bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene expression profiles in formalin-fixed, paraffin-embedded (FFPE) core biopsies predict docetaxel chemosensitivity
Authors: Chang J. C. , Makris A. , Hilsenbeck S. G. , Hackett J. R. , Jeong J. , Liu M. , Baker J. , Sexton K. , Osborne C. K. , Shak S. 
Published: March 2020

538 Background: Docetaxel has one of the highest response rates as a single agent in breast cancer, but de novo resistance is frequent. Previously, we had identified a 92-gene expression pattern that predicted response to neoadjuvant docetaxel. Other studies have validated that a high Recurrence Score (RS) by the 21-gene RT-PCR assay is predictive of worse prognosis (Paik, NEJM 2004) but better response to chemotherapy (Gianni, JCO 2005). We investigated whether tumor gene expression of these 21 genes and other candidate genes can predict response to docetaxel. Methods: Core biopsies from 97 patients were obtained before treatment with neoadjuvant docetaxel (4 cycles, 100 mg/m2 q3 weeks). Baseline and post-treatment measurements of the primary breast cancers were recorded. Three 10-micron FFPE sections were submitted for quantitative RT-PCR assays of 192 genes that were selected from our previous work and the literature. Results: Of the 97 patients, 81 (84%) had sufficient invasive breast cancer, 80 (82%) had sufficient RNA for assay of 192 genes, and 72 (74%) had clinical response data. Mean age was 48.5 years, and the median tumor size was 6 cm. Clinical complete responses (CR) by RECIST were observed in 12 (17%), partial responses in 41 (57%), stable disease in 17 (24%), and progressive disease in 2 patients (3%). The concordance of IHC and RT-PCR results was >80% for ER, PgR, and HER2. By univariate logistic regression, a significant correlation (p<0.05) between gene expression and CR was observed for 14 genes. Notably, CYBA-1 involved in mitochondrial metabolism, identified by gene expression profiling, significantly predicted CR (p=0.006). CR was associated with lower expression of the ER gene group and higher expression of the proliferation gene group. Multivariate analysis indicated that panels of genes better predictors of docetaxel response. Of note, CR was more likely with high RS and less likely with a low RS (p=0.008). Conclusion: We have established molecular profiles for breast cancers either responding or not responding to neoadjuvant docetaxel. This technology is a potential predictive test for docetaxel sensitivity by using small amounts of FFPE material, and may reduce unnecessary treatment, toxicity, and cost for breast cancer patients. [Table: see text]
Distinct PIK3CA mutation profiles in estrogen receptor (ER) negative breast cancer (BC) subsets
Authors: Doane A. S. , Danso M. , Lal P. , Donaton M. , Wheler J. , Moynahan M. , Zhang L. , Hudis C. , Gerald W. 
Published: March 2020

540 Background: ER negative, progesterone receptor (PR) negative BC is clinically heterogeneous and underlying biology may be complex. We have identified two primary subtypes of ER(-)/PR(-) BC based on genome-wide molecular analysis (Doane et al., 2005, Oncogene, In Press), however the biological mechanisms underlying these molecular differences are not known. Methods: We performed genome-wide expression analysis of 99 primary BC samples and 13 BC cell lines. Total RNA was extracted and hybridized to Affymetrix HG-U133 oligonucleotide microarrays. Unsupervised and supervised analyses were used to investigate gene expression profiles. Predictive models were developed using a supervised k-nearest neighbor technique. Samples were further characterized by immunohistochemistry (IHC) for selected gene products, and HER2 status was determined by IHC and FISH. PIK3CA exons 9 and 20 were sequenced by RT-PCR amplification, direct sequencing, and restriction enzyme digest. Results: Genes differentially expressed between ER(-)/PR(-) subsets (designated class A and B) included SPDEF, ALCAM, AR, and FGFR4 (p<0.0001). Further study revealed a significant association with class A and the PIK3CA A3140G:H1047R activating mutation among ER(-)/PR(-) BC (p=0.012). HER2 status (gene amplification or 3+ IHC) was not significantly associated with this subtype (p=0.33). MDA-MB-453 corresponded to class A according to molecular profile and PIK3CA mutation status. This cell line demonstrated a proliferative response to androgen (A) in an androgen receptor (AR) dependent and ER-independent manner. In addition the A-induced transcriptional program of MDA-MB-453 significantly overlapped the molecular signature of ER(-)/PR(-) class A human BC (p<0.0001). Conclusion: Hormonal signaling through the AR may be significantly different in ER(-)/PR(-) molecular subsets. Enhanced AR signaling may be due to cooperation with growth factor signaling through PI3K. The potential molecular crosstalk between activated PI3K and the androgen signaling pathway provides therapeutic opportunities and deserves further study. No significant financial relationships to disclose.
