarrhea (18.2% of patients with grade 3) and rash (13.6% of patients with grade 3). The primary objective was met; the median overall survival was 10.7 months (90% confidence interval [90% CI], 8.7-12.9 months). The overall response rate was 25% (90% CI, 15%-38%). The median progression-free survival was 4.2 months (90% CI, 3.6-5.1 months). The results were not substantially different when subdivided by p16 status. Only 2 patients were positive for human epidermal growth factor receptor 2 by immunohistochemistry.The current study met its primary objective of survival comparable to the combination of cisplatin, 5-FU and cetuximab regimen, and the toxicity of this all-oral regimen was tolerable. Cancer 2016;122:2350-2355. © 2016 American Cancer Society.

Purpose Appropriate therapy for Eastern Cooperative Oncology Group (ECOG) performance status (PS) -2 patients with advanced non–small-cell lung cancer (NSCLC) remains challenging. PS-2 patients on ECOG 1594 had a median survival (MS) of only 4.1 months and 1-year overall survival (OS) of 19%. Three percent had grade 5 toxicity. Patients and Methods ECOG 1599, the first PS 2–specific, US cooperative group trial for treatment-naïve advanced NSCLC, randomly assigned patients to dose-attenuated carboplatin/paclitaxel (the least toxic regimen in ECOG 1594) or gemcitabine/cisplatin (which yielded an MS of 7.9 months in PS-2 patients). Patients received either carboplatin (area under the concentration-time curve, 6) and paclitaxel 200 mg/m2 every 3 weeks (CbP) or gemcitabine 1 g/m2 days 1 and 8 and cisplatin 60 mg/m2 day 1 every 3 weeks (CG). Results One hundred three patients were enrolled; 100 proved eligible. Median age was 66 years; 46% had at least 5% weight loss; 88% had stage IV or recurrent disease. Median number of cycles administered was three per arm. CbP featured more grade 3 neutropathy (10% v 0%) and more grade ≥ 3 neutropenia (59% v 33%), whereas CG yielded more grade ≥ 3 thrombocytopenia (33% v 14%), more grade ≥ 3 fatigue (22% v 14%), and more grade ≥ 1 creatinine elevations (43% v 6%). One grade 5 toxicity, confined to the CbP arm, occurred. Response rate, time to progression, MS, and 1-year OS rates for CG and CbP, were 23%, 4.8 months, 6.9 months, and 25%, and 14%, 4.2 months, 6.2 months, and 19%, respectively. Conclusion Platinum-based combination chemotherapy for PS-2 patients with NSCLC is feasible with acceptable toxicity, but survival in these patients remains inferior to that of PS-0 to -1 patients.

To provide guidance to physicians and patients with regard to the use of definitive external beam radiation therapy (RT) in locally advanced non-small cell lung cancer (LA NSCLC) based on available medical evidence complemented by consensus-based expert opinion.A panel authorized by the American Society for Radiation Oncology (ASTRO) Board of Directors and Guidelines Subcommittee conducted 3 systematic reviews on the following topics: (1) ideal radical RT dose fractionation for RT alone; (2) ideal radical RT dose fractionation for chemoradiation; and (3) ideal timing of radical radiation therapy with systemic chemotherapy. Practice guideline recommendations were approved using an a priori-defined consensus-building methodology supported by ASTRO and approved tools for the grading of evidence quality and the strength of guideline recommendations.For patients managed by RT alone, a minimum dose of 60 Gy of RT is recommended. Dose escalation beyond 60 Gy in the context of combined modality concurrent chemoradiation has not been found to be associated with any clinical benefits. In the context of combined modality therapy, chemotherapy and radiation should ideally be given concurrently to maximize survival, local control, and disease response rate.A consensus and evidence-based clinical practice guideline for the definitive radiotherapeutic management of LA NSCLC has been created that addresses 3 important questions.

