Neoadjuvant Treatment Regimens Research Articles

Surgery for pancreatic disease

Surgery for pancreatic diseases is one of the most studied fields in general surgery and continues to evolve. This review focuses on recent advances in pancreatic surgery and summarizes the published research. Surgery for pancreatic diseases is an evolving field with a wide range of innovations. Especially, contributions by high-volume pancreas centers have greatly improved outcomes in pancreatic surgery. In chronic pancreatitis, recent studies demonstrate that early surgical treatment should be favored over repeated endoscopic interventions, and local organ-preserving resection techniques should be preferred over classic Whipple resection. Major advances have also been made on the diagnosis of pancreatic cystic lesions; however, the assessment of the current guidelines is still evolving. In pancreatic cancer, neoadjuvant treatment regimens appear to be promising, and extended pancreatic resections with vascular resection can now be offered with lower mortality and morbidity rates. Minimal-invasive laparoscopic and robotic surgical techniques are being used more frequently for the resection of pancreatic tumors and have seen major progress. In recent years, the outcome of patients undergoing pancreatic surgery improved due to better knowledge about the biology of the disease, more accurate diagnostic modalities, the application of organ-preserving surgical techniques in benign disorders and new advances in management strategies.

Abstract P1-14-16: Weekly paclitaxel, trastuzumab, carboplatin is a highly effective neoadjuvant regimen in HER2-positive breast cancer: Results from the TRAIN-study

Abstract Background A trastuzumab/carboplatin/docetaxel regimen is an established alternative for the more commonly used and toxic anthracycline/cyclophosphamide containing regimen in HER2-positive breast cancer. Weekly paclitaxel, however, may be more effective and better tolerable than three-weekly docetaxel. Aim To assess the efficacy and safety of an anthracycline/cyclophosphamide-free neoadjuvant treatment regimen with weekly paclitaxel, carboplatin and trastuzumab in HER2-positive breast cancer. Patients and methods The TRAIN-study is a multicenter phase II trial which was developed during the 9th ECCO/AACR/ASCO Workshop on "Methods in Clinical Cancer Research" in Flims, Switzerland. Patients with stage II or III HER2-positive breast cancer were eligible. Treatment consisted of weekly administrations of paclitaxel ([P], 70mg/m2), trastuzumab ([T], 2mg/kg, loading dose 4mg/kg), and carboplatin ([C], AUC = 3mg/ml/minute) for a total of 24 weeks. In cycles 7, 8, 15, 16, 23 and 24 only trastuzumab was administered. The primary endpoint was pathologic complete response (pCR), defined as no residual invasive tumor cells in the breast and axilla. Event-free survival was evaluated as a secondary endpoint. In addition, we report efficacy results in an additional cohort of patients treated with the same regimen after study closure. Toxicity data were only recorded for the study population. Results Baseline characteristics of 109 study patients and 72 additional patients were similar. The pCR rate in the study population was 43% (95% confidence interval [CI] 33-53%) and in all evaluable patients combined 47% (95% CI 39-54%). The median follow-up was 41 months (interquartile range [IQR] 20-53). The 3-year event-free survival estimate was 89% (95% CI 84-95%). Patients who achieved a pCR had a better prognosis than patients who did not (hazard ratio [HR] 0.33; 95% CI 0.11-1.00, p<0.05). In the study population the most common grade 3-4 adverse events were neutropenia (67%) and thrombocytopenia (43%). Febrile neutropenia occurred in less than five percent of patients. During the neoadjuvant treatment period no symptomatic left ventricular systolic dysfunction was observed. Dose reductions were implemented in 56% of study patients and at least one chemotherapy dose was skipped in 67% of patients. Conclusion Weekly paclitaxel, trastuzumab, and carboplatin is a highly effective neoadjuvant regimen in HER2-positive breast cancer with manageable toxicity. In the currently running randomized TRAIN-2 study this regimen will be directly compared to an anthracycline/cyclophosphamide containing neoadjuvant regimen in the setting of dual HER2-blockade with pertuzumab (clinicaltrials.gov NCT01996267). Pathologic complete response rate according to population and hormone receptor status All patientsER- and PR-ER+ and/or PR+Study population (n=108)43%53%34%Additional cohort (n=70)53%71%36%Combined population (n=178)47%60%35% Citation Format: van Ramshorst MS, van Werkhoven E, Mandjes IAM, Schot M, Wesseling J, Vrancken Peeters M-JTFD, Rodenhuis S, Oosterkamp HM, Bos MEM, Meerum Terwogt JM, Linn SC, Sonke GS. Weekly paclitaxel, trastuzumab, carboplatin is a highly effective neoadjuvant regimen in HER2-positive breast cancer: Results from the TRAIN-study. [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 P1-14-16.

