Clinical Tumor Response Research Articles

Weekly taxane\u2013anthracycline combination regimen versus tri-weekly anthracycline-based regimen for the treatment of locally advanced breast cancer: a randomized controlled trial

BackgroundExtensive studies have confirmed the efficacy of taxanes in combination with anthracycline-based chemotherapy on breast cancer. However, few studies have assessed the efficacy of weekly taxane–anthracycline regimens on locally advanced breast cancer. This study was to compare the efficacy and safety of a weekly taxane–anthracycline regimen with those of tri-weekly anthracycline-based regimen in patients with locally advanced breast cancer.MethodsPatients with locally advanced breast cancer were randomized to receive 4–6 cycles of neoadjuvant chemotherapy with tri-weekly 5-fluorouracil–epirubicin–cyclophosphamide (FEC) regimen or weekly paclitaxel–epirubicin (PE) regimen. The primary endpoint was the pathologic complete response (pCR) rate. Other endpoints included the clinical tumor response, breast-conserving surgery rate, and adverse events.ResultsBetween March 2010 and September 2013, 293 patients were randomized to the FEC (n = 151) and PE (n = 142) arms. The overall clinical response rate was significantly higher in the PE arm than in the FEC arm (76.06% vs. 59.95%, P = 0.001). Consistently, the post-chemotherapy pathologic T and N stages were significantly lower in the PE arm than in the FEC arm (P < 0.001). However, the pCR rate was similar in the two arms (10.61% vs. 12.31%, P = 0.665). Overall, 36 (27.27%) patients in the FEC arm and 6 (35.28%) in the PE arm were qualified for breast-conserving surgery. Most adverse events were comparable in both arms, with more severe neutropenia in the PE arm than in the FEC arm (11.97% vs. 5.96%, P = 0.031).ConclusionsIn patients with locally advanced breast cancer, weekly PE was not superior to FEC in terms of pCR. However, weekly PE has a higher response rate and superior down-staging effects. On this account, the PE regimen may be considered an alternative option for locally advanced breast cancer. Long-term follow-up data are needed to confirm the efficacy of this regimen on locally advanced breast cancer.Trial registration Chinese clinical trial registry, ChiCTR-TRC-10001043, September 21, 2014

Best time to assess complete clinical response after chemoradiotherapy in squamous cell carcinoma of the anus (ACT II): a post-hoc analysis of randomised controlled phase 3 trial

SummaryBackgroundGuidelines for anal cancer recommend assessment of response at 6–12 weeks after starting treatment. Using data from the ACT II trial, we determined the optimum timepoint to assess clinical tumour response after chemoradiotherapy.MethodsThe previously reported ACT II trial was a phase 3 randomised trial of patients of any age with newly diagnosed, histologically confirmed, squamous cell carcinoma of the anus without metastatic disease from 59 centres in the UK. We randomly assigned patients (by minimisation) to receive either intravenous mitomycin (one dose of 12 mg/m2 on day 1) or intravenous cisplatin (one dose of 60 mg/m2 on days 1 and 29), with intravenous fluorouracil (one dose of 1000 mg/m2 per day on days 1–4 and 29–32) and radiotherapy (50·4 Gy in 28 daily fractions); and also did a second randomisation after initial therapy to maintenance chemotherapy (fluorouracil and cisplatin) or no maintenance chemotherapy. The primary outcome was complete clinical response (the absence of primary and nodal tumour by clinical examination), in addition to overall survival and progression-free survival from time of randomisation. In this post-hoc analysis, we analysed complete clinical response at three timepoints: 11 weeks from the start of chemoradiotherapy (assessment 1), 18 weeks from the start of chemoradiotherapy (assessment 2), and 26 weeks from the start of chemoradiotherapy (assessment 3) as well as the overall and progression-free survival estimates of patients with complete clinical response or without complete clinical response at each assessment. We analysed both the overall trial population and a subgroup of patients who had attended each of the three assessments by modified intention-to-treat. This study is registered at controlled-trials.com, ISRCTN 26715889.FindingsWe enrolled 940 patients from June 4, 2001, until Dec 16, 2008. Complete clinical response was achieved in 492 (52%) of 940 patients at assessment 1 (11 weeks), 665 (71%) of patients at assessment 2 (18 weeks), and 730 (78%) of patients at assessment 3 (26 weeks). 691 patients attended all three assessments and in this subgroup, complete clinical response was reported in 441 (64%) patients at assessment 1, 556 (80%) at assessment 2, and 590 (85%) at assessments 3. 151 (72%) of the 209 patients who had not had a complete clinical response at assessment 1 had a complete clinical response by assessment 3. In the overall trial population of 940 patients, 5 year overall survival in patients who had a clinical response at assessments 1, 2, 3 was 83% (95% CI 79–86), 84% (81–87), and 87% (84–89), respectively and was 72% (66–78), 59% (49–67), and 46% (37–55) for patients who did not have a complete clinical response at assessments 1, 2, 3, respectively. In the subgroup of 691 patients, 5 year overall survival in patients who had a clinical response at assessment 1, 2, 3 was 85% (81–88), 86% (82–88), and 87% (84–90), respectively, and was 75% (68–80), 61% (50–70), and 48% (36–58) for patients who did not have a complete clinical response at assessment 1, 2, 3, respectively. Similarly, progression-free survival in both the overall trial population and the subgroup was longer in patients who had a complete clinical response, compared with patients who did not have a complete clinical response, at all three assessments.InterpretationMany patients who do not have a complete clinical response when assessed at 11 weeks after commencing chemoradiotherapy do in fact respond by 26 weeks, and the earlier assessment could lead to some patients having unnecessary surgery. Our data suggests that the optimum time for assessment of complete clinical response after chemoradiotherapy for patients with squamous cell carcinoma of the anus is 26 weeks from starting chemoradiotherapy. We suggest that guidelines should be revised to indicate that later assessment is acceptable.FundingCancer Research UK.

