Bhumsuk Keam

6078 Background: Human papilloma virus (HPV)-associated locally advanced head and neck squamous carcinoma (LA HNSCC) shows favorable treatment outcome, and treatment de-escalation is actively under-investigated. However, not all the HPV+ LA HNSCCs are curable, and some of them shows poor prognosis. The purpose of this study is to identify poor prognostic factors in HPV+ LA HNSCC patients. Methods: Patients who were diagnosed as LA HNSCC and tested for HPV status from 2000 to 2015 were included in this retrospective analysis. Demographic data (age, gender), smoking status, comorbidity, and clinical information about stage, pathology, type of definite treatment were obtained. HPV typing was conducted using HPV DNA genotyping chip or liquid bead microarray. Expression of p16 was assessed by immunohistochemistry. Univariate and multivariate analyses were done with factors associated with overall survival (OS) by Cox regression analysis. Results: One hundred fifty two HPV+ LA HNSCC patients were included in this study. Male patients were 82.2% and 43.4% were current or ex-smoker. Oropharyngeal cancer was 84.2%. In univariate analysis, old age, poor performance, non-oropharynx, advanced T stage (T3, 4), N0 stage, HPV genotype 18 were significantly associated with poor OS. Smoking was not associated with OS. In multivariate analysis, poor performance (ECOG PS≥1), non-oropharyngeal location were independently associated with shorter overall survival (HR 4.82, p = 0.003; HR 7.36, p = 0.001, respectively). Furthermore, HPV genotype 18 positivity was also independent poor prognostic factor for OS in HPV+ LA HNSCC (HR 11.41, p < 0.001). Conclusions: Non-oropharyngeal cancer, poor performance status, HPV genotype 18 were independent poor prognostic factors in HPV+ LA HNSCC. These patients should not be candidate of de-escalated treatment.

6090 Background: Salivary gland cancers (SGC) are histologically uncommon but heterogeneous, accounting for less than 5% of all head and neck cancers. No specific therapy including targeted agents has been associated with improved clinical outcome in recurrent/metastatic SGC. Recent studies suggest VEGF and PDGFR might play an important role in SGC. Nintedanib is a potent small molecule triple receptor tyrosine kinase inhibitor (VEGFR1-3, FGFR 1-2, and PDGFR α/ß). We sought to determine nintedanib’s antitumor activity in patients with recurrent or metastatic SGC. Methods: This open-label, multicenter, phase II, single-arm study was conducted at 11 hospitals in Korea. Patients with pathologically confirmed recurrent and/or metastatic SGC who had undergone cytotoxic chemotherapy were enrolled. Nintedanib was given orally at 200mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was response rate. Secondary endpoints were progression-free survival, overall survival, toxicity, and disease control rates. Simon two-stage optimal design was used. Results: Median age was 54 years, 62% of patients were female, and 95% had an ECOG performance status of 0 or 1. The majority of patients had adenoid cystic carcinoma (65%), and 40% of all of patients had received at least two prior chemotherapies. After 20 patients were enrolled, the study was stopped because no responder was observed at Stage I. There was no partial response, but the disease control rate was 75% (15/20). The median duration of stable disease was 8.3 months (range 3.5-12.4). At the time of data cutoff with median follow-up of 9.5 months, median overall survival had not been reached, and the progression-free survival rate at 6 months was 60% (CI.0.34-0.79). Grade 3 adverse events included liver enzyme elevation (25%) and nausea/vomiting (5%). Five patients required dose reduction. Conclusions: Single agent nintedanib did not show partial response, but did achieve a 75% control rate with long stabilization in these SGC patients. Nintedanib was tolerable and toxicities were manageable. Given the high rate and long duration of disease control, further investigation is needed. Clinical trial information: NCT02558387.

