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Advanced gall bladder cancer (GBC) is an aggressive disease, and there is no consensus on treatment options beyond first-line chemotherapy. We report a case of an elderly male with FGFR2-altered advanced adenocarcinoma of the gallbladder who failed two prior lines of chemotherapy but had sustained response and stable disease on sequential FGFR-directed targeted therapy.We describe a case of FGFR2-altered metastatic adenocarcinoma of the gallbladder who failed two prior lines of chemotherapy. The treatment was based on comprehensive genomic profiling when the patient was found to have FGFR2 single amino acid mutation (S252W) in one of his tissue samples. A novel therapeutic regimen with sequential anti-FGFR tyrosine kinase inhibitors was later initiated.The patient tolerated the sequential targeted therapy very well and had a sustained response and stable disease. He had an overall survival of nearly five years. Unfortunately, GBC is an aggressive disease, and there is no consensus on treatment options beyond first-line chemotherapy.Through this patient, we demonstrate that advanced-metastatic GBC with FGFR alterations can be maintained on anti-FGFR therapy for prolonged periods of time, with improved survival. Therefore, we endorse the need for comprehensive genomic profiling in advanced-metastatic GBC and the need to study the role of FGFR inhibitors as a viable treatment option in these patients.

We provide the South Asian Declaration, containing the consensus guidelines for coronavirus disease 2019 (COVID-19) vaccination in cancer patients.

Purpose Selection of cytotoxic chemotherapy agents (CCA) based on pre-treatment evaluation of drug sensitivities is a desirable but unmet goal for personalized anticancer treatment strategies. Prior attempts to correlate in vitro Chemo-Response Profiles (CRP) of tumor explants or Circulating Tumor Cells (CTCs) with clinical outcomes have been largely unsuccessful. Methods We present results from a large cohort (n = 5090, three Arms) of patients with various solid organ tumors, where CRP of Circulating Tumor-Associated Cells (C-TACs) was determined against cancer-specific CCA panels to generate a database of 56,466 unique CRP. Results In Arm 1 (n = 230), 93.7% concordance was observed between CRP of C-TACs and concurrently obtained Tumor tissue Derived Cells (TDCs). In arm 2 (n = 2201, pretreated), resistance of C-TACs to ≥ 1 CCA was observed in 79% of cases. In a blinded subset analysis of 143 pretreated patients with radiologically ascertained disease progression, CRP of C-TACs was 87% concordant with in vivo treatment failure. In Arm 3 (n = 2734, therapy naïve), innate resistance of C-TACs to ≥ 1 CCA was observed in 61% of cases. In a blinded subset analysis of 77 therapy naïve patients, in vitro chemo-sensitivity of C-TACs was concordant with radiologically ascertained treatment response to first line CCA in 97% of cases. Conclusion To our knowledge, this is the first expansive and in-depth study demonstrating that real-time CRP of C-TACs is a viable approach for non-invasive assessment of response to CCA in solid organ cancers.

Background Histopathologic examination (HPE) of tumor tissue obtained by invasive biopsy is the standard for cancer diagnosis but is resource‐intensive and has been associated with procedural risks. The authors demonstrate that immunocytochemistry (ICC) profiling of circulating ensembles of tumor‐associated cells (C‐ETACs) can noninvasively provide diagnostic guidance in solid organ cancers. Methods The clinical performance of this approach was tested on blood samples from 30,060 individuals, including 9416 individuals with known cancer; 6725 symptomatic individuals with suspected cancer; and 13,919 asymptomatic individuals with no prior diagnosis of cancer. C‐ETACs were harvested from peripheral blood and profiled by ICC for organ‐specific and subtype‐specific markers relevant to the cancer type. ICC profiles were compared with HPE diagnoses to determine concordance. Results The presence of malignancy was confirmed by the detection of C‐ETACs in 91.8% of the 9416 individuals with previously known cancer. Of the 6725 symptomatic individuals, 6025 were diagnosed with cancer, and 700 were diagnosed with benign conditions; C‐ETACs were detected in 92.6% of samples from the 6025 individuals with cancer. In a subset of 3509 samples, ICC profiling of C‐ETACs for organ‐specific and subtype‐specific markers was concordant with HPE findings in 93.1% of cases. C‐ETACs were undetectable in 95% of samples from the 700 symptomatic individuals who had benign conditions and in 96.3% of samples from the 13,919 asymptomatic individuals. Conclusions C‐ETACs were ubiquitous (>90%) in various cancers and provided diagnostically relevant information in the majority (>90%) of cases. This is the first comprehensive report on the feasibility of ICC profiling of C‐ETACs to provide pan‐cancer diagnostic guidance with accuracy comparable to that of HPE., Immunocytochemistry profiling of circulating ensembles of tumor‐associated cells conveys malignancy status as well as the organ of origin in several cancers, including brain cancer, with high sensitivity, specificity, and accuracy. This approach addresses the long‐unmet need for the noninvasive diagnostic triaging of symptomatic individuals with suspected cancers.

Circulating ensembles of tumor‐associated cells (C‐ETACs) which comprise tumor emboli, immune cells and fibroblasts pose well‐recognized risks of thrombosis and aggressive metastasis. However, the detection, prevalence and characterization of C‐ETACs have been impaired due to methodological difficulties. Our findings show extensive pan‐cancer prevalence of C‐ETACs on a hitherto unreported scale in cancer patients and virtual undetectability in asymptomatic individuals. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples of 16,134 subjects including 5,509 patients with epithelial malignancies in various organs and 10,625 asymptomatic individuals with age related higher cancer risk. PBMCs were treated with stabilizing reagents to protect and harvest apoptosis‐resistant C‐ETACs, which are defined as cell clusters comprising at least three EpCAM+ and CK+ cells irrespective of leucocyte common antigen (CD45) status. All asymptomatic individuals underwent screening investigations for malignancy including PAP smear, mammography, low‐dose computed tomography, evaluation of cancer antigen 125, cancer antigen 19‐9, alpha fetoprotein, carcinoembryonic antigen, prostate specific antigen (PSA) levels and clinical examination to identify healthy individuals with no indication of cancer. C‐ETACs were detected in 4,944 (89.8%, 95% CI: 89.0–90.7%) out of 5,509 cases of cancer. C‐ETACs were detected in 255 (3%, 95% CI: 2.7–3.4%) of the 8,493 individuals with no abnormal findings in screening. C‐ETACs were detected in 137 (6.4%, 95% CI: 5.4–7.4%) of the 2,132 asymptomatic individuals with abnormal results in one or more screening tests. Our study shows that heterotypic C‐ETACs are ubiquitous in epithelial cancers irrespective of radiological, metastatic or therapy status. C‐ETACs thus qualify to be a systemic hallmark of cancer., What's new? Circulating Ensembles of Tumor Associated Cells (C‐ETACs) comprised of tumor emboli, immune cells, and fibroblasts pose well‐recognized risks of thrombosis and aggressive metastasis. However, the detection and characterization of C‐ETACs have been impaired by methodological difficulties. Here, the authors have developed a label‐free non‐mechanical process that permits enrichment of viable apoptosis‐resistant C‐ETACs from peripheral blood. They show that heterotypic C‐ETACs are not merely incidental findings in cancer but rather a systemic manifestation of malignancy. C‐ETACs are present in a significant proportion of all solid organ malignancies and are rare in asymptomatic individuals. Monitoring of C‐ETACs could help inform cancer management.