ERBB2-Mutated Metastatic Non–Small Cell Lung Cancer: Response and Resistance to Targeted Therapies

IntroductionErb-b2 receptor tyrosine kinase 2 gene (ERBB2) (also called HER2) has long been recognized as an oncogenic driver in some breast and gastroesophageal cancers in which amplification of this gene confers sensitivity to treatment with Erb-b2 receptor tyrosine kinase 2 (ERBB2)-directed agents. More recently, somatic mutations in ERBB2 have been reported in 1% to 2% of patients with lung adenocarcinoma. Previous case series have suggested clinical tumor responses using anti-ERBB2 small molecules and antibody therapies. MethodsHere we report the outcomes of nine patients with metastatic lung adenocarcinoma with ERBB2 mutations being treated with ERBB2-targeted therapies. ResultsFour of the nine patients had response to targeted therapies, with durations of response ranging from 3 to 10 months. We identified a de novo phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation and ERBB2 copy number gain as potential resistance mechanisms. ConclusionsWe showed patients with ERBB2-mutated lung adenocarcinoma can respond to targeted therapies, and we identified potential resistance mechanisms upon progression to targeted therapies.

The lymphocyte-monocyte ratio predicts tumor response and survival in patients with locally advanced esophageal cancer who received definitive chemoradiotherapy.

BackgroundThe lymphocyte–monocyte ratio (LMR), a simple biomarker that can reflect the antitumor immune response of the host, has been associated with patient prognosis in several solid tumors. The aim of this study was to evaluate whether LMR can predict clinical tumor response and prognosis in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who received definitive chemoradiotherapy (CRT).Patients and methodsA total of 162 advanced ESCC patients treated at our institution between January 2012 and December 2013 were retrospectively recruited for analysis. Patients were treated with a platinum-based bimodal cytotoxic drug chemotherapy and concurrent radiation therapy. The LMR was calculated from blood counts in samples collected prior to treatment initiation. The predictive value of LMR for clinical tumor response and prognosis was examined.ResultsThe LMR before CRT was significantly higher in 48 patients who achieved clinical complete response (CR) compared to that in patients who did not achieve clinical CR (4.89±1.17 vs 3.87±1.29, P<0.001). Compared to their matched counterparts, patients in the high LMR group (LMR >4.02) showed a good clinical tumor response (P<0.05). A significant independent association between a high pretreatment LMR and better outcomes was identified in a multivariate analysis for progression-free survival (PFS; hazard ratio [HR]=2.17; P<0.001) and overall survival (OS; HR=2.02; P=0.002).ConclusionIn ESCC patients, a high LMR before treatment, which indicates a robust host immune system, is associated with both a good clinical tumor response after definitive CRT and favorable prognosis.

Endorectal Brachytherapy Boost After External Beam Radiation Therapy in Elderly or Medically Inoperable Patients With Rectal Cancer: Primary Outcomes of the Phase 1 HERBERT Study

To evaluate the toxicity and efficacy of the combination of external beam radiation therapy (EBRT) followed by high-dose-rate endorectal brachytherapy (HDREBT) boost in elderly and medically inoperable patients with rectal cancer. A phase 1 dose-escalation study was performed. Treatment consisted of EBRT (13×3Gy) followed by 3 weekly brachytherapy applications 6weeks later. The HDREBT dose started at 5Gy per fraction, increasing with 1Gy per fraction if dose-limiting toxicity (DLT, defined as grade ≥3 proctitis <6weeks after HDREBT) occurred in ≤2 patients per dose level. The primary endpoint was the maximum tolerated dose, defined as 1 dose level below the dose at which 3 patients experienced DLT. Secondary endpoints were toxicity, clinical tumor response, freedom from local progression, and local progression-free and overall survival (L-PFS and OS). Thirty-eight patients with a median age of 83years were included in the study. Thirty-two were evaluable for DLT and late toxicity and 33 for response evaluation. Maximum delivered dose was 8Gy per fraction, resulting in a recommended dose of 7Gy per fraction. Response occurred in 29 of 33 patients (87.9%), with 60.6% complete response (CR). The L-PFS and OS rates were 42% and 63%, respectively, at 2years. Patients with CR showed a significantly improved L-PFS (60% at 2years, P=.006) and a trend in improved OS (80% at 2years, P=.11). Severe late toxicity occurred in 10 of 32 patients. We found that HDREBT after EBRT results in a high overall response rate, with improved L-PFS for patients with a CR. The high observed rate of severe late toxicity requires further evaluation of the risks and benefits of an HDREBT boost.