Pharmacogenomic analysis of HER2 amplified breast cancer treated with preoperative trastuzumab and paclitaxel, 5-fluorouracil, epirubicin, cyclophosphamide (T/FEC) chemotherapy
Authors: Esteva F. J. , Anderson K. , Lin F. , Nahta R. , Mejia J. , Altundag K. , Buzdar A. U. , Hortobagyi G. N. , Symmans W. F. , Pusztai L. 
Published: March 2020

545 Background: We performed gene expression analysis to identify molecular predictors of resistance to preoperative concomitant trastuzumab and T/FEC chemotherapy. Methods: Pretreatment fine needle aspirations from 21 patients with HER2 amplified, stages II-III breast cancer were available for transcriptional profiling with Affymetrix U133 A chips. Results: Overall pathologic complete response (pCR) rate was 71%. Age, nuclear grade, tumor size, nodal status or quantitative estrogen and HER2 receptor mRNA expression showed no association with response in univariate and multivariate logistic regression. We tested the accuracy of a 30-gene pCR predictor that was previously developed from patients who received T/FEC only preoperative chemotherapy. This predictor was accurate in validation in T/FEC treated patients (n=51) but showed low sensitivity in patients who also received trastuzumab (sensitivity 53% versus 92%). We could not identify any differentially expressed genes between pCR (n=15) and residual disease (RD, n=6) at a false discovery rate (FDR) <90% in the HER2 amplified trastuzumab-treated cases. Hierarchical clustering using the “Perou intrinsic gene set” also failed to separate pCR from RD. Gene Set Enrichment Analysis with 22 genes from trastuzumab-resistant cell lines showed a modest association with RD (FDR=9%). Conclusions: Clinical variables and pharmacogenomic predictors that predict pCR in the absence of trastuzumab are no longer accurate when trastuzumab is included in the treatment. Trastuzumab-resistance associated genes identified in vitro are also associated with resistance in vivo. Support: Ellence Foundation. No significant financial relationships to disclose.
Phase II trial of trastuzumab (T), paclitaxel (P) and cisplatin (C) in metastatic (M) or recurrent (R) head and neck squamous cell carcinoma (HNSCC): Response by tumor EGFR and HER2/neu status
Authors: Gillison M. L. , Glisson B. S. , O’Leary E. , Murphy B. A. , Levine M. A. , Kies M. S. , Chan D. , Forastiere A. A. 