Angiogenesis inhibitors (AGI) are not presently used for the treatment of gastric cancers. This report demonstrates that angiogenesis inhibitor can be safely and effectively used in combination with cytotoxic anti‐cancer agents for treatment of Gastric cancers., This case of Gastric Adenocarcinoma had progressed following failure of several prior lines of standard of care regimens. Multi‐analyte profiling of freshly biopsied tumor sample indicated FGFR3 amplification along with sensitivity of tumor cells towards various chemotherapy drugs. The patient received personalized combination regimen of Pazopanib with Gemcitabine and Pemetrexed which yielded significant regression of metastatic deposits.

Background: The early detection of breast cancer (BrC) is associated with improved survival. We describe a blood-based breast cancer detection test based on functional enrichment of breast-adenocarcinoma-associated circulating tumor cells (BrAD-CTCs) and their identification via multiplexed fluorescence immunocytochemistry (ICC) profiling for GCDFP15, GATA3, EpCAM, PanCK, and CD45 status. Methods: The ability of the test to differentiate BrC cases (N = 548) from healthy women (N = 9632) was evaluated in a case–control clinical study. The ability of the test to differentiate BrC cases from those with benign breast conditions was evaluated in a prospective clinical study of women (N = 141) suspected of BrC. Results: The test accurately detects BrAD-CTCs in breast cancers, irrespective of age, ethnicity, disease stage, grade, or hormone receptor status. Analytical validation established the high accuracy and reliability of the test under intended use conditions. The test detects and differentiates BrC cases from healthy women with 100% specificity and 92.07% overall sensitivity in a case–control study. In a prospective clinical study, the test shows 93.1% specificity and 94.64% overall sensitivity in differentiating breast cancer cases (N = 112) from benign breast conditions (N = 29). Conclusion: The findings reported in this manuscript support the clinical potential of this test for blood-based BrC detection.

We have previously shown that circulating ensembles of tumor-associated cells (C-ETACs) are a systemic hallmark of cancer based on analysis of blood samples from 16,134 individuals including 10,625 asymptomatic individuals and 5,509 diagnosed cases of cancer. C-ETACs were ubiquitously (90%) detected across all cancer types and were rare (3.6%) among the asymptomatic population. Consequently, we hypothesized that asymptomatic individuals with detectable C-ETACs would have a definitively elevated risk of developing cancer as compared with individuals without C-ETACs. In the present manuscript we present 1-year follow-up data of the asymptomatic cohort which shows that C-ETAC positive individuals have a 230-fold (P < 0.00001) higher 1-year cancer risk as compared with individuals where C-ETACs were undetectable. Simultaneously, we also expanded the study to include 4,419 symptomatic individuals, suspected of cancer, prior to undergoing an invasive biopsy for diagnosis. C-ETACs were detected in 4,101 (92.8%) of these 4,419 cases where cancer was eventually confirmed. We conclude that detection of C-ETACs can identify patients at risk of cancer and can be reliably used to stratify asymptomatic individuals with an elevated 1-year risk of cancer. Prevention Relevance: The study evaluated a blood test that can determine if healthy (‘asymptomatic’) individuals without a history of cancer have an increased risk of developing cancer within the next one year. This test can significantly minimize radiological or invasive screening in the majority individuals who do not have any increased risk.

BACKGROUND The addition of cisplatin or cetuximab to radiation therapy (RT) improves outcomes in comparison with RT alone in the nonoperative management of head and neck squamous cell carcinoma (HNSCC), but limited data exist for comparing these approaches. Using Veterans Health Affairs data, this study compared the outcomes of patients treated with RT plus cisplatin or cetuximab. METHODS Patients with stage III to IVb HNSCC who had been treated nonsurgically with RT and cisplatin or cetuximab from 2000 to 2016 within the Veterans Health Affairs system were identified. Patients were analyzed by the drug used in the first treatment cycle (intent to treat). Overall survival (OS) was compared by treatment group with Cox regression models, and propensity score (PS) methods were used to account for a treatment allocation bias. The risk of toxicities was determined, with logistic regression models fit into propensity-matched cohorts. RESULTS A total of 4520 patients were included in the analysis with a median follow-up of 3 years: 83% received cisplatin. Cisplatin patients were younger (P < .001) and had fewer comorbidities (P < .001). In an unmatched analysis, cetuximab was associated with inferior OS (P < .001). After PS matching, cetuximab treatment remained statistically significantly associated with inferior OS (1.7 vs 4.1 years; hazard ratio, 1.61; 95% confidence interval, 1.44-1.79; P < .001). These differences remained significant across all primary HNSCC subsites and in comparison with low- and high-dose cisplatin. CONCLUSIONS Cetuximab with RT yields inferior OS in comparison with cisplatin for the nonoperative management of stage III to IVb HNSCC. According to this study, cisplatin may be the most appropriate partner for RT in this setting.

BACKGROUND: Concurrent chemoradiotherapy is an established component of the nonoperative management of locally advanced head and neck squamous cell carcinoma (HNSCC), but the standard dose of 100 mg/m(2) cisplatin every 3 weeks is associated with clinically significant toxicity. Interest in a more tolerable regimen has led to the widespread use of weekly lower dose cisplatin, but few randomized trials have compared these approaches. METHODS: We examined outcomes of patients with stage III–IVb HNSCC treated with definitive intent chemoradiotherapy using either high-dose cisplatin (HDC) or low-dose cisplatin (LDC), using population-based Veterans Affairs data. In an intent-to-treat analysis, patients were assigned to the HDC vs LDC group according to the dose of their first cycle. Variables potentially influencing treatment decisions including cancer site, stage, smoking/alcohol use, and comorbidities were used to generate propensity scores (PS) for the use of HDC. We compared overall survival (OS) by treatment group using Cox regression, adjusting for PS. We then determined the risk of toxicities using PS-adjusted logistic regression. RESULTS: A total of 2901 patients were included in the analysis; 2200 received HDC (mean initial dose 100 mg/m(2)). The mean initial dose of LDC was 40 mg/m(2). After PS adjustment, HDC was not associated with improved OS over LDC (hazard ratio = 0.94, 95% confidence interval = 0.80 to 1.04). Adjusting for PS, HDC was associated with an increased risk of acute kidney injury, neutropenia, dehydration/electrolyte disturbance, and hearing loss. CONCLUSION: In this large, population-based study of US military veterans, LDC was associated with similar survival to HDC in the nonoperative definitive management of locally advanced HNSCC of the oral cavity, oropharynx, and hypopharynx/larynx. HDC was associated with statistically significantly more toxicity than LDC. Adoption of LDC may reduce toxicity burden while maintaining OS.