The role of hepatic trans-arterial chemoembolization in metastatic medullary thyroid carcinoma: a specialist center experience and review of the literature.

Liver metastases are relatively common in patients with metastatic medullary thyroid carcinoma (MTC), carrying a negative impact on disease prognosis. The options for selective therapy of liver metastases in MTC patients are limited to catheter-guided procedures such as trans-arterial chemoembolization (TACE). Data regarding the effectiveness and safety of this procedure in MTC are limited. To explore the clinical outcome, survival and safety profile of TACE for liver metastases in a group of MTC patients. Retrospective case series of patients treated at a single tertiary University Medical Center from 2005 to 2015. Seven consecutive patients (mean age 64.5 ± 10.9 years, 5 females) with histologically confirmed MTC with liver metastases were included. Metastatic involvement of the liver was less than 50% of the liver volume in all patients. The median size of the largest liver lesion was 40 ± 6.9 mm. The patients underwent in total 20 sessions of TACE. Clinical improvement as well as tumor response (PR) were observed in all patients. The median time to tumor progression was 38 months (range 8-126). Three patients were still alive at the end of the follow-up period (a median overall survival rate of 57 ± 44 months). TACE in MTC patients with hepatic metastases is usually well tolerated and induces both clinical improvement and tumor response for prolonged periods of time in the majority of patients. This therapeutic option should always be considered, irrespective of the presence of extrahepatic metastasis.

Опыт применения методики интраоперационной лучевой терапии после неоадъювантного системного лекарственного лечения и биопсии сигнальных лимфатических узлов у больных раком молочной железы с клинической стадией T2N0M0

Relevance. Breast cancer is the leading oncological disease among female population. In some cases, clinical stage T2N0M0 is contraindication to breast-concerving surgery due to a big size of the primary tumor. Mastectomy is an optimal surgery in this situation. However, removal of the breast is a serious psychological trauma for the patient, causing quality of life decrease. Attempting to perform breast-conserving surgery is quite logical. Due to this we investigated a method of complex treatment of breast cancer using intraoperative radiation therapy, sentinel lymph node biopsy and neoadjuvant systemic drug therapy. Goal: the main goal is to improve the results of early breast cancer treatment, through the introduction into clinical practice of the original method of complex treatment. Materials and methods. 101 patients treated in the State clinical oncology department of St. Petersburg in the period from 2014 to 2016 were included in the study. The main inclusion criteria was a clinical stage T2N0M0. All the patients are not the candidates for breast - conserving surgery. In the experience group were patients (n=51) who received treatment on the method studied. 50 patients were randomized to the control group, where the mastectomy was performed. In the experience group late toxicity was evaluated after radiosurgery using modified LENT-SOMA scale. Quality of life was assessed by questionnaire QLQ-C30 in both groups. Results. 49 (96%) patients of the experience group were treated by breast-conserving surgery (lumpectomy with intraoperative radiation) due to clinical and radiological tumor response to neoadjuvant therapy. After systemic therapy 10 (20%) women were performed axillary lymph node dissection. Quality of life in the experience group was significantly higher. Late toxicity was not significant after application of intraoperative and whole breast radiotherapy. Conclusion. The investigated method of a complex treatment of early breast cancer is safe and effective and is able to provide the same control of locoregional recurrence as modified radical mastectomy. However, the proposed method provides a statistically significant better quality of life.

Add-On Therapy with Traditional Chinese Medicine Improves Outcomes and Reduces Adverse Events in Hepatocellular Carcinoma: A Meta-Analysis of Randomized Controlled Trials.

Background and Aims Traditional Chinese medicine (TCM) therapy for hepatocellular carcinoma remains controversial. This study aimed to evaluate the efficacy and safety of TCM regimens in HCC treatment. Methods Randomized controlled trials (RCTs) up to June 1, 2016, of the TCM treatment for hepatocellular carcinoma were systematically identified in PubMed, CNKI, Ovid, Embase, Web of Science, Wanfang, VIP, CBM, AMED, and Cochrane Library databases. Results A total of 1010 and 931 patients in 20 RCTs were randomly treated with add-on TCM therapy and conventional therapy, respectively. The additional use of TCM significantly improved six-month, one-year, two-year, and three-year overall survival rates in HCC cases (RR = 1.3, P = 0.01; RR = 1.38, P = 0.0008; RR = 1.44, P < 0.0001; RR = 1.31, P = 0.02, resp.). Add-on TCM therapy significantly increased PR rate and total response rate (tRR) and reduced PD rate compared to those in control group (34.4% versus 26.3%, RR = 1.30, P = 0.002; 41.6% versus 31.0%, RR = 1.30, P < 0.0001; and 16.6% versus 26.5%, RR = 0.64, P < 0.0001, resp.). Additionally, TCM combination therapy significantly increased the quality of life (QOL) improvement rate and reduced adverse events including leukopenia, thrombocytopenia, anemia or erythropenia, liver injury, and gastrointestinal discomfort in HCC patients (all P < 0.05). Conclusion Add-on therapy with TCM could improve overall survival, increase clinical tumor responses, lead to better QOL, and reduce adverse events in hepatocellular carcinoma.