Published: March 2020

5511 Background: EGFR expression is associated with poor prognosis and resistance of HNSCC to therapy. EGFR/Her2/neu heterodimers may potentiate receptor signaling and therapy resistance. T enhances cytotoxic effects of C and P in Her2/neu+ cell lines. Methods: A phase II trial evaluated the response rate (RR) of HNSCC pts to TPC as a function of Her2/neu and EGFR expression by immunohistochemistry (IHC). Secondary outcomes included toxicity, one-year progression-free (PFS) and overall (OS) survival. Eligible pts had M or R HNSCC, ECOG PS 0–1, CrCl >50 ml/min, and ANC >1500. Chemotherapy regimen consisted of P (175 mg/m2) and C (75 mg/m2) IV on day 1 and T (4 mg/kg day 1, cycle 1, 2 mg/kg subsequent) IV on day 1, 8 and 15 of 21. Paraffin embedded tumor was analyzed for Her2/neu (HercepTest) and EGFR (Zymed Lab) expression by IHC and for Her2/neu amplification by FISH (−/+) at LabCorp. Two-stage Simon design had 80% power for a 15% improvement in RR over 35% and required response in ≥ 14/42 pts by ECOG response criteria. Results: 61 pts (55 R HNSCC) received a median of 4 cycles (range 1–14) of TPC. Membrane staining of ≥ 10% of cells was observed for Her2/neu in 4/58 (6.9%, 95% CI 2–17) and for EGFR in 41/57 (72%, 95% CI 58–83). Her2/neu amplification was absent in 55/55 (0%, one-sided 97.5% CI 0–6.7) tumors. A RR of 36% (95% CI 24–50) was observed in 58 evaluable pts. RR was lower in pts with ≥ 10% staining by EGFR (25% versus 62.5%, p = 0.01). Her2/neu expression had no effect on RR (p = 0.75). Toxicities included two grade 5 dehydration/hypokalemia, and grade 3–4 neutropenia, fatigue, infection, nausea, vomiting, and neuropathy were common. Median follow-up was 4.2 yrs. For all 61 pts: median TTP was 4.3 mos, PFS 19.8% (95% CI 10.6–30.9) and OS 44% (95% CI 31.6–56.2) at 1 yr. Pts with <10% EGFR membrane staining had improved median PFS (6.7 vs 3.1 mos, p = 0.003) and OS (16.1 vs 7.4 mos, p = 0.005) when compared to patients with tumors with ≥ 10% EGFR. Conclusions: T did not improve RR to PC, likely because Her2/neu gene amplification and expression was rare. Tumor EGFR status significantly affected RR, PFS, and OS to the underlying regimen of PC. Sponsored by Bristol-Myers Squibb, Genentech, and Damon Runyon Cancer Research Foundation (MG). [Table: see text]
Long-term results of Intergroup RTOG 91–11: A phase III trial to preserve the larynx—Induction cisplatin/5-FU and radiation therapy versus concurrent cisplatin and radiation therapy versus radiation therapy
Authors: Forastiere A. A. , Maor M. , Weber R. S. , Pajak T. , Glisson B. , Trotti A. , Ridge J. , Ensley J. , Chao C. , Cooper J. 
Published: March 2020

5517 Background: The 2-year results of Intergroup RTOG 91–11 were published in 2003 (NEJM 349:2091–8,2003). We now present the 5-year results (after median follow-up for surviving patients of 6.9 years) of 515 eligible pts with resectable stage III or IV (excluding T1 and high volume T4), cancer of the glottic or supraglottic larynx. Methods: Patients were randomized to induction cisplatin/5-FU (CF) with responders then receiving RT (I+RT) (n = 173); or concurrent cisplatin (100 mg/m2 q 21 days × 3) and RT (CRT) (n = 171); or RT alone (R) (n = 171). Laryngectomy was performed for < partial response to induction CF, for persistent/recurrent disease or for laryngeal dysfunction. Results: At 5 years, laryngectomy-free survival (LFS) was significantly better with either I+RT (44.6%, p = 0.011) or CRT (46.6%, p = 0.011) compared to R (33.9%). There was no difference in LFS between I+RT and CRT (p = 0.98). Laryngeal preservation (LP) was significantly better with CRT (83.6%) compared to I+RT (70.5%, p = 0.0029) or R (65.7%, p = 0.00017). Local-regional control (LRC) was significantly better with CRT (68.8%) compared to I+RT (54.9%, p = 0.0018) or R (51%, p = 0.0005). I+RT compared to R for LP and LRC showed no significant difference (p = 0.37 and 0.62, respectively). The distant metastatic rate was low (I+RT 14.3%, CRT 13.2%, R 22.3%) with a trend (p ∼0.06) for benefit from chemotherapy. Disease-free survival (DFS) was significantly better with either I+RT (38.6%, p = 0.016) or CRT (39%, p = 0.0058) compared to R (27.3%). Overall survival rates were similar for the first 5 years (I+RT 59.2%, CRT 54.6%, R 53.5%); thereafter I+RT had a non-significant lower death rate. Compared to CRT, significantly more pts in the R group died of their cancer (34% vs 58.3%, p = 0.0007); the rate for I+RT was 43.8%. Conclusion: These 5-year results differ from the 2-year analysis by a significant improvement in LFS now seen for both I+RT and CRT treatments compared to R. For the endpoints of LP and LRC, CRT is still the superior treatment with no advantage seen to the addition of induction CF to R. There is no significant difference in overall survival. [Table: see text]
Locally advanced resectable larynx (L) or oropharynx (OP) cancer: Updated results of organ preservation trial ECOG 2399
Authors: Cmelak A. J. , Li S. , Murphy B. , Burkey B. , Adams G. L. , Cannon M. , Pinto H. , Rosenthal D. I. , Ridge J. A. , Forastiere A. A. 