The purpose of the present study was to explore the antiproliferative effect of BYL719, a specific inhibitor for phosphatidylinositol 3-kinase (PI3K) p110α, in human head and neck cancer cell lines, as a single agent or in combination with the irreversible EGFR tyrosine kinase inhibitor, dacomitinib. Six head and neck cancer cell lines consisting of two PIK3CA mutant cell lines, SNU-1076 and Detroit562, and four PIK3CA wild-type cell lines, SNU-1066, SNU-1041, FaDu and SCC25, were analyzed. The PIK3CA-mutant cell lines were more sensitive to BYL719 than the PIK3CA wild-type cell lines. Following BYL719 treatment, all PIK3CA wild-type cell lines, except for the SNU-1066 cell line, exhibited higher IC50 values compared to the PIK3CA mutant cell lines. Administration of BYL719 induced cell cycle G0/G1 arrest and resulted in increased apoptosis in a dose-dependant manner. Furthermore, the administration of BYL719 reduced the level of p-mTOR, p-AKT and p-S6 expression indicating the down-regulation of downstream signaling. BYL719, a PI3K alpha selective blocker, could be a promising factor in the treatment of head and neck cancer either as a single agent or in combination with dacomitinib.

We aimed to clarify the prognostic significance of HER2 positivity in advanced gastric cancer. The cohort included patients with initially metastatic or recurrent gastric cancer treated with first-line modified FOLFOX-6. The HER2 status was analyzed according to modified scoring criteria specific for gastric cancer. HER2 positivity was shown in 10 out of 114 patients (9.0%). The median time-to-progression (TTP) (4.3 months, 95% confidence interval (CI)=3.6-4.9) and the overall survival (OS) (7.5 months, 95% CI=6.1-8.8) of patients with HER2-positive gastric cancer tended to be shorter than the median TTP (5.9 months, 95% CI=4.5-7.2) and OS (10.8 months, 95% CI=9.2-12.3) of those with HER2-negative gastric cancer (TTP, p=0.177; OS, p=0.068). Particularly in the subgroup of patients without diffuse-type histology, HER2-positive gastric cancer had a worse TTP than those with HER2-negative gastric cancer (p=0.024). In multivariate analysis of this subgroup, HER2 positivity and ECOG performance status of 2 were associated with shorter TTP (hazard ratio (HR)=2.926, p=0.014; HR=2.489, p=0.035, respectively). HER2-positive gastric cancer seems to confer poorer prognosis, particularly in patients without diffuse-type tumor, treated with modified FOLFOX-6.

Background: This study was aimed 1) to investigate the predictive value of FDG PET/CT (fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography) for histopathologic response and 2) to explore the results of FDG PET/CT by molecular phenotypes of breast cancer patients who received neoadjuvant chemotherapy. Methods: Seventy-eight stage II or III breast cancer patients who received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this study. FDG PET/CTs were acquired before chemotherapy and after the first cycle of chemotherapy for evaluating early metabolic response. Results: The mean pre- and post-chemotherapy standard uptake value (SUV) were 7.5 and 3.9, respectively. The early metabolic response provided by FDG PET/CT after one cycle of neoadjuvant chemotherapy was correlated with the histopathologic response after completion of neoadjuvant chemotherapy (P = 0.002). Sensitivity and negative predictive value were 85.7% and 95.1%, respectively. The estrogen receptor negative phenotype had a higher pre-chemotherapy SUV (8.6 vs. 6.4, P = 0.047) and percent change in SUV (48% vs. 30%, P = 0.038). In triple negative breast cancer (TNBC), the pre-chemotherapy SUV was higher than in non-TNBC (9.8 vs. 6.4, P = 0.008). Conclusions: The early metabolic response using FDG PET/CT could have a predictive value for the assessment of histopathologic non-response of stage II/III breast cancer treated with neoadjuvant chemotherapy. Our findings suggest that the initial SUV and the decline in SUV differed based on the molecular phenotype. Trial Registration: ClinicalTrials.gov: NCT01396655

Triple negative breast cancer (TNBC) has a poorer survival, despite a higher response rate to neoadjuvant chemotherapy. The purpose of this study was to identify the predictive or prognostic value of Ki-67 among patients with TNBC treated with neoadjuvant chemotherapy, and the role of Ki-67 in further classification of TNBC. A total of 105 TNBC patients who received neoadjuvant docetaxel/doxorubicin chemotherapy were included in the present study. Pathologic complete response (pCR) rate, relapse-free survival (RFS), and overall survival (OS) were compared according to the level of Ki-67. pCR was observed in 13.3% of patients. TNBC with high Ki-67 expression (≥10%) showed a higher pCR rate to neoadjuvant chemotherapy than TNBC with low Ki-67 expression. None of the low Ki-67 group achieved pCR (18.2% in the high Ki-67 group vs. 0.0% in the low Ki-67 group, P = 0.019). However, a high Ki-67 expression was significantly associated with poor RFS and OS in TNBC, despite a higher pCR rate (P = 0.005, P = 0.019, respectively). In multivariate analysis, high Ki-67 was an independent prognostic factor for RFS in TNBC (hazard ratio = 7.82, P = 0.002). The high Ki-67 group showed a similar pattern of recurrence with overall TNBC, whereas the low Ki-67 group demonstrated a relatively constant hazard rate for relapse. TNBC with high Ki-67 was associated with a more aggressive clinical feature despite a higher pCR rate. High proliferation index Ki-67 can be used for further classification of TNBC into two subtypes with different responses and prognosis.