Outcome and long-term efficacy of four facio-cervical fields conformal radiotherapy for nasopharyngeal carcinoma.

PurposeTo evaluate the outcomes of 255 patients with nasopharyngeal carcinoma (NPC) treated with four facio-cervical fields conformal radiotherapy (4F-CRT).ResultsIn one patient's 3 different RT treatment modalities, the 4F-CRT techniques resulted in sharper of the dose-volume histograms (DVHs) for primary gross tumor volume (PGTVnx) and planning target volume (PTVnx), similar to the intensity modulated radiation therapy (IMRT). The median follow-up duration was 43 months. Locoregional relapse and distant metastases as the first treatment failure events occurred in 32 (32/255, 12.5%) and 20 (30/255, 11.8%) patients, respectively. The 3-year and 5-year local control, disease-free survival, and overall survival rates were 83.3%, 82%, 83.8%, and 76.1%, 73.2%, 76.3% respectively. Univariate analysis displayed that clinical stage, T-stage, N-stage, and tumor response were related to prognosis. Multivariate analysis indicated that age, T-stage, N-stage, and combined chemotherapy were independent prognosticators. The incidence of grade 1–2 acute mucositis and leukocytopenia were 93.7% and 91.0%, respectively, with no cases of grade 4 toxicity detected.Materials and MethodsFrom November 2007 to December 2011, 255 patients with histologically diagnosed, non-metastatic NPC were enrolled into this study and received 4F-CRT. Magnetic resonance imaging scans of the nasopharynx were performed on every patient. All patients received definitive radiotherapy with 6 MV X-rays using conventional fractions at 2 Gy daily, 5 fractions per week, and 231 patients with stage IIb-IV received concurrent chemotherapy and cisplatin-based adjuvant chemotherapy. The accumulated survival was calculated according to the Kaplan-Meier method; the log-rank test was used to compare survival differences. Multivariate analysis was performed using Cox's proportional hazard model.ConclusionsCompared with the conventional treatment plans, the 4F-CRT plan delivered more dose to cover the tumor volume and reduces the doses of the normal tissues including the parotid gland, TMJs and so on. The long-term efficacy of 4F-CRT is satisfactory and its toxicities are tolerable.

110P Predictive value of tumor response rate for axillary response of neoadjuvant chemotherapy in patients with clinically nodepositive breast cancer

Background Neoadjuvant chemotherapy (NAC) is the standard treatment for patients withclinicallynode-positivebreastcancer. Anaxillarypathologiccompleteresponse (pCR) isassociatedwith excellentprognosis, andpatients whoachieveaxillarypCRcan besparedaxillarylymphnodedissection(ALND). Theaimofthisstudywastoassess the factors thatpredictedaxillarypCR and evaluateda model predicting ofaxillarypCR in our patient population. Methods We retrospectively identified 201 patients with clinically node-positive breast cancer who were treated with NAC and underwent ALND between 2010 and 2015 at Seoul St. Mary's Hospital, Catholic University ofKorea. We analyzed the Baseline patient and tumor characteristics, clinical tumor response rate, pathologic nodal responses.Thetumorresponseratewascalculatedbytherateoftumorandnodalsize reductionbytheResponseEvaluationCriteriainSolidTumorsver.1.1.Theoverall predictionofthemodelincludingtumorresponseratewasassessedbythe discriminative performance by receiver operating characteristic (ROC) curve analysis. Results AxillarypCR was achieved for68 patients (33.8%) who underwentALND after NAC.Patientspresentingwithhighnucleargrade[grade3vs.1 and2,oddsratio(OR) 2.59], higherKi-67 value [>14% vs.(14%, odds ratio (OR) 1.97] andtumorresponse rate [>47.1% vs. < 47.1%, odds ratio (OR) 3.86] were morelikelyto achieve nodalpCR. In multivariate analysis, tumor response rate was the only independent predictor of a pCR (p = 0.0006). The analysis oftumor response ratevalues revealed that 47.1%was a reasonablecutoffvalueforpredictingtheresponsetonodalpCR.Thediscriminationof the model using tumor response rate status versus excluding tumor response rate status [areaunderthecurve(AUC)67.5%,95%CI,0.59-0.76]wassignificantlyimproved using tumorresponseratestatus[areaunderthecurve(AUC) 74.9%,95% CI, 0.68-0.82, P=0.01]. Conclusions Tumor response rate can predict axillary pCR in node-positive patients receiving NAC. This prediction model including tumor response rate shows reasonable accuracy for predicting axillary pCR and may have utility for informing treatment decisions. Legal entity responsible for the study Seoul St. Mary's Hospital Funding Seoul St. Mary's Hospital Disclosure All authors have declared no conflicts ofinterest.