Published: March 2020

5527 Background: Taxane-based concurrent chemoradiation (CCR) for head and neck cancers has proven feasible and has a favorable toxicity profile compared to concurrent cisplatin and radiation. This phase II multi-institutional trial evaluates taxane-based induction chemotherapy followed by CCR for organ preservation in resectable Stage III/IV L and OP patients. Methods: Eligibility: Resectable stage T2N+, or T3-T4N0–3M0 biopsy-proven squamous Ca, age ≥18, PS 0–2, good organ function, and no prior chemotherapy or radiation. Treatment: induction paclitaxel (P) 175 mg/m2 and carboplatin (C) AUC 6 for 2 cycles q21d followed by concurrent P 30 mg/m2 q7d with 70 Gy if no evidence of progression. Weekly epoetin alpha 40kU was used if Hgb ≤15 (male) or ≤14 (female). The primary endpoint is organ preservation (freedom from salvage surgery with preserved speech and swallowing). Results: 105/111 pts (69 OP, 36 larynx) were eligible. Median FU is 33 months. No grade 5 toxicities occurred. 94% received full dose RT and 91% received ≥5 cycles of concurrent paclitaxel. At one year post-treatment, 13 (12%) patients required salvage surgery at the primary site (7-L, 6-OP), and 6 pts (6%) progressed and died (3-L, 3-OP). 1 pt (1%) died without progression and 85 pts (81%) are alive without progression (25-L, 60-OP). 12 pts (10%) have developed distant mets (6-L, 6-OP). 1-yr and 2-yr PFS for all pts is 77% and 64%. 12/69 OP and 9/36 L pts have died of disease. 1-yr event-free survival (EFS = no salvage surgery, recurrence or death) is 72% (77%-OP, 64%-L), and 2-yr EFS is 57% (68%-OP, 34%-L) (p = 0.02). 1-yr OS is 93%, 2-yr OS is 74% (OP vs. L p = 0.11). Conclusions: This regimen is well tolerated and is feasible in a multi-institutional setting. EFS with this regimen is lower than expected in larynx patients. The benefit of induction chemotherapy in this setting remains unproven but does not preclude CCR delivery. Funded, in part, by Bristol-Myers Squibb. [Table: see text]
Comparison of two induction chemotherapy regimens in combination with radiotherapy in patients with advanced nasopharyngeal carcinoma
Authors: Chua D. T. , Ma J. , Sham J. , Mai H. , Hong M. , Lu T. , Ming H. 
Published: March 2020

5535 Background: Prospective randomized trials failed to show any survival benefits associated with the use of induction chemotherapy in nasopharyngeal carcinoma (NPC). Although cisplatin-based regimens were commonly used in these trials, the impact of cisplatin dose was not clear. Methods: Individual patient data of two published phase III trials using different cisplatin-based induction chemotherapy regimens were pooled together for analysis. A total of 365 patients with stage II-IV NPC received either cisplatin & epirubicin (EP, n = 144) or cisplatin, bleomycin & fluorouracil (PBF, n = 221) followed by radiotherapy between September 1989 and July 1994. The mean total cisplatin dose received by patients ranged from 162 mg/m2 in EP group to 232 mg/m2 in PBF group. Median follow-up time was 59 months. Results: The response rates at the end of induction chemotherapy were 86% in PBF group and 84% in EP group. No significant differences in tumor control and survival were observed between the two groups. Five-year overall survival rates were 63% in PBF group and 62.5% in EP group. Five-year loco-regional failure-free rates were 74% in PBF group and 65% in EP group, the difference being not significant after adjusting for stage grouping. Conclusions: No significant difference in treatment outcome was observed in patients using different cisplatin-based induction chemotherapy. The absence of survival benefits in chemotherapy arms was probably not related to the dose-intensity of cisplatin used, and escalating the total cisplatin dose alone in induction chemotherapy is not likely to improve survival. No significant financial relationships to disclose.