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.

The success of treatment in solid organ cancers is ascertained by radiologic imaging as per standard-of-care protocol, with PET-CT being the modality of choice. However, even in cases where complete resolution of the disease is noted radiologically, recurrence or emergence of new metastases is not uncommon. To explore the underlying cause of such recurrence, we hypothesized that circulating metastatic disease (CMD) in the nature of viable tumor cells or clusters would be a persistent systemic feature of solid organ cancers, although there may be no overt evidence of disease. We identified 1,217 patients with known and previously treated cases of various solid organ cancers (metastatic and nonmetastatic), where a recent PET-CT scan showed no radiologic evidence of disease. 15 mL peripheral blood was collected from these patients. Peripheral blood mononuclear cells (PBMCs) were harvested by centrifugation. Circulating ensembles of tumor-associated cells (C-ETACs) were enriched from PBMCs using an epigenetically acting stabilization process, which is cytotoxic towards nonmalignant cells but confers survival privilege on apoptosis-resistant cells of tumorigenic origin as well as their heterotypic clusters (C-ETACs). C-ETACs were characterized by immunostaining for EpCAM, pan-CK, and CD45 as well as for organ-specific markers. Among the 1,217 patients with no radiologic evidence of disease, C-ETACs were detected in 1,118 (91.9%) and were confirmed by immunostaining. In a subset analysis, C-ETACs from 80 samples were immunostained for organ- or subtype-specific antigens including those from head and neck (P63), breast (GCDFP15), colorectum (CDX2), liver (Hep Par-1), ovary (CA125), prostate (PSMA), cervical (P63), and lung (TTF-1/Napsin-A). Circulating metastatic disease (CMD) in the form of viable C-ETACs is a potent threat in patients with solid organ cancers despite complete radiologic response to treatment. Citation Format: Sewanti A. Limaye, Timothy Crook, Dadasaheb Akolkar, Darshana Patil, Pradip Devhare, Revati Patil, Shoeb Patel, Shabista Khan, Raja Dhasarathan, Vineet Datta, Cynthe Sims, Ajay Srinivasan, Rajan Datar. Viable circulating ensembles of tumor-associated cells persist in pretreated patients with solid organ cancers showing no radiologically detectable disease [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A49.

3525 Background: Despite the development of targeted therapy agents and immune checkpoint inhibitors (ICI), cytotoxic anticancer agents remain the mainstay of treatment in several solid organ cancers. However, instances of innate and acquired resistance towards these anticancer agents can lead to treatment failures, which remain undetectable until clinical or radiological manifestation of symptoms suggestive of disease progression. There are presently no viable means or markers to detect or monitor for chemoresistance in real time. Owing to this unmet need, cancer treatment strategies face risks of failure and poor outcomes. Methods: We obtained 15 mL blood from 3,662 patients with various solid organ cancers, of various states and including treatment-naïve and pretreated patients. Circulating Tumor Associated Cells (C-TACs) were enriched and harvested from PBMCs using an epigenetically activating medium that is cytotoxic towards non-malignant epithelial and hematolymphoid cells in blood, but confers survival benefit on apoptosis resistant cells of tumorigenic origin (Circulating Tumor Associated Cells, C-TACs). In a subset of patients, fresh tumor tissue was also obtained from which viable tumor derived cells (TDCs) were obtained. Viable TDCs and C-TACs were treated with a panel of anticancer agents and the surviving cell fraction estimated to determine chemoresistance. Results: Among the 1,325 therapy naïve patients, resistance towards treatment agents was observed in C-TACs from 56.3 % of samples. Among 2,201 pretreated patients’ samples, resistance towards treatment agents was observed in C-TACs from 77.8% of samples. The increased resistance in C-TACs from pretreated patients indicated that the C-TACs had been resistance-educated by prior therapies. In a subset of patients, Chemoresistance profile of C-TACs was observed to be 96.9% concordant with that of tumor derived cells (TDCs) which were concurrently obtained from tumor tissue indicating that C-TACs accurately represent chemo-antecedents of the tumor. Conclusions: Non-invasive chemoresistance profiling of C-TACs is a viable strategy to monitor treatment efficacy in real time. Adoption of this strategy in the clinic will not only guide treatment selection with reduced risk of failure, but will also enable timely therapeutic course correction upon detection of acquired chemoresistance.

e15623 Background: Tumor tissue profiling following invasive biopsies is presently the standard approach for indication-based therapy management in solid organ cancers. However, challenges in biopsy are traditionally described due to proximity to vital organs, or patients’ co-morbidities or unwillingness for an invasive procedure. Liquid biopsies for evaluation of cancers are also largely restricted to single gene testing for selection of targeted therapy agents. We developed a comprehensive liquid biopsy based multi-analyte (molecular and functional) investigation of the cancer (eLBx: Encyclopedic Liquid Biopsy) for selection and management of individualised treatments in a cohort of advanced refractory cancers. Methods: We obtained 20 mL blood from 65 patients with solid organ cancers where the disease had progressed following failure of at least two lines of systemic therapies and where biopsy to obtain tumor tissue for molecular profiling of tumor was unviable. Cell free tumor DNA (ctDNA) was interrogated for mutations, while exosomal mRNA was profiled for gene expression. Viable circulating tumor associated cells (C-TACs) were tested in vitro for chemoresistance and used to determine expression of cell surface signalling receptors by immunocytochemistry (ICC). The findings were integrated to generate patient-specific treatment regimens. In patients who received treatment, response was determined radiologically. Results: Fifty-one patients received eLBx-guided personalized treatments with combinations of cytotoxic, targeted and endocrine agents. No two patients received the same treatment regimen. Forty-three patients were evaluable for treatment response per protocol among whom Partial Response (PR) was observed in 14 patients yielding an Objective Response Rate (ORR) of 32.6%. Additionally, 23 patients showed Stable Disease thus yielding an overall Disease Control rate of 86.1%. Median Progression Free Survival (PFS) was 108 days. There were no Grade IV therapy related Adverse Events or therapy related deaths. Conclusions: The ability to make informed treatment choices from a convenient blood draw implies a reduced dependence on invasive biopsies for disease management. We demonstrate successful management of advanced refractory solid tumor malignancies using an integrational non-invasive multi-analyte liquid biopsy approach. Clinical trial information: CTRI/2019/02/017548.

