Combined CD44, c-MET, and EGFR expression in p16-positive and p16-negative head and neck squamous cell carcinomas.

PURPOSE/OBJECTIVE(S): To examine the association between CD44 and c-MET expression in relation to p16 and EGFR in patients with head and neck squamous cell carcinoma (HNSCC). MATERIALS/METHODS: Immunohistochemical staining of CD44, p16, EGFR, and c-MET was performed on 105 locally advanced HNSCC patients treated with chemoradiation. CD44 expression was correlated with c-MET, EGFR, and p16, locoregional control (LRC), distant metastases (DM), disease-free survival (DFS) and overall survival (OS). RESULTS: High CD44 expression was present in 33% of patients and was associated with non-oropharynx primaries (P < 0.001), high c-MET expression (P < 0.001), p16-negative (P < 0.001) and EGFR-positive tumors (P < 0.001). Fifty-seven percent of CD44 high expressing tumors had high c-MET expression compared to 21% of CD44 low expressing tumors (P < 0.001). High CD44 expression predicted for worse LRC (HR: 2.44; 95% CI: 1.16-5.13; P = 0.018), DFS (HR: 2.61; 95% CI: 1.46-4.67; P = 0.001), and OS (HR: 2.52; 95% CI: 1.30-4.92; P = 0.007) but not DM (P = 0.57) on univariate analysis. Patients with both high CD44 and c-MET expression had a poor prognosis with a 2-year DFS of 30% compared to 70% in the rest of the cohort (P = 0.003). On multivariable analysis, after adjusting for site, T-stage, smoking history, and EGFR status, high c-MET (P = 0.039) and negative p16 status (P = 0.034) predicted for worse DFS, while high CD44 expression did not (P = 0.43). CONCLUSIONS: High CD44 expression is associated with high c-MET expression, p16-negative tumors, and EGFR-positive tumors. The combination of these markers predicts for poor prognosis in HNSCC patients treated with chemoradiation.

Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome.

Macrophages, a key cell in the inflammatory cascade, have been associated with poor prognosis in cancers, including breast cancer. In this study, we investigated the relationship of a subset of macrophages-proliferating macrophages (promacs)-with clinico-pathologic characteristics of breast cancer, including tumor size, grade, stage, lymph node metastases, hormone receptor status, subtype, as well as early recurrence, and survival. This study included a discovery and validation set that was conducted at two institutions and laboratories (University of California, San Francisco and University of Chicago) using two independent cohorts of patients with breast cancer. Formalin-fixed, paraffin-embedded sections and/or tissue microarrays were double-stained with anti-CD68 (a macrophage marker) and anti-PCNA (a proliferation marker) antibodies. The presence of intratumoral promacs was significantly correlated with high grade, hormone receptor negative tumors, and a basal-like subtype. In contrast, there was no correlation between promacs and tumor size, stage, or the number of the involved lymph nodes. These findings were consistent between the two study cohorts. Finally, promac numbers were a significant predictor of recurrence and survival. In the pooled analysis, elevated promac levels were associated with a 77% increased risk of dying (P = 0.015). The presence of promacs in human breast cancer may serve as a prognostic indicator for poor outcomes and early recurrence and serve as a potential cellular target for novel therapeutic interventions.

Dual blockade of PI3K and MEK in combination with radiation in head and neck cancer.

BACKGROUND AND PURPOSE: In this study we have combined fractionated radiation treatment (RT) with two molecular targeted agents active against key deregulated signaling pathways in head and neck cancer. MATERIALS AND METHODS: We used two molecularly characterized, low passage HNSCC cell lines of differing biological characteristics to study the effects of binimetinib and buparlisib in combination with radiation in vitro and in vivo. RESULTS: Buparlisib was active against both cell lines in vitro whereas binimetinib was more toxic to UT-SCC-14. Neither agent modified radiation sensitivity in vitro. Buparlisib significantly inhibited growth of UT-SSC-15 alone or in combination with RT but was ineffective in UT-SCC-14. Binimetinib did cause a significant delay with RT in UT-SCC-14 and it significantly reduced growth of the UT-SCC-15 tumors both alone and with RT. The tri-modality treatment was not as effective as RT with a single effective agent. CONCLUSIONS: No significant benefit was gained by the combined use of the two agents with RT even though each was efficacious when used alone.

Antitumor activity of the dual PI3K/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer.

BACKGROUND AND PURPOSE: Head and neck squamous cell carcinoma (HNSCC) remains a clinical challenge where new treatments are required to supplement the current-standard-of care of concurrent chemoradiation. The PI3K/AKT/MTOR pathway has been identified from several next generation DNA sequencing studies to be commonly altered and activated in HNSCC. MATERIAL AND METHODS: In this study we investigated the activity of PF-04691502, an orally active ATP-competitive, dual inhibitor of PI3K and mTOR, in combination with a clinically relevant fractionated radiation treatment in two contrasting, well characterized, low passage HNSCC models. RESULTS: We found that PF-04691502 combined synergistically with radiation in the UT-SCC-14 model derived from a primary cancer but was ineffective in the UT-SCC-15 model which was derived from a nodal recurrence. Further examination of the status of key signaling pathways combined with next generation DNA sequencing of a panel of 160 cancer-associated genes revealed crucial differences between the two models that could account for the differential effect. The UT-SCC-15 cell line was characterized by a higher mutational burden, an excess of variants in the PI3K/AKT/MTOR pathway, increased constitutive activity of PI3K, AKT1 and 2 and MTOR and an inability to inhibit key phosphorylation events in response to the treatments. CONCLUSION: This study clearly highlights the promise of agents such as PF-04691502 in selected HNSCCs but also emphasizes the need for molecular characterization and alternative treatment strategies in non-responsive HNSCCs.