Abstract CT070: Biomarker and clinical response of oral cavity squamous cell carcinoma to the MEK 1/2 inhibitor trametinib: A phase II neoadjuvant window of opportunity clinical trial

Abstract Purpose: Ras/MEK/ERK pathway activation is common in oral cavity squamous cell carcinoma (OCSCC). To determine biomarker and clinical tumor response of MEK inhibition in patients with OCSCC, we performed a neoadjuvant window of opportunity trial in which the MEK inhibitor trametinib was administered before surgery (NCT01553851). Patients and Methods: Patients with untreated Stage II-IV OCSCC were scheduled to receive trametinib 2 mg/day orally for 7-14 days prior to surgery (last dose 24 hours before surgery). Tumor specimens from the primary site obtained before and after trametinib underwent immunohistochemistry staining for p-ERK1/2 (a marker of Ras/MEK/ERK activation) and CD44 (a protein upregulated by ERK activation), which represented the primary endpoint. Secondary endpoints included comparison of changes in pre- and post-trametinib tumor measurement by clinical examination and in metabolic activity (SUVmax) by FDG-PET/CT (partial response: &amp;gt;25% reduction). Adverse events (AE) and surgical/wound complications were evaluated. Results: Of the 20 enrolled patients, 17 (85%) completed the study as planned. Three patients withdrew from the study due to AE, two (nausea; duodenal perforation) related to trametinib and one (constipation) related to narcotics. The most common drug-related AE was mild rash (9/20 patients, 45%). Nineteen patients (95%) underwent surgery and neck dissection with no unexpected surgical/wound complications. Fifteen patients (75%) were evaluable for the primary biomarker endpoint. 5 (25%) patients either had insufficient pre- or post-treatment biopsies or did not complete the trial. Reduction in p-ERK1/2 expression occurred in 7/15 evaluable patients (47%), whereas a reduction in CD44 occurred in 3/15 (20%). Reduction in tumor size (median 40%, range -74 to +17%) assessed by clinical examination was observed in 12/17 (71%) evaluable patients, and partial metabolic tumor response assessed by FDG-PET/CT was observed in 5/13 (38%) patients. Conclusions: Trametinib was safe to administer as a neoadjuvant treatment in patients with OCSCC and several patients displayed significant reduction in Ras/MEK/ERK pathway activation, and in clinical and metabolic tumor responses. Further exploration of trametinib response in OCSCC patients is warranted. Citation Format: Ravindra Uppaluri, Ashley Winkler, Tianxiang Lin, Jonathan Law, Bruce Haughey, Brian Nussenbaum, Randal Paniello, Jason Rich, Jason Diaz, Loren Michel, Tanya Wildes, Gavin Dunn, Dorina Kallogjeri, Paul Zolkind, Farrokh Dehdashti, Barry Siegel, Rebecca Chernock, James S. Lewis, Jay Piccirillo, Douglas Adkins. Biomarker and clinical response of oral cavity squamous cell carcinoma to the MEK 1/2 inhibitor trametinib: A phase II neoadjuvant window of opportunity clinical trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT070.

Abstract 1653: A novel role for Wnt/β-catenin signaling in mediating resistance of colorectal cancer to chemoradiotherapy

Abstract Background: Preoperative chemoradiotherapy represents the standard treatment for patients with rectal cancer. However, the clinical response of individual tumors to multimodal treatment is not uniform, and ranges from complete response to complete resistance. Therefore, the identification of novel therapeutic targets whose modification could be harnessed to sensitize a priori resistant tumors is exceedingly important. Previously, we demonstrated that the Wnt transcription factor TCF7L2 (also known as TCF4) was overexpressed in primary rectal cancers that were resistant to chemoradiotherapy (CRT), and that TCF7L2 functionally mediates resistance of CRC cells to clinically relevant doses of ionizing radiation (IR). Methods: Using siRNAs we silenced CTNNB1 (β-catenin), another key-component of canonical Wnt-signaling, in colorectal cancer cell lines LS1034, SW480, and SW837. To asses influence on CRT, cells were exposed to 0, 1, 2, 4, 6 and 8 Gy of X-rays and 5-FU. Wnt- signaling was stimulated in retinal pigment epithelial cells (RPE) either by adding Wnt-3A, or overexpressing non degradable β-catenin (S33Y-mutated) and analyzed changes in CRT. Finally we repetitively irradiated SW1463 (68Gy) to establish an isogenic radio-resistant cell line and examined changes in protein expression. Results: Silencing of CTNNB1 resulted in (chemo-) radiation-sensitization of all three CRC-cell lines. To further investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, non-tumorigenic RPE cells were stimulated with Wnt-3A, which significantly increased resistance to CRT. This effect could be recapitulated by overexpression of β-catenin (S33Y-mutated), resulting in a significantly increased resistance to CRT. The effect could be rescued by siRNA mediated knockdown of β-catenin. Consistent with these findings, we observed higher expression levels of active (unphosphorylated) β-catenin as well as increased TCF reporter activity in SW1463 cells that were rendered radiation-resistant due to repeated IR treatment. Conclusion: Together, these findings strongly support the interpretation that Wnt/β-catenin signaling plays a central role in mediating resistance of CRC cells to CRT. Hence, pathway inhibition may represent a promising strategy to increase therapeutic responsiveness to CRT, which represents the standard treatment for locally advanced rectal cancers. This would have considerable clinical implications. Citation Format: Georg Emons, Melanie Spitzner, Sebastian Reineke, Frank Kramer, Margret Rave-Fraenk, Jochen Gaedcke, Michael Ghadimi, Thomas Ried, Marian Grade. A novel role for Wnt/β-catenin signaling in mediating resistance of colorectal cancer to chemoradiotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1653.