e15624 Background: Treatment of advanced refractory cancers face challenges in non-availability of systemic therapy regimens with evidenced benefit. Post failure of two to three lines of systemic treatments, patients with such cancers are usually considered for palliation or clinical trials. Prior attempts at label-agnostic treatment regimens (precision medicine) in such populations were largely based on a single-indication-single-drug paradigm which had limited application. We hypothesized that advanced refractory malignancies have latent vulnerabilities which can be identified by an integrational multi-analyte interrogation of the tumor, and can be targeted using patient-specific combination regimens to yield clinical benefit. Methods: Fresh tumor tissue and blood samples were obtained from 158 patients with solid organ cancers where the disease had progressed following failure of at least two lines of standard of care systemic treatment options. These samples were used for Encyclopedic Tumor Analysis (ETA) which interrogated gene mutations, gene overexpression, pathway dysregulation, immunohistochemistry as well as in vitro chemosensitivity profiling of viable tumor cells. Integration of datasets from the multi-analyte ETA was used to generate patient-specific therapy recommendations. Patients who received ETA-guided treatments were followed up and response to treatment was retrospectively evaluated from radiological scans. Results: All patients received ETA-guided individualized treatments which were combinations of cytotoxic, targeted and endocrine agents. No two patients received the same treatment regimen. Complete or Partial Response (CR or PR) was observed in 76 patients yielding an Objective Response Rate (ORR) of 48.1%. 67 patients showed Stable Disease (SD), thus yielding a Disease Control Rate (DCR) of 90.5%. Median Progression Free Survival (PFS) was 117 days (Range 27 – 379 days). There were no Grade IV therapy related Adverse Events or therapy related deaths. Conclusions: Viable efficacious combination treatment options can be made available for patients with advanced refractory malignancies via ETA, despite perceived non-availability or non-viability of standard of care treatment options.

3544 Background: There are presently no accepted non-invasive means for detection of cancers in asymptomatic individuals or suspected cases. Radiological and serological investigations, though non-invasive, are not confirmatory and necessitate an invasive biopsy to establish malignant status of suspected findings. Invasive biopsies, in turn, face challenges due to non-representative tumor tissue or in cases where biopsy is impossible or unviable. We hypothesized that Circulating Microtumors (also called as C-ETACs: Circulating Ensembles of Tumor Associated Cells) in peripheral blood are universally present in solid organ cancers and their detection can be linked to malignant status. Methods: We obtained peripheral blood from 14,138 patients with various solid organ cancers as well as 10,625 asymptomatic individuals with age associated elevated risk of cancer. Out of the 14,138 patients with cancer, 25.1 % had local (non-metastatic) disease and 56.4% had metastatic disease as confirmed by radiological evaluation. C-ETACs were enriched and harvested from PBMCs using an epigenetically activating medium that is cytotoxic towards non-malignant epithelial and hematolymphoid cells in blood but confers survival benefit on apoptosis resistant circulating cells of tumorigenic origin and their heterotypic clusters (C-ETACs) in peripheral blood. Viable C-ETACs were identified and further characterized by immunocytochemistry (ICC) profiling. Results: C-ETACs were detected in 89.7% of samples from solid organ cancers irrespective of stage, treatment or present radiological status. C-ETACs were rarely detected (3.0%) in asymptomatic individuals. The asymptomatic individuals where C-ETACs were detected are being followed up periodically so as to enable detection of cancer based on clinical or radiological manifestation of symptoms. Conclusions: C-ETACs are ubiquitous in cancers and unexpected in asymptomatic individuals. Detection of C-ETACs in asymptomatic individuals may be indicative of risk of latent undiagnosed malignancy. The non-invasiveness of this approach makes it convenient for screening large populations for cancer.

799 Background: Definitive diagnosis of gastrointestinal (GI) malignancies is reliant on histopathological examination of tumor tissue obtained by invasive biopsies. However, invasive biopsies are associated with procedural risks, complications and expenses. A non-invasive technique for diagnosis of GI cancers is presently unavailable. Here we present a non-invasive diagnostic approach for GI cancers based on immunocytochemical (ICC) profiling of Circulating Tumor Associated Cells (C-TAC) enriched from peripheral blood. Methods: We collected 15 mL peripheral blood from 1052 patients with known diagnosis of Ca Oesophagus (244), Ca Stomach (170) and Ca Colorectum (638) and with histopathological information available from prior tissue analysis. CTACs were harvested following negative enrichment. C-TACs were identified by immunostaining with EpCAM and panCK. Deep ICC characterization was carried out in a subset of 203 samples (100 colorectal, 19 Gastric and 84 Esophageal) using organ specific markers. A subset of 19 samples from Gastric and 94 samples Esophageal cancers were profiled for Her2 and PD-L1 status. Results: C-TACs could be identified and enriched in 1012 out of 1052 patients (96.2% overall sensitivity). Immunostaining for organ-specific markers was possible in all 203 (100%) samples. Her2 positivity was observed in 2/19 Gastric and 19/84 Esophageal samples. PD-L1 (22C3) positivity was observed in 5/19 Gastric and 32/84 Esophageal samples while PD-L1 (28-8) positivity was observed in 2/19 Gastric and 16/84 Esophageal samples. Conclusions: Our results show that ICC profiling of C-TACs can provide necessary diagnostic information non-invasively to substitute conventional procedures dependent on tissue extraction. This approach fulfils most clinical decision-making requirements in GI malignancies.

194 Background: Resistance to combination regimens of fluorouracil, oxaliplatin and irinotecan are commonly observed in Colorectal cancers (CRC). There are presently no viable approaches for ‘real-time’ monitoring of innate and acquired chemoresistance. We used a novel method for chemo-interrogation (CI) by harvesting from peripheral blood sufficient numbers of Circulating-Tumor Associated Cells (CTACs) which are defined as apoptosis-resistant cells of tumorigenic origin which are positive for Epithelial Cell Adhesion Molecule (EpCAM) and pan-cytokeratins (pan-CK) irrespective of CD45 status. Methods: Peripheral blood was collected from 110 patients with confirmed diagnosis of CRC, among whom 56 were recently diagnosed and therapy naïve while 54 were pre-treated. Peripheral blood mononuclear cells (PBMCs) were harvested by centrifugation and treated with commercially available stabilizing agents by a proprietary protocol to stabilize apoptosis resistant C-TACs. Surviving C-TACs were confirmed by immunostaining for EpCAM and pan-CK. Harvested C-TACs were treated in vitro with 5-fluorouracil, irinotecan and oxaliplatin and the fraction of surviving cells estimated to determine resistance profiles. Results: Among the 56 cases of recently diagnosed therapy naïve CRC, innate chemoresistance was observed in 37.5%, 47.3% and 41.8% of samples (unique patient-drug combinations) towards 5-fluorouracil, irinotecan and oxaliplatin respectively. Among the 54 cases of previously treated CRC, acquired chemoresistance was observed in 92.6%, 92.6% and 95.5% of samples towards 5-fluorouracil, irinotecan and oxaliplatin respectively. Conclusions: We show for the first time that sufficient C-TACs can be harvested for meaningful CI in newly diagnosed treatment naïve CRC as well as refractory CRCs. Post-treatment chemoresistance being an order of magnitude higher than the untreated cohort indicates that C-TACs in CRC are resistance-educated by previous treatments and can guide treatment strategy.