Chemo-selection of patients (pts) for organ preservation in advanced laryngeal cancer: Failure of chemotherapy (CT) as the sole treatment for complete histologic responders (CHR) to neoadjuvant chemotherapy
Authors: Worden F. P. , Wolf G. , Eisbruch A. , Lee J. , Bradford C. , Chepeha D. , Teknos T. , Prince M. , Hogikyan N. , Tsien C. , Urba S. 
Published: March 2020

5560 Background: We conducted a phase II organ preservation trial for stage III/IV laryngeal cancer pts in an attempt to identify pts, who were CHR after 1 cycle of induction CT, who might be curable with CT alone. Methods: Pts received 1 cycle of cisplatin 100 mg/m2 & 5-FU 1000 mg/m2/day x 5 days (P+5FU). CHR received 1 cycle of P+5FU, followed by weekly docetaxel (D) 35 mg/m2 x 3 wks, followed by 1 cycle of P+5FU, & no radiotherapy (RT). Pts with >50% (but < 100%) response (PR) received chemoradiation (CRT) with 70 Gy & P 100 mg/m2 days 1, 22, & 43. Pts with < 50% response underwent laryngectomy. Final planned tumor assessment with direct laryngoscopy with biopsy was done 8 wks after CRT or 3 wks after the last cycle of P+5FU (CT alone arm). CHR after CT alone received 2 cycles of P+5FU alternating with 2 cycles of D. CHR after CRT received 2 cycles of P+5FU, & pts with residual disease had planned salvage surgery. Results: 32 eligible pts were enrolled, 24 M; 8 F; median age 56, stage III/IV- 7/25. After 1 cycle CT, 4 pts (13%) had CHR & received CT alone; 24 (75%) had PR & received CRT; 3 had surgery; & 1 refused surgery. Of pts who had CT alone, 4/4 had regional failures; 3/4 underwent neck dissection & 1/4 had laryngectomy & neck dissection; all had adjuvant RT because of multiple nodes or extracapsular spread; 3/4 are alive without disease & 1/4 is dead of complications. 5/24 who received CRT failed; 2/24 had surgery & 3/24 were unresectable. Toxicity: Gr 3/4 granulocytopenia 19%, Gr 3/4 mucositis with CT alone 12.5%. Median follow-up is 16.5 months. 2 yr overall survival is 88.2% (95% CI = 75.3%, 100%). 1 yr disease-free survival (DFS) is 81.8% (CI=67.2%, 96.5%). 2 yr DFS is 76% (CI=58.4%, 93.5%). The proportion of pts alive & free of cancer with intact larynx at 1 yr is 69.1% (CI = 51.9%, 86.3%) & at 2 yrs is 63.8% (CI=45%, 82.5%). 1 pt developed distant metastases. Larynx preservation was achieved in 24 pts (75%). Conclusions: CT alone is not an effective strategy for advanced laryngeal cancer pts, even in CHR after 1 cycle of induction CT, due to high nodal failure rate. Planned integration of early regional control by surgery or lower-dose RT may be necessary to allow treatment approaches that spare selected pts high-dose RT. No significant financial relationships to disclose.
The role of panendoscopy in the staging of high risk head & neck squamous cell carcinoma prior to therapy: Is it of value?
Authors: Bhandari T. 