Efficacy and safety of extended use of platinum-based doublet chemotherapy plus endostatin in patients with advanced nonsmall cell lung cancer.

The aim of this study was to investigate the efficacy and safety of the extended use of platinum-based doublet chemotherapy (PT-DC) plus endostatin in patients with advanced nonsmall cell lung cancer (NSCLC).We performed a retrospective analysis of 200 newly diagnosed advanced NSCLC patients who had received at least 1 cycle of endostatin plus PT-DC between September 2009 and November 2014. Of these patients, 155 received 4 or more cycles of therapy (the extended therapy group), while 45 received less than 4 cycles of therapy (the control group). Clinical tumor responses, progression-free survival (PFS), overall survival (OS), and toxicity profiles were recorded and retrospectively analyzed.In the extended therapy group, 67 patients (43.2%) achieved a best overall response rate of partial response (PR), while in the control group, 13 patients (28.9%) had a best overall response rate of PR. After a median follow-up of 15.9 months, the median PFS and OS were 8.0 and 23.1 months in the extended arm and 5.8 and 14.0 months in the control arm, respectively. There were statistically significant differences in median PFS and OS between these 2 arms. Hematologic and gastrointestinal toxicities occurred more frequently in the extended therapy group, but no statistically significant difference was detected in grade 3 to 4 toxicities overall between these 2 groups.In conclusion, extended treatment using endostatin combined with PT-DC can provide additional survival benefits and satisfactory toxicity profiles in previously untreated patients with NSCLC, which merits further evaluation in a larger prospective study.

Correlation of Methylated Circulating Tumor DNA With Response to Neoadjuvant Chemotherapy in Breast Cancer Patients

BackgroundCirculating tumor DNA (ctDNA) is known to harbor tumor-specific genetic or epigenetic alterations. In the present study, the correlation of ctDNA with tumor response to neoadjuvant chemotherapy (NAC) was evaluated in primary breast cancer patients. Patients and MethodsPlasma samples were obtained from 87 primary breast cancer patients (stage II-III) before and after NAC, as well as 1 year after surgery. Methylated ctDNA (met-ctDNA) was determined by one-step methylation-specific PCR (OS-MSP) for the promoter region of RASSF1A. ResultsThe positivity (23.0%, 20/87) of met-ctDNA before NAC was significantly (P < .05) higher than that of carcinoembryonic antigen (CEA) (8.6%) and cancer-associated antigen (CA) 15-3 (7.4%). In the patients with positive met-ctDNA before NAC, met-ctDNA significantly decreased after NAC in those with disease that responded to therapy (P = .006), but not in patients whose disease did not respond to therapy. Met-ctDNA after NAC was found to be significantly (P = .008) correlated to the extent of residual tumor burden. Of the 7 patients who showed an increase in met-ctDNA at 1 year after surgery, 3 developed recurrence. ConclusionMet-ctDNA is a more sensitive marker than CEA and CA15-3, and it might be useful in monitoring the clinical tumor response to NAC. In addition, the potential use of met-ctDNA as a tumor marker for monitoring postoperative recurrence has been suggested.

Application of immunomodulatory therapeutic antibodies - a new perspective in oncology

In the past decade major advances in tumor immunology, a better understanding of antigen recognition by T-cells likewise discovering the regulatory inhibitory signals resulted in the development of new immunotherapies with promising durable responses in various solid tumor types and in hematologic malignancies. This review focuses on immunomodulatory antibodies, namely immune checkpoint inhibitor therapy. The prototype of this new class of immune stimulating agents was cytotoxic T-lymphocyte antigen-4 (CTLA-4) antagonists. After demonstrating enhanced survival, ipilimumab was approved first in the United States in 2011, further on in the European Union for second-line (2011) and for first-line therapy (2013) of metastatic melanoma. Additional T-cell intrinsic pathways were identified and targeted for clinical development. Antibodies blocking the PD-1 pathway also showed promising clinical activity and objective tumor response in several types of tumors, including metastatic melanoma, non-small- cell lung cancer. On the other hand antitumor activity is frequently accompanied by significant reversible immune-related adverse events. To explore potential new immune checkpoint targets bring forth several challanges. Future clinical development will involve identifying potential biomarkers anticipating responsiveness to pathway blockade and additional tumor types likely to respond to the therapy. Furthermore, combination strategies, immune checkpoint inhibitors combined with cancer vaccines, targeted inhibitors and traditional chemotherapies are being evaluated in pre-clinical studies. Orv. Hetil., 2016, 157(Suppl. 2), 9-16.