e18230 Background: Medical insurance coverage is known to correlate with improved long-term (LT) outcomes in head and neck cancers (HNC) patients. However, associations with dental insurance coverage (DI) are not established. Methods: In 2012, we sent surveys to determine DI and LT symptom (Sx) burden (EORTC QLQ-30, National Health and Nutrition Examination Survey Oral Health, and Vanderbilt Head and Neck Sx Survey) to patients who had completed definitive chemoradiotherapy (sequential or concurrent) for locally advanced (LA) HNC at the Dana-Farber Cancer Institute from 2002-2011 (2013 ASCO annual meeting, abstract 9530). In 2019, we retrospectively collected demographic and clinical information from patient charts and publicly available records and correlated these data with 2012 survey data. We used Fisher’s exact tests for association of categorical variables and Student’s t-tests for continuous variables. We used univariate and multivariate Cox proportional hazard modeling for hazard ratios (HRs). Results: Of the 103 survey responders, 84% were male. Most had oropharyngeal (90, 88%) or unknown primary (9, 9%) and 52 (50%) tested positive for human papilloma virus-associated disease (40% not tested). 71 (69%) had DI, while 100 (98%) had medical health insurance. Subjects with DI were diagnosed (Dxed) at a younger age (53 vs. 59, p < 0.01). Stage at Dx did not vary by DI status (p = 0.27). At median follow-up of 10.4 years from Dx (range 2.0 -16.6), recurrence was not associated with DI status (6 (8%) for DI vs. 4 (13%) for no DI, p = 0.27, HR 0.55, 95% CI 0.15-1.93, p = 0.35). We identified 9 subjects (9%) who had died of any cause. Subjects with DI experienced lower mortality from all causes than those without (3% vs. 19%, p = 0.01) and longer median overall survival (OS) (range 4.3 - 16.6 years, HR 0.19, 95% CI 0.05-0.76, p = 0.02) on univariate analysis. The longer OS was not significant when controlling for age and stage at Dx (p = 0.12). DI was also associated with less frequent need for liquid supplements to maintain weight (p = 0.01). Conclusions: In our cohort, DI was associated with Dx at a younger age and longer OS, although future work should consider possible confounding factors such as differences in socioeconomic status. Our data highlight the need for further research to investigate the importance of DI in improving LT outcomes in HNC patients.

BACKGROUND Oral mucositis (OM) is a significant toxicity of induction chemotherapy for locally advanced head and neck cancer (LAHNC). The safety and tolerability of AG013, an oral rinse containing recombinant Lactococcus lactis secreting mucosal protectant human trefoil factor 1 (hTFF1), was evaluated in a phase 1b study in LAHNC subjects who received induction with cisplatin, 5-fluorouracil, with or without docetaxel. Preliminary efficacy data were also obtained. METHODS A total of 25 of 52 LAHNC subjects who were followed during induction cycle 1 developed ulcerative oral mucositis (UOM; World Health Organization grade > 2) and were randomized to AG013:placebo (5:2 ratio) for cycle 2. Dosing schedules of 1, 3, or 6 times daily were evaluated (2 × 1011, 6 × 1011, and 1.2 × 1012 colony forming units per day, respectively). OM was evaluated daily from cycle 2, day 1 through 14, using World Health Organization criteria. Pharmacokinetic assessment was also conducted. RESULTS AG013 bacteria were not detected in blood. Oral live AG013 bacterial and hTFF1 levels in saliva and oral mucosa were equivalent among treatment groups. The most frequently occurring adverse events were nausea, oral pain, fatigue, diarrhea, and mucosal inflammation. Only 12% (3 of 25 adverse events), mainly nausea, were attributed to the investigational medicinal product: AG013 or placebo. Efficacy analysis showed a 35% reduction in percentage of days with UOM in AG013-subjects versus placebo. All placebo subjects experienced ≥ 2 days of UOM, whereas 29% of AG013 subjects had UOM for 0 or 1 day. AG013 use resulted in fewer unscheduled office and emergency room visits. No differences were noted in mouth and throat soreness, opioid use, or gastrostomy tube placement. CONCLUSIONS AG013 was safe and well tolerated. Preliminary efficacy data support further study. Cancer 2013;119:4268–4276. © 2013 American Cancer Society.

Summary Objectives There are limited chemotherapeutic options for advanced recurrent or metastatic SCCHN. The efficacy and toxicity of docetaxel with or without vandetanib was investigated in these patients. Materials and Methods Patients with pathologically confirmed, recurrent or metastatic SCCHN who had progressed on platinum based therapy given as definitive or palliative treatment, were randomized in this open label, multicenter phase II study of docetaxel (75 mg/m2 IV Q3 weeks) with or without vandetanib (100 mg PO daily). The primary objective was response rate (RR) and secondary objectives were progression free survival (PFS), overall survival (OS), disease control rate (DCR) and duration of response (DOR). Results 29 analyzable patients were enrolled, 14 in docetaxel arm and 15 in combined arm. PR was achieved in 1 patient in the docetaxel arm and 2 patients in the combined arm. The objective RR was 7% (1/14) (95% CI 0.2–33.8%) in the single and 13% (2/15) (95% CI 1.6–40.4%) combined arm. The median PFS was 3.21 (95% CI 3.0–22.0) and 9 (95% CI (5.86–18.1) weeks; median OS was 26.8(95% CI 17.7–100.7+) and 24.1 (95% CI, 16.4–171.1+) weeks. Most common adverse events were fatigue, dysphagia, diarrhea or constipation, cytopenias and alopecia. Conclusions Although an initial benefit in response was noted and statistical criteria met there was only a minor trend towards improved PFS for the combined arm. The study was designed with low threshold for activity in each arm and results were deemed not to be of enough clinical significance in this group of patients to continue accrual.

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 5 mm planning target volume (PTV) margin. For postoperative cases, a 5 mm 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 60 Gy (range, 59.4–70 Gy). Most patients (88%) received concurrent chemotherapy including induction (16%). The median overall survival was 1.8 years. 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.

Purpose To determine the predictors of distress in older patients with cancer. Patients and Methods Patients age ≥ 65 years with a solid tumor or lymphoma completed a questionnaire that addressed these geriatric assessment domains: functional status, comorbidity, psychological state, nutritional status, and social support. Patients self-rated their level of distress on a scale of zero to 10 using a validated screening tool called the Distress Thermometer. The relationship between distress and geriatric assessment scores was examined. Results The geriatric assessment questionnaire was completed by 245 patients (mean age, 76 years; standard deviation [SD], 7 years; range, 65 to 95 years) with cancer (36% stage IV; 71% female). Of these, 87% also completed the Distress Thermometer, with 41% (n = 87) reporting a distress score of ≥ 4 on a scale of zero to 10 (mean score, 3; SD, 3; range, zero to 10). Bivariate analyses demonstrated an association between higher distress (≥ 4) and poorer physical function, increased comorbid medical conditions, poor eyesight, inability to complete the questionnaire alone, and requiring more time to complete the questionnaire. In a multivariate regression model based on the significant bivariate findings, poorer physical function (increased need for assistance with instrumental activities of daily living [P = .015] and lower physical function score on the Medical Outcomes Survey [P = .018]) correlated significantly with a higher distress score. Conclusion Significant distress was identified in 41% of older patients with cancer. Poorer physical function was the best predictor of distress. Further studies are needed to determine whether interventions that improve or assist with physical functioning can help to decrease distress in older adults with cancer.