Published: March 2020

5569 Background: Panendoscopy (triple endoscopy) has historically been advocated to adequately stage patients w/ head & neck squamous cancer, especially in the setting of neoadjuvant therapy. This role is controversial by in view of comparable information provided by current imaging techniques Objective: The primary objective was to analyze the results of panendoscopy in a series of patients enrolled in a neoadjuvant chemo radiation protocol. Methods: We reviewed the panendoscopy results of 69 pts w/ stage III/IV head & neck squamous cell carcinoma (H&N ca) treated w/ neoadjuvant chemo radiation at a single institution from 1996–2005. All pts had detailed laryngoscopy/microlaryngoscopy w/ strategic biopsies, esophago-duodeno-scopy (selected biopsies for Barretts) & placement of percutaneous gastrostomy (PEG) & bronchoscopy washings for cytology. Pts were initially treated w/chemo radiation protocols (H&N 53,67); subsequent protocols utilized induction chemotherapy/chemo radiation (H&N 79,86). Results: Two of 69 pts had malignant cells in bronchial cytology in absence of any lung findings (both were NED at 5 yrs). A radiologically occult primary bronchial cancer was found in an additional pt excluding pt from the protocol. Two pts were diagnosed w/ Barrett’s esophagus; another pt also had a synchronous primary cancer of the cervical esophagus. Nine of 69 pts underwent panendoscopy for cervical metastases from an apparent unknown primary ca (at initial diagnosis). The primary cancer was demonstrated in 6 pts at staging panendoscopy and in another patient at follow up panendoscopy. Conclusion: Panendoscopy is essential in staging high risk H & N ca pts prior to initiation of therapy. A detailed laryngoscopy (micro-laryngoscopy) w/ strategic biopsies is required for adequate staging of all cancers of oropharynx & larynx. Esophago-gastro-duodenoscopy had a low but definable yield, but is also necessary for PEG placement to ensure adequate nutrition during neoadjuvant therapy. Bronchoscopy has a limited role in the absence of radiologic chest findings. No significant financial relationships to disclose.
Celecoxib (Ce) + exemestane (Ex) versus placebo + Ex in post-menopausal (PM) metastatic breast cancer (MBC) patients (pts): A double-blind phase III GINECO study
Authors: Freyer G. , Debled M. , Geay J. F. , Bachelot T. , Blot E. , Cretin J. , Delozier T. , Mille D. , Ferrero J. M. , Romestaing P. , Pujade-Lauraine E. 
Published: March 2020

565 Background: in vitro and in vivo studies suggest that COX-2 inhibitors have proper antitumor effect and could enhance the activity of aromatase inhibitors (AI). Methods: PM first-line MBC pts without previous adjuvant AI were randomized to receive per os until progression either A: Ce (400 mg bid) + Ex (25mg/d) or B: placebo (1 tablet bid) + Ex (25mg/d). PFS was the main end-point. The trial was prematurely stopped (Dec 2004) with 157/342 pts enrolled (A: 74, B: 83 pts) after occurrence of Ce cardio-vascular toxicity in other trials. Results: patient (median age, A:61, B:63 yrs) characteristics were well balanced between A and B (%) : ER and/or PR positive (93, 94), HER2 positive (4, 5), adjuvant chemotherapy (45, 53) or tamoxifen (57, 61), ECOG PS 0–1 (90, 90), visceral (63, 53) or bone involvement (35, 41). Tolerance: compared to placebo (B), pts treated with Ce (A) experienced less gr 2–3 CTCAE: pain (A:52, B:63%), arthralgias (19, 28), asthenia (20, 30), Gr 1–3 insomnia (32, 47), but more hypersentivity reactions (7,0) and oedema (8, 2). Gastro-intestinal toxicity was not increased in A. One episode of paroxystic arythmia occurred in the Ce arm, without complication in a patient with known cardiopathy. Overall response rate was significantly higher in A (35 vs 20%, p=.034). Median PFS in intent-to-treat analysis was similar in A (9.8 months) and B (9.8), but tend to be superior in A (A:12.2, B:9,8, p=.09) in pts who were included at least 3 months before early trial stopping. In addition, PFS was significantly longer in pts treated with Ce +Ex (A: 8.4 months, B: 4.7, p=.019) in the subgroup of pts who developed MBC under Tam or within 12 months after Tam stopping (A: 26, B: 29 pts). Conclusion: The combination of celecoxib and exemestane is promising and should be further explored in MBC with adequate cardiac monitoring. No significant financial relationships to disclose.