Multimodal Rectal Cancer Treatment: In Some Cases, Less May Be More.

A series of clinical trials in the last several decades has resulted in the development of multimodality treatment of locally advanced rectal cancer that includes neoadjuvant (preoperative) chemoradiotherapy, total mesorectal excision, and postoperative adjuvant chemoradiotherapy. Owing to this regimen, patients with locally advanced rectal cancer have better survival rates than patients with colon cancer, but at the cost of substantial morbidity and reduced quality of life. The challenge is to identify treatment approaches that maintain or even improve oncologic outcomes while preserving quality of life. We have identified different tumor characteristics that are associated with recurrence and probability of survival for locally advanced rectal cancer. This risk stratification, based on baseline clinical staging and tumor response to chemoradiotherapy, has led us to question whether all patients with locally advanced rectal cancer require every component of the multimodal regimen. In this article, we will review recent evidence that some patients with locally advanced rectal cancer can be spared one or more treatment modalities without compromising long-term oncologic outcomes and while preserving quality of life.

Quantitative ultrasound assessment of breast tumor response to chemotherapy using a multi-parameter approach.

PurposeThis study demonstrated the ability of quantitative ultrasound (QUS) parameters in providing an early prediction of tumor response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC).MethodsUsing a 6-MHz array transducer, ultrasound radiofrequency (RF) data were collected from 58 LABC patients prior to NAC treatment and at weeks 1, 4, and 8 of their treatment, and prior to surgery. QUS parameters including midband fit (MBF), spectral slope (SS), spectral intercept (SI), spacing among scatterers (SAS), attenuation coefficient estimate (ACE), average scatterer diameter (ASD), and average acoustic concentration (AAC) were determined from the tumor region of interest. Ultrasound data were compared with the ultimate clinical and pathological response of the patient's tumor to treatment and patient recurrence-free survival.ResultsMulti-parameter discriminant analysis using the κ-nearest-neighbor classifier demonstrated that the best response classification could be achieved using the combination of MBF, SS, and SAS, with an accuracy of 60 ± 10% at week 1, 77 ± 8% at week 4 and 75 ± 6% at week 8. Furthermore, when the QUS measurements at each time (week) were combined with pre-treatment (week 0) QUS values, the classification accuracies improved (70 ± 9% at week 1, 80 ± 5% at week 4, and 81 ± 6% at week 8). Finally, the multi-parameter QUS model demonstrated a significant difference in survival rates of responding and non-responding patients at weeks 1 and 4 (p=0.035, and 0.027, respectively).ConclusionThis study demonstrated for the first time, using new parameters tested on relatively large patient cohort and leave-one-out classifier evaluation, that a hybrid QUS biomarker including MBF, SS, and SAS could, with relatively high sensitivity and specificity, detect the response of LABC tumors to NAC as early as after 4 weeks of therapy. The findings of this study also suggested that incorporating pre-treatment QUS parameters of a tumor improved the classification results. This work demonstrated the potential of QUS and machine learning methods for the early assessment of breast tumor response to NAC and providing personalized medicine with regards to the treatment planning of refractory patients.

Robotic Surgery in Patients With Locally Advanced Cervical Cancer After Neoadjuvant Chemotherapy: Survival Outcomes.

To evaluate the survival outcomes of consecutive patients with locally advanced cervical cancer (LACC) who underwent comprehensive robotic surgery after neoadjuvant chemotherapy (NACT). Since 2009, patients with LACC (FIGO [International Federation of Gynecology and Obstetrics] stages IB2-IIB) were submitted to robotic surgical staging after 3 cycles of NACT. Clinical objective tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors, whereas pathologic responses were defined according to the criteria of the European study SNAP01. Univariable and multivariable analyses were performed to assess potential clinicopathologic prognostic factors affecting progression-free survival and overall survival (OS). During the study period, 32 patients meeting the inclusion criteria were managed. The median (range) age and body mass index were 47.3 (8.6-75.5) years and 22.7 (17.5-37.1) kg/m(2), respectively. Overall, 28.0 (range, 12-58) lymph nodes were retrieved. According to the final pathologic examination, 6 (18.8%) women had positive pelvic lymph nodes, whereas 16 (50.0%) patients achieved an optimal pathological response. After a median follow-up of 36.3 (range, 5.2-71.1) months, 6 (18.8%) patients had a recurrence and subsequently died of disease.Positive nodal status was the only independent predictor of both progression-free survival (12.5 [2.3-69.1]; P < 0.0001) and OS (12.0 [2.0-60.4]; P < 0.0001) at multivariable analysis. Nodal status represents the strongest predictor of survival in women with LACC. Similarly, NACT including 3 agents (TIP [paclitaxel 175 mg/m(2) + ifosfamide 5 g/m(2) + cisplatin 75 mg/m(2)] and TEP [paclitaxel 175 mg/m(2) + epirubicin 80 mg/m(2) + cisplatin 75 mg/m(2)] regimens) warranted better OS than those achieved by other schedules.