Objectives. Two cases of adenoid cystic carcinoma (ACC) of the larynx were treated with chemoradiotherapy (CRT) for organ preservation. We reviewed case series and current literature to contrast the potential role of primary CRT as an organ-sparing modality with standard laryngectomy and radiotherapy in patients with laryngeal ACC. Methods. Two treatment-naïve patients with laryngeal ACC treated at Dana-Farber Cancer Institute between 2002 and 2007 were identified. Both patients were offered standard laryngectomy followed by adjuvant radiotherapy or organ-sparing treatment modality. Results. Both patients were males, aged 57 and 73. The patients completed a course of combined chemoradiotherapy with weekly carboplatin and paclitaxel and 7–8 weeks of radiotherapy to a total dose of 6,600 and 7,000 cGy over 50 and 57 days, respectively. There were no treatment breaks or delays because of toxicity. The major toxicities reported by both patients, as anticipated, were Grade 3 mucositis, desquamative dermatitis, and severe dysphagia, all of which resolved. Both patients are alive with local regional control and functional larynx; one at 112+ months with pulmonary metastases at 54 months, and the other disease free at 60+ months. Conclusions. Definitive chemoradiation with weekly carboplatin and paclitaxel may be a potential alternative to the current standard of surgery and radiation for patients with locally advanced laryngeal ACC who request an organ-sparing approach. In this group of patients, salvage laryngectomy may be reserved for those who are locally recurrent or chemoradiotherapy resistant. Although CRT provided long-term local regional control in our two patients, there are evident limitations in obtaining evidence for a determination of treatment of rare diseases. This report provides support for following an organ preservation plan in selected patients.

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.

6023 Background: We present results of an open label phase II study of the mTOR inhibitor Everolimus in patients (pts) with RAIR TC. Methods: Pts with metastatic, incurable RAIR TC who had shown radiographic progression within 6 months prior to enrollment received Everolimus 10mg orally once daily. Responses were monitored by CT's every two months. The primary endpoint was progression free survival. Sequential biopsies were obtained in selected pts. Results: Enrollment to the differentiated TC (DTC) cohort finished in Jan 2013 and included 33 pts, among them 11 with Hurthle cell TC. Exploratory cohorts enrolled 10 pts with medullary [MTC] and 5 with anaplastic [ATC] with 2 added openings remaining for ATC. For the DTC cohort, median time on study to date is 10 months (mo) (

9530 Background: OPC treatment is associated with significant long-term toxicity. Very little is known about the long-term symptom burden and orodental health in OPC survivors >2 yrs from treatment. Methods: Survivors treated for OPC with CRT/ST (involving definitive RT) at Dana Farber Cancer Institute between 2002-2011 and >2 yrs from treatment completion, were identified by chart review and asked to complete the Vanderbilt Head and Neck Symptom Survey version 2 (VHNSS v2), National Health And Nutrition Examination Survey for Oral Health Questionnaire, health care availability survey. Results: 200 survivors were contacted, 127 responded (RR: 64%). Median age at diagnosis was 54 yrs; 85% males; 85% stage IVA/B, 13% stage III; 56% CRT, 43% ST. HPV status: 47% (+), 10% (-), 43% unknown. Median time from treatment completion: 50 mths (24-135 mths). Residual moderate to severe toxicities reported in VHNSS v2: 71% dry mouth; 59% difficulty chewing/swallowing food; 53% feeling of food becoming stuck in the throat; 53% prolonged time to eat; 31% thick mucus, 6% had difficulty sleeping secondary to this; 16% trouble speaking, 27% trouble hearing;30% limitation of neck/shoulder movement; altered taste/smell - 45%/23%; sensitivity to spicy food and dryness-57%/62%; 30% decreased desire to eat, 11% had moderate weight loss. Orodental health assessment: 13% thermal sensitivity, 21% teeth cracking and chipping, 20% loose teeth, 33% had treatment for gum disease, 42% had lost bone around teeth. 98% survivors had health insurance; only 66% had dental insurance. No statistically significant difference was noted with respect to symptoms between CRT or ST. ST did not affect long-term toxicity compared to CRT alone. Conclusions: OPC is known to correlate with HPV positivity, early age at diagnosis and high rates of long-term survival after appropriate therapy. Our study documents that the OPC survivors have substantial residual long-term head and neck and orodental symptoms directly related to the treatment that significantly impacts their quality of life. A substantial number of patients lack dental health coverage, which likely further impacts symptom burden and QOL.

9024 Background: Oral mucositis (OM) is a significant toxicity of ICT in LAHNC. AG013, a mouth rinse composed of a recombinant Lactococcus lactis (sAGX0085) engineered to secrete human Trefoil Factor 1 (hTFF1) and deficient in the gene encoding thymidylate synthase, was investigated in patients receiving ICT (cisplatin, 5-fluorouracil +/-docetaxel:PF+/-T). TFFs have wound-healing properties and are protective of mucosal tissues. Methods: To evaluate the safety, tolerability, PK profile and efficacy of AG013 in attenuating ICT-associated OM, 52 patients (pts) with newly diagnosed LAHNC receiving ICT (24TPF, 1PF) were screened in ICT cycle (Cy) 1 for symptomatic OM (SOM). 25 pts who developed SOM in Cy1 were enrolled into 3 successive groups of at least 7 pts each in the active phase and randomly assigned at the Baseline visit (d1 of ICT Cy2) in a 5:2 ratio to receive AG013 or placebo during ICT Cy2. Dose was escalated in successive groups from 1 x/day (qd) to 3 x/day (tid) and to 6 x/day, resulting in doses of 2 x 1011, 6 x 1011, and 1.2 x 1012 colony-forming units (CFU)/day respectively. Pts were assessed daily from Cy 2 d1 to d14 for OM using WHO criteria. Safety endpoints and PK (mucosal, salivary and blood samples) were assessed. Results: AG013-sAGX0085 could not be detected in blood. Recovered oral live bacterial levels were high immediately after dosing, decreased by 90 minutes post dose, and undetectable at study end. No differences in hTFF1 serum levels were seen. Pts in the placebo group had ulcerative OM (UOM) on nearly 60% of the days vs. 35-40% days in the AG013 group. 29 % pts who received AG013 had 0 or 1 day of UOM vs. at least 2 days of UOM in the placebo group. Pts who received AG013 on any dosing schedule had a lower % of days with OM, fewer unplanned office and emergency room visits compared to pts who received placebo. No differences were noted in mouth and throat soreness, opioid use, or gastrostomy tube placement. Conclusions: Topical administration of AG013 appears safe, well tolerated and effective in reducing the severity and course of OM in patients receiving ICT for HNC.