The Radiation Therapy Oncology Group enrolled 30 patientswith recurrent malignant astrocytomas onto a phase IIstudy (RTOG 91-13). Patients were treated with all-trans-retinoicacid at a starting dose of 120 mg/m2per day orally continuously until disease progression. Fourteenpatients had glioblastoma, 14 had anaplastic astrocytoma, and2 had other histologies; 53% were under 50years of age. All patients had failed radiationtherapy and/or at least one chemotherapy regimen. Allpatients had a Karnofsky performance status score ofat least 70, but only 37% had aKPS of 90-100. Forty percent had a neurologicfunction status of grade 1 (able to work).A minimum of 4 weeks of all-trans-retinoic aciddefined adequate treatment. Twenty-five patients received adequate therapy.Most common toxicities were dry skin, cheilitis, anemia,and headache; 3 patients had grade 3 headacherequiring suspension of all-trans-retinoic acid. No grade 3hematologic toxicity was observed. Of 25 adequately treatedpatients, 3 showed objective regression of tumor onmagnetic resonance imaging and computed tomography scans, 3patients remained stable, and 19 patients had diseaseprogression. The median time to tumor progression was3.8 months and the median survival time was5.7 months.This study suggests that this dose of singleagent all-trans-retinoic acid has modest clinical activity againstrecurrent malignant gliomas with tolerable side effects. Aresponse rate of 12% and a stabilization rateof 12% are lower than expected. Future studieswith higher dosage or in combination with biologicalresponse modifiers or chemotherapy may be warranted.

The median age of presentation with lung cancer is 71, making the elderly the dominant subgroup. Although some elderly patients are frail, others have great physiological reserve. Geriatric assessment can clarify the specific strengths and weaknesses of older patients, improving management. This assessment should, at the minimum, encompass performance status, comorbidity, medications, level of independence in activities of daily living and instrumental activities of daily living, cognitive assessment, nutrition assessment, and assessment of social support. The fit elderly with localized disease should be offered curative resection; video-assisted thoracic surgery may be preferred over thoracotomy. Fit septuagenarians with node positive or > 4 cm primary tumors should then be considered for adjuvant chemotherapy. For less fit patients, the data on stereotactic radiosurgery indicate that it presents a viable treatment option. Data on stage III disease are limited but suggest that chemoradiotherapy, particularly when the chemotherapy is administered on a weekly schedule, is feasible in fit older patients. For the older patients with metastatic cancer, abundant tissue should be obtained at diagnosis to allow for comprehensive molecular characterization with the hopes of rendering the patient eligible for targeted therapy. When such a targeted therapy is not available, there is duration of life and quality of life benefit to the administration of cytotoxic chemotherapy. The standard of care for older patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 is a platinum-based doublet. Prospective data on second-line therapy after failure of first-line therapy are limited but suggest a benefit to treatment.

Purpose Elderly patients often have comorbidities and other characteristics that make the selection of treatment daunting. Methods We have reviewed the available evidence in the literature to gauge the results of therapy for elderly lung cancer patients. Results The beneficial results achieved with adjuvant chemotherapy in the general population with early non–small-cell lung cancer (NSCLC) cannot be automatically extrapolated to the elderly, who are at higher risk of toxicity. Retrospective analyses of combined chemoradiotherapy in locally advanced NSCLC patients suggest equivalent therapeutic benefit for younger and older patients, despite heightened toxicity. There have been no elderly-specific phase III trials for locally advanced NSCLC. For advanced NSCLC, on the basis of evidence-based data, single-agent chemotherapy remains the standard of care for nonselected elderly patients. However, retrospective analyses suggest that the efficacy of platinum-based combination chemotherapy is similar in fit older and younger patients, with increased but acceptable toxicity for elderly patients. In limited-disease small-cell lung cancer (SCLC), sequential chemoradiotherapy is clearly less toxic compared with a standard concurrent approach, but our assessment of treatment is hindered by the absence of prospective elderly-specific trials. Although prophylactic cranial irradiation has emerged as a standard strategy, it should be omitted in patients with cognitive impairment. In extensive SCLC, etoposide in combination with either cisplatin or carboplatin has emerged as standard treatment; hematopoietic support may be necessary. Conclusion With the exception of advanced NSCLC, prospective elderly-specific studies are lacking. Available data suggest that outcomes in the fit elderly mirror results observed in younger patients, although toxicity is generally worse.