Abstract P6-13-19: Adding zoledronic acid to neo-adjuvant chemotherapy may improve the efficiency of chemotherapy in locally advanced breast cancer: Results from the prospective randomized study NEOZOL

Abstract Background : There is extensive preclinical evidence that bisphosphonates, especially zoledronic acid (ZOL), exhibit anti-tumor effects (inhibition of tumor cell adhesion, migration, invasion and proliferation, and induction of cell death). ZOL reduces tumor-associated angiogenesis and vascular endothelial growth factor (VEGF) production in different animal models of cancer. In the Adjuvant Treatment with Zoledronic Acid in Stage II/III Breast Cancer Study (AZURE), it was observed a reduction in residual invasive tumor size, ∼ 2-fold improved complete pathologic response rates, and lower mastectomy rates with chemotherapy plus ZOL versus chemotherapy alone. The current hypothesis is that adding ZOL to neoadjuvant chemotherapy will increase the efficacy of this neoadjuvant treatment, thanks to a direct anti-cancer activity of ZOL and/or a synergic anti-cancer effect with chemotherapy. The aim of this study was to evaluate the clinical, pathological and biological impact of adding ZOL to neoadjuvant chemotherapy in locally advanced breast cancer. Methods : A multicenter prospective phase II trial (NEOZOL) was performed in France to compare the effects of adding ZOL to neoadjuvant chemotherapy with that of neoadjuvant chemotherapy alone. Patients were randomized 1:1 to receive 4-mg ZOL monthly or no ZOL with chemotherapy cycles. Patient's eligibility criteria were women 18 years of age or older with absence of contraindication to treatment with ZOL and breast cancer (TNM IIa, IIb, IIIa) larger than 2cm in maximal diameter able to benefit from neoadjuvant chemotherapy. The primary end point was circulating concentrations of VEGF. The secondary end points were clinical, radiological, pathological and biological tumor response rates, and the breast conservation rate. The planned sample size was 38 patients per arm with a power of 95,4 %. The protocol has been funded by Novartis and was reviewed by an Ethical Committee (CPP Lyon IV). This study is registered in the NCI database. Results: due to low accrual, the study was stopped after inclusion of 71 patients between May 2010 and July 2013. 53 patients were randomized and 3 patients were excluded after randomization due to deviation to the protocol. Of the remaining 50 patients, 24 were randomized in arm A (ZOL treatment) and 26 in arm B (control arm). Baseline clinicopathologic characteristics were well balanced. .No side effect related to ZOL treatment was reported. Circulating VEGF levels did not statistically significantly differ between both arms. Regarding secondary end-points, there was a trend towards a more conservative surgery in arm A, compared with arm B. Conclusion : adding ZOL to neoadjuvant chemotherapy in locally advanced breast cancer may increase the efficiency of chemotherapy, improving surgical treatment. Citation Format: Mathevet P, Magaud L, Clézardin P. Adding zoledronic acid to neo-adjuvant chemotherapy may improve the efficiency of chemotherapy in locally advanced breast cancer: Results from the prospective randomized study NEOZOL. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-19.

Palliative radiotherapy and chemotherapy instead of surgery in symptomatic rectal cancer with synchronous unresectable metastases: Final overall survival analysis of phase II study.

726 Background: A palliative surgery and chemotherapy is the standard of care in stage IV rectal cancer patients with pelvic symptoms. Recently we published primary results of the single-arm phase II study on combination of short-course radiation (5x5 Gy) with an oxaliplatin-based chemotherapy started after one-week rest (NCT01157806). The study met its primary end-point with only 17.5% (95% CI 13% to 22%) of patients (pts) who needed stoma throughout the observation and 67% (95% CI 58% to 76%) of pts having significant resolution of pelvic symptoms. Here we provide the long-term follow up data after median 60 months of observation. Methods: 40 consecutive patients with symptomatic rectal cancer with unresectable distant metastases were enrolled from September 2009 to February 2011. The time of treatment failure on chemotherapy (TTF3) was measured from the start of radiation to disease progression on fluoropiridine, oxaliplatin and irinotecan. All eligible patients were assessed for KRAS/NRAS status. Due to limitations in access to targeted agents none of patients were treated with anti-angiogenic agents and anti-EGFR treatment was restricted to third line. Results: Total 40 pts were assessed for pelvic symptoms, chemotherapy response and overall survival. In the group of patients with survival reaching over 2 years we have not observed any additional local complications which were treated surgically. The patients with total symptoms’ resolution after one month had significantly longer time-to-treatment failure (TTF3) than non-responders (median 22.5 vs 5 months, p &lt; 0.05), while patients with minor local response had intermediate TTF3. The subgroup of patients who experienced clinical complete response of rectal tumor had a median TTF3 and overall survival reaching median 40 months. Conclusions: In the palliative setting short-course radiotherapy and early chemotherapy allowed for acceptable and durable local control. Metastatic rectal cancer patients with early symptomatic response of primary tumor had significantly better prognosis. Clinical trial information: NCT01157806.