5582 Background: HPV status is a major prognostic marker for survival in patients with OPC. We examined overall survival (OS) and progression free survival (PFS) in patients with OPC and known HPV status treated at Dana-Farber Cancer Institute with ST and CRT between 2002 and 2011. Methods: 280 patients with OPC and known HPV status were identified retrospectively and clinical information was recorded. Results: 174 patients were treated with CRT (124 HPV positive, 50 HPV negative) and 106 patients were treated with ST (77 HPV positive, 29 HPV negative). For all 280 patients, OS and PFS were significantly better for patients who were HPV positive compared to those who were HPV negative. 3 year OS was 89.1% for HPV positive (95% CI, 83.8-94.7) and 70.5% for HPV negative patients (95%CI, 59.9-83%, HR 0.37, p=0.0007). Among HPV positive patients treated with CRT, 13/124 had died at 3 years (OS 88.5%, 95%CI 81.7-95.9) while 13 deaths were recorded among 50 HPV negative patients (OS 72.2%, 95% CI 59.1-88.2, HR 0.38, p=0.011). PFS at 3 years was also significantly better for HPV positive versus HPV negative patients(81.7% vs 58.8%, HR 0.42, p=0.006). In the group treated with ST, outcomes were similar despite a higher rate of stage IV versus stage III disease compared to the group treated with CRT (100% stage IV in ST versus 77% stage IV and 23% stage III disease in CRT group). Three year OS was 89.7% for HPV positive and 68.2% in the HPV negative group (8/77 HPV pos vs 10/29 HPV neg, HR 0.33, p=0.015). PFS was borderline better for HPV positive patients (81% vs 61.7%, HR 0.48, p= 0.058). Conclusions: We present the DFCI experience treating OPC with ST and CRT for patients with known HPV status over one decade.OS and PFS were superior for HPV positive versus HPV negative patients. Outcomes were virtually identical for patients treated with CRT versus ST despite a higher rate of stage IV disease in the ST group. Outcomes for the HPV negative patients in particular were superior compared to the published literature.

e16060 Background: Chemotherapy has been used concurrently with radiation for local control as adjuvant treatment or for locally recurrent thyroid cancer. We present our experience using IMRT with or without sensitizing concurrent chemotherapy in this setting. Methods: All patients with thyroid carcinoma with or without minimal metastatic disease treated since 2005 at DFCI were reviewed. We collected data and analyzed the outcomes of patients treated with IMRT with or without concurrent chemotherapy for local control. Results: Twenty-two patients were identified: 13 Males, 9 Female, Median age 60 years There were 11 papillary, 6 medullary, 4 anaplastic, and1 follicular. Thirteen patients were treated adjuvantly, seven for locally recurrent disease and two definitively for unresectable disease. All patients with papillary and follicular thyroid cancer had prior surgery and radioactive iodine therapy. Patients with medullary carcinoma had surgery alone. Two patients with anaplastic carcinoma had surgery and two were found to be unresectable.. Seventeen patients received concurrent weekly carboplatin AUC1.5 and paclitaxel 30mg/m2 with radiation. Five patients did not receive any concurrent chemotherapy and were treated with radiotherapy alone. Radiation fields encompassed the thyroid bed, bilateral neck and in some cases the mediastinum. The radiation dose ranged from 5600cGy to 6600cGy. Mean follow up was 42 months. The overall survival at 36 months was 89.5% (95% CI, 76.7-100). Two patients with unresectable anaplastic thyroid cancer died from progressive disease. Loco-regional control rate at 36 months was 78.9% (95% CI, 62.6-99.6). No grade 3 or 4 toxicities were reported during treatment. Conclusions: IMRT with or without concurrent chemotherapy provided excellent loco regional control and might have contributed to improved overall survival in patients with locally advanced thyroid cancer.

Background: ABT-806 is a humanized recombinant IgG1α monoclonal antibody that binds to a unique EGFR epitope exposed only in the EGFRde2-7 (EGFRvIII) deletion mutant and activated EGFR proteins. Preclinical data suggest that ABT-806 does not significantly bind to non-activated, wild-type EGFR expressed on normal tissues. This phase I study evaluates the safety, pharmacokinetic (PK) profile, and antitumor activity of ABT-806 in patients (pts) with advanced solid tumors and suggests a recommended phase 2 dose (RPTD). Methods: Pts with advanced solid tumors thought to be EGFR expressing, adequate organ function and ECOG performance status were eligible for enrollment. Glioblastoma pts were not eligible for the dose escalation phase. Pts received ABT-806 intravenously at a rate no higher than 15 mg/min. Doses explored were 2, 6, 12, 18, and 24 mg/kg every other week, preceded by 30 min with acetaminophen 650 mg and diphenhydramine 25Δ50 mg. A 3+3 dose escalation design was followed. Assessments included adverse events (AEs) graded by NCI CTCAE v4.0, PK, maximum tolerated dose (MTD), RPTD, and tumor response by RECIST. Results: At the time of reporting, 26 pts (M/F, 14/12; median age, 63 y; range, 39α81 y) have been dosed. No dose limiting toxicities (DLTs) were observed at the 2, 6, 12, and 18 mg/kg dose levels. One pt in the 24 mg/kg group experienced a DLT of a grade 3 morbilliform rash, resolving after the administration of loratidine. Other ABT-806αrelated grade 3/4 AEs were dyspnea (15%) and hypotension (12%). Frequently occurring AEs (≥10%) possibly or probably related to ABT-806 were nausea (23%), vomiting (19%), fatigue (15%), and rash (12%). The systemic exposures (AUC and Cmax) to ABT-806 were dose-proportional between 2α24 mg/kg and the terminal half-life (mean t1/2) was ∼9 days. Sixteen pts had at least 1 post-baseline tumor assessment. Five pts achieved stable disease (more than 8 weeks) as best response (head and neck cancer, 2; colorectal cancer, 2; lung cancer, 1). One pt with EGFR amplified head and neck cancer at 6 mg/kg dose had stable disease for 23 weeks. The RPTD was determined as the highest protocol-defined dose tested at 24 mg/kg, as the MTD was not reached. Infrequent episodes of rash were observed, 5 pts with grade 1/2 and only 1 pt with grade 3. Three pts reported grade 1 diarrhea. EGFR H-score has been performed for each pt enrolled and will be correlated with clinical outcome. EGFRde2-7 analysis is in process. Conclusions: ABT-806 showed a unique PK and safety profile distinct from other anti-EGFR therapies. The PK appeared to be linear across doses. The RPTD was the highest dose tested (24 mg/kg). Unlike other EGFR inhibitors, rash was infrequent and typically grade 1 or 2. The exception was 1 grade 3 morbilliform rash that had a very different morphology than the typical acneiform rash associated with EGFR inhibitors. Phase 2 development in the EGFR amplified and/or EGFRde2-7 pts is planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2506. doi:1538-7445.AM2012-2506

17033 Background: Concomitant chemoradiotherapy (CRT) with cisplatin, given every three weeks, is a standard treatment option in the management of unresectable/ locally advanced squamous cell carci...