Image-guided radiation therapy for prostate cancer: A computed tomography-based assessment of fiducial marker migration between placement and 7 days.

PURPOSE: This study was conducted to determine whether clinically significant fiducial marker migration occurs immediately after prostatic implantation. METHODS AND MATERIALS: One hundred patients with transperineal (n = 39) or transrectal (n = 61) placement of 3 gold fiducial markers underwent computed tomography scans on day 0 (after placement) and day 7 (at radiation planning). Each marker was marked as a point of interest in a treatment planning system. An automated point-based algorithm was then used to coregister the day 0 and day 7 images by matching the markers through rigid translations and rotations. The mean distance between fiducial pairs (d¯) was recorded to assess the degree of seed migration. Prostate contours were delineated, and the day 0 prostate volumes were uniformly expanded by 1, 3, and 5 mm. The percentage of the day 7 prostate volume covered by each day 0 prostate with expansion was calculated to assess whether prostate contours, if performed on day 0, would adequately cover the prostate on day 7. RESULTS: The average d¯ for all patients was 0.78 ± 0.45 mm; only 1 patient had d¯ > 2 mm. Placement technique, hormonal therapy, prostate size, and marker distance from the capsule were not associated with d¯ (P > .05). The mean percentages of day 7 prostate volumes covered by the day 0 prostate plus 1, 3, and 5 mm were 98.3%, 99.8%, and 100%, respectively. With an expansion of 3 mm, 98% of men had >95% of day 0 volume covered; with an expansion of 5 mm, 100% of men had 100% of the day 0 volume covered. CONCLUSIONS: There is minimal change in the relative positions of fiducial markers (average d¯ < 1.0 mm) 1 week after placement. A 1- to 3-mm expansion would account for the variation in seed position for the vast majority of cases. These results suggest that planning could be performed on the day of implantation without adverse consequence.

Combined-modality therapy for rectal cancer: analysis of potential differences in disease presentation, treatment adherence, and treatment outcome according to race.

OBJECTIVES: Population-based studies suggest African Americans (AAs) with rectal cancer have a worse overall outcome compared with non-AAs. This relationship was explored in a cohort of rectal cancer patients treated with preoperative chemoradiation therapy (CRT) and surgery at 2 academic cancer centers. METHODS: A total of 146 patients (26 AA, 120 non-AA) underwent treatment with curative intent. The median age was 57 years. Median dose was 50.4 Gy, given with 5-fluorouracil-based concurrent chemotherapy. Differences in disease presentation, adherence to recommended therapy, and treatment outcome (freedom from failure) by race were analyzed. Median follow-up was 34 months from completion of CRT. RESULTS: AAs had longer time from diagnosis to start of therapy (median, 45 vs. 35 d; P<0.01) and from CRT completion to surgery (median, 42 vs. 46 d; P=0.03). AA patients presented with more favorable disease (20% stage I, 33% stage III) compared with non-AA patients (0% stage I, 48% stage III, P<0.01). AA patients were less likely to receive adjuvant chemotherapy (58% vs. 89%, P=0.01). Log-rank analysis showed AAs were not more likely to recur after therapy (freedom from failure at 3 y, 100% for AA patients vs. 81% for non-AA patients, P=0.09). The difference in time from preoperative therapy to surgery and a lower rate of adjuvant therapy in AA patients did not seem to result in inferior disease outcome for this cohort. CONCLUSIONS: Further study is necessary to explore the reasons underlying the delays in therapy and lower rates of adjuvant chemotherapy for AA patients.

Statin use and risk of prostate cancer recurrence in men treated with radiation therapy.

PURPOSE: There has been growing interest in the potential anticancer activity of statins based on preclinical evidence of their antiproliferative, proapoptotic, and radiosensitizing properties. The primary objective of this study was to determine whether statin use is associated with improved clinical outcomes in patients treated with radiotherapy (RT) for prostate cancer. PATIENTS AND METHODS: In total, 691 men with prostate adenocarcinoma treated with curative-intent RT between 1988 and 2006 were retrospectively analyzed. Of those, 189 patients (27%) were using statins, either during initial consultation or during follow-up. Lipid panels were collected (n = 298) a median of 5 months before RT start. Median follow-up was 50 months after RT. RESULTS: Statin use was associated with improved freedom from biochemical failure (FFBF; P < .001), freedom from salvage androgen deprivation therapy (FFADT; P = .0011), and relapse-free survival (RFS; P < .001). Improved FFBF for statin users was seen in low-, intermediate-, and high-risk groups (P = .0401, P = .0331, and P = .0034, respectively). The improvement in FFBF with statin use was independent of ADT use or radiation dose. On multivariable analysis, statin use was associated with improved FFBF (P < .001) along with pretreatment prostate-specific antigen < or = 8.4 (P < .001), stage less than T2b (P = .0111), and Gleason score < 7 (P = .0098). On univariate analysis, pretreatment total cholesterol < 187 (89% v 80%; P = .0494) and low-density lipoprotein (LDL) < 110 (96% v 85%; P = .0462) were associated with improved 4-year FFBF. CONCLUSION: Statin use was associated with a significant improvement in FFBF, FFADT, and RFS in this cohort of men treated with RT for prostate cancer. The favorable effect of statins may be mediated by direct effect or via the LDL-lowering effect of these medications.