Background: The objective of this study was to evaluate the efficacy and toxicity of infusional 5-fluorouracil (5-FU), folinic acid and oxaliplatin (modified FOLFOX-6) in patients with advanced gastric cancer (AGC), as first-line palliative combination chemotherapy. We also analyzed the predictive or prognostic value of germline polymorphisms of candidate genes associated with 5-FU and oxaliplatin. Methods: Seventy-three patients were administered a 2 hour infusion of oxaliplatin (100 mg/m²) and folinic acid (100 mg/m²) followed by a 46 hour continuous infusion of 5-FU (2,400 mg/m²). Genomic DNA from the patients' peripheral blood mononuclear cells was extracted. Ten polymorphisms within five genes were investigated including TS, GSTP, ERCC, XPD and XRCC. Results: The overall response rate (RR) was 43.8%. Median time to progression (TTP) and overall survival (OS) were 6.0 months and 12.6 months, respectively. Toxicities were generally tolerable and manageable. The RR was significantly higher in patients with a 6-bp deletion homozygote (-6 bp/-6 bp) in TS-3'UTR (55.0% vs. 30.3% in +6 bp/+6 bp or +6 bp/-6 bp, p = 0.034), and C/A or A/A in XPD156 (52.0% vs. 26.1% in C/C, p = 0.038). The -6 bp/-6 bp in TS-3'UTR was significantly associated with a prolonged TTP and OS. In a multivariate analysis, the 6-bp deletion in TS-3'UTR was identified as an independent prognostic marker of TTP (hazard ratio = 0.561, p = 0.032). Conclusion: Modified FOLFOX-6 chemotherapy appears to be active and well tolerated as first line chemotherapy in AGC patients. The 6-bp deletion in TS-3'UTR might be a candidate to select patients who are likely to benefit from 5-FU based modified FOLFOX-6 in future large scale trial.

Background: Prognostic factors in locally advanced breast cancer treated with neoadjuvant chemotherapy differ from those of early breast cancer. The purpose of this study was to identify the clinical significance of potential predictive and prognostic factors in breast cancer patients treated by neoadjuvant chemotherapy. Methods: A total of 145 stage II and III breast cancer patients received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this study. We examined the clinical and biological factors (ER, PR, p53, c-erbB2, bcl-2, and Ki-67) by immunohistochemistry. We analyzed clinical outcome and their correlation with clinicopathologic parameters. Results: Among the clinicopathologic parameters investigated, none of the marker was correlated with response rate (RR) except triple negative phenotype. Patients with triple negative phenotype showed higher RR (83.0% in triple negative vs. 62.2% in non-triple negative, p = 0.012) and pathologic complete RR (17.0% in triple negative vs. 3.1% in non-triple negative, p = 0.005). However, relapse free survival (RFS) and overall survival (OS) were significantly shorter in triple negative breast cancer patients (p < 0.001, p = 0.021, respectively). Low histologic grade, positive hormone receptors, positive bcl-2 and low level of Ki-67 were associated with prolonged RFS. In addition, positive ER and positive bcl-2 were associated with prolonged OS. In our homogeneous patient population, initial clinical stage reflects RFS and OS more precisely than pathologic stage. In multivariate analysis, initial clinical stage was the only significant independent prognostic factor to impact on OS (hazard ratio 3.597, p = 0.044). Conclusion: Several molecular markers provided useful predictive and prognostic information in stage II and III breast cancer patients treated with neoadjuvant docetaxel/doxorubicin chemotherapy. Triple negative phenotype was associated with shorter survival, even though it was associated with a higher response rate to neoadjuvant chemotherapy.