Purpose Etoposide and cisplatin (EP) has been a standard treatment for extensive-disease small-cell lung cancer (SCLC). An earlier phase III trial reported improved survival for patients receiving irinotecan plus cisplatin (IP) versus EP. Our trial was designed to determine if a modified weekly regimen of IP would provide superior survival with less toxicity than EP. Patients and Methods The primary objective was to compare overall survival in extensive-disease SCLC patients randomly assigned to receive IP (n = 221) or EP (n = 110). Patients were randomly assigned in 2:1 ratio to cisplatin 30 mg/m2 intravenously (IV) + irinotecan 65 mg/m2 IV on days 1 and 8 every 21 days, or cisplatin 60 mg/m2 IV on day 1, and etoposide 120 mg/m2 IV on days 1 to 3 every 21 days for at least four cycles, until progressive disease, or until intolerable toxicity resulted. Results Selected grade 3/4 toxicities for IP/EP were: neutropenia (36.2% v 86.5%; P < .01), febrile neutropenia (3.7% v 10.4%; P = .06), anemia (4.8% v 11.5%; P = .02), thrombocytopenia (4.3% v 19.2%; P < .01), vomiting (12.5% v 3.8%; P = .04), and diarrhea (21.3% v 0%; P < .01). There was no significant difference in response rates (48% v 43.6%), median time to progression (4.1 v 4.6 months), or overall survival (median survival time, 9.3 months v 10.2 months; P = .74). Conclusion Treatment with this dose and schedule of IP did not result in improved survival when compared with EP. Fewer patients receiving IP had grade 3/4 anemia, thrombocytopenia, neutropenia, and febrile neutropenia compared with patients receiving EP, but more had grade 3/4 diarrhea and vomiting.

Traditionally, systemic chemotherapy has been the main form of treatment for recurrent squamous carcinoma of the head and neck. Unfortunately, response rates are seldom higher than 20-30%, with median survival times of 6-8 months. This paper explores the emerging role of reirradiation in the setting of recurrent squamous cell carcinoma of the head and neck; it reviews the existing literature focusing on radiation alone in this setting, and more recent literature integrating systemic radiosensitizing cytotoxics with reirradiation. Data from recent series using fluorinated pyrimidines and hydroxyurea, as well as platinating agents and taxanes, suggest occasional longterm survival benefits that exceed the historic norm. These approaches, largely confined to single institutions or small consortiums to date, are being evaluated prospectively in the cooperative group setting.

Previous evaluation of HER2 overexpression in salivary gland cancers indicated an incidence varying between 7 and 56%, with no clear difference among three histologically different subtypes. As part of a Phase II trial of trastuzumab for treatment of incurable salivary gland cancer, we screened 137 tumors for HER2 expression.Unstained sections of paraffin-embedded tumor samples were stained with p185/HER2 receptor antibody. Tumors with moderate (2+) to strong (3+) complete membrane staining in at least 10% of the tumor cells were scored as positive for overexpression.The overall frequency of overexpression for HER2 was 17% (23 of 137), whereas it was only 8% in the three most common histological subtypes screened. Overexpression was distinctly rare in the most common subtype screened, adenoid cystic carcinoma (4%, 3 of 70). Overexpression was very common in salivary duct cancers; 10 (83%) of 12 were positive for HER2. This observation is consistent with the typical high-grade histological features and aggressive behavior of this subtype as well as with its histogenetic similarity to breast cancer. Analysis based on histogenesis (intercalated duct versus excretory duct) indicated a higher frequency of overexpression in the latter (55%) than in the former (7%).Our overall results suggest that trastuzumab will not have a major role in treatment of salivary gland cancers of intercalated duct origin. Further systematic evaluation of trastuzumab in subtypes of excretory duct origin could be supported.