16523 Background: Malignant salivary gland tumors comprise 3 to 6% of Head and Neck cancers. Long term survival data for salivary gland tumors are lacking. We undertook an analysis of all such patients treated at our institution over a 15 yr period. Methods: IRB approval was obtained for this retrospective analysis. Tumor registry data were reviewed for all adult patients diagnosed with salivary gland malignancies for the years 1990 - 2005. Age, Gender, Stage, histology, treatment modalities and survival data were recorded. Results: 200 patients were identified. Median age was 64 yrs (59–69). M:F ratio was 1:1.1 (M: 96; F: 104). Histology and stages: ( Table 1 )Mucoepidermoid Carcinoma (n=50), Adenoid Cystic Carcinoma (n=21), Acinar Cell Carcinoma (n=19), Adenocarcinoma (n=22; Stages: I= 7, II= 4, III= 3, IV= 8), Squamous (n= 12; Stages: I= 1, II= 3, III= 3, IV=5), Poorly Differentiated Carcinoma(n=10), Epithelial Myoepithelial Carcinoma (n=7), Malignant Mixed Carcinoma (n=4), Malignant Myoepithelioma (n=2), Carcinoma in Pleomorphic Adenoma (n=2) and Others (n=15). Hodgkin's and NHL (n=36).Treatment modalities: Surgery (S): n=88 (44%), Radiotherapy (RT): n=6 (3%); Chemotherapy (CT): n=6 (3%); S+RT: n =76(38%); S+CT: n=8 (4%); RT+CT: n =2(1%); S+RT+CT: n =4 (2%). Observation only : n=10(5%). Survival data (Med. survival and 5 yr OS respectively) for all histologies excluding lymphomas are: Stage I - 84 mos,93%; II - 93 mos,85%; III - 39 mos,60 %; IV - 24 mos, 40%. Survival data (Med survival and 5 yr OS) for lymphomas: Stage I - 55 mos,85%; II - 20 mos, 0%; III - 100 mos, 100%; IV- 48 mos, 25%. Median survival of all histology types excluding lymphoma by treatment: S=55 mos, S+RT= 60 mos, S+ CT= 56 mos, RT= 53 mos, RT+CT=15 mos, CT= 24 mos. Conclusions: This large series provides long term outcome data for a relatively rare group of HNCs. Long term survival is noted in several histological sub-types even in the setting of advanced disease. These data should help further define the natural history and biological behaviors of these tumors. [Table: see text] No significant financial relationships to disclose.

16531 Background: Concomitant Chemoradiotherapy (CRT) is a standard treatment modality for locally advanced squamous cell head and neck cancer (HNC). This treament is often associated with significant weight loss which is commonly attributed to nutritional depletion secondary to mucositis, pain and inadequate oral intake. We undertook an evaluation of thyroid function as measured by Thyroid Stimulating Hormone (TSH) levels during CRT to evaluate the possible role of a thyroid hormone flare during treatment that may account for part of this weight loss. Methods: Institutional Review Board approval was obtained to conduct this retrospective analyses. Patients treated at our institution during the past six months who were treated with CRT for HNC and had recorded TSH levels at baseline (when available), mid treatment (week 4 to 6 of CRT), and post CRT (6 to 9 weeks later), at least 5% weight loss during treatment, and feeding tube requirement data available were identified. Age, Gender, Stage and Primary site of disease, Radiation dose and fields, chemotherapy regimen, were recorded. Results: Twelve patients were identified. Mid treatment TSH levels were suppressed below normal reference range (0.49–4.67 mIU/L) in 7of 12 pts (58%). A decline in TSH levels was noted in all 8 of 8 pts (100%) that had recorded pre-CRT TSH levels and mid treatment levels. Improvement of TSH levels was noted in all 9 of 9 patients that had mid treatment and post treatment TSH levels recorded, although in three of these nine patients TSH levels remained below normal range. Four of twelve pts required PEG placements for nutritional support. Conclusions: Transient suppression of TSH levels suggesting a thyroid flare is frequently observed early during CRT for HNC and appears to improve by 6–9 weeks post treatment. This may contribute to weight loss in this nutritionally challanged population. Further studies evaluating more specialised thyroid function testing to exclude sick euthyroid states and other etiologies for suppressed TSH levels are warranted. In addtion, therapeutic methods to abbrogate this flare may reduce weight loss during aggressive CRT treatment protocols. No significant financial relationships to disclose.

5501 Background: PARADIGM is a multicenter phase III study comparing TPF (docetaxel, cisplatin, and 5-fluorouracil)-based ST (Arm A) to upfront cisplatin CRT (Arm B) in patients (pts) with LAHNC. Pt accrual was terminated in 12/2008 due to slow enrollment with 145 of 300 planned analyzable patients accrued. Safety data was previously presented at the 2010 ASCO annual meeting showing no unusual pattern of toxicities in either arm. Here we present the survival results. Methods: Pts were randomized to receive arm A-ST (as induction chemotherapy (ICT) with TPF x 3) followed by CRT with either weekly carboplatin and once daily radiotherapy, or weekly docetaxel and accelerated boost radiotherapy based on adequate response to ICT; or arm B - accelerated boost CRT with bolus cisplatin x 2. The primary endpoint was survival. With original accrual target of 300 analyzable patients, this study was powered at 80% to detect an improvement in 3-year survival from 55% (arm B) to 70% (arm A). Results: A total of 145 previously untreated pts were enrolled (Arm A: 70; Arm B: 75), of whom 127 were male and 127 were Caucasian. Median age was 55; patients had PS of 0 (97) or 1 (48). Sites of disease were oropharynx: 80, larynx: 24, hypopharynx: 15, and oral cavity: 26. Disease stages were II (1 pt), III (20 pts) and IV (124 pts). After a median follow-up of 49 months, 41 pts have died (20 in arm A and 21 in arm B). Three-year survival was 73% (arm A) and 78% (arm B) (HR1.09; 95% CI 0.59 to 2.03 p=0.77). Three-year progression-free survival was 67% (arm A) and 73% (arm B) (HR 1.2; 95% CI 0.65 to 2.22; p=0.55). Patterns of failure will be presented at the meeting. Conclusions: Althoughthese results suggest no survival differences between CRT and ST for patients with LAHNC, the study was terminated before the planned accrual could be reached. HPV status for the oropharynx cases which represented the majority of patients was not available for stratification; and excellent survival was seen in both arms.