Abstract P3-07-15: Prosigna® subtype correlation is a strong predictor of response to neoadjuvant chemotherapy (NAC) in early breast cancer (EBC) study

Abstract Background: Prosigna's ROR score was demonstrated as a strong predictor of response to NAC in a representative cohort of EBC patients including HR+/HER2- N0-N1 patients.1 Given that the ROR score is partially derived from the correlation of the tumor's expression profile to that of the four prototypical intrinsic subtypes, we determined the relative strength of the association between each subtype correlation and the likelihood of response to NAC. Methods: We analyzed 294 FFPE breast cancer samples from pts treated with NAC (anthracyclines and taxanes) in a multi-center Spanish cohort. The Prosigna Assay was performed on the NanoString nCounter® Dx Analysis System at HU Virgen de la Victoria de Málaga/CIMES-UMA. Pathologic complete response (pCR) was used as the primary endpoint for this study and was determined using the Miller and Payne scoring criteria. Results: Mean patient age in this population was 50 (±11yr). Apart from targeted therapy, all patients received a standard neoadjuvant treatment regimen consisting of 8-12 cycles of anthracyclines and taxanes. 58% of patients were HR+/HER2- while 24% were classified as HER2+ and 18% were TNBC patients. Of the 311 pts samples previously tested, subtype correlation data was available for 294. Overall subtype concordance between IHC and Prosigna was 72% (K=0.66). The overall pCR rate in this population was 24.9%. Prosigna subtype breakdown in the full study population was 60 Luminal A, 118 Luminal B, 69 HER2-enriched and 47 Basal-like with response rates of 7.2%, 7.2%, 46.2% and 57.4%, respectively. We found that in all study populations, subtype correlation was a strong predictor of response to NAC. Tumors with expression profiles that correlated well with the Luminal prototypical centroids were found to be largely unresponsive to NAC (Luminal A Odds ratio=0.074 per unit increase, p<0.0001; Luminal B Odds ratio=0.059 per unit increase, p<0.0001). Conversely, higher HER2E and Basal-like correlations were associated with increased probability of response (HER2E Odds ratio=11.2 per unit increase, p<0.0001; Basal-like Odds ratio=9.0 per unit increase, p<0.0001). Increased proliferation-score (p-score) was also associated with increased probability of response to NAC (Odds ratio=3.43 per unit increase, p<0.0001). Conclusions: In a representative cohort of breast cancer patients, both the magnitude of the subtype correlation to the prototypical centroids as well as p-score, as determined by the Prosigna Assay, were strong predictors of response to NAC. This data underlines the importance of molecular testing for optimal systemic therapy indications in EBC. 1Rodriguez B, Lavado Fernandez A, Ribelles N, et al. Prosigna (PAM50) to predict response to neoadjuvant chemotherapy (NAC) in HR+/HER2- early breast cancer (EBC) patients. J Clin Oncol 33, 2015 (suppl; abstr 11049). Citation Format: Chica Parrado R, Jiménez-Rodríguez B, Sánchez Rovira P, Álvarez M, Vicioso L, Fernandez AI, de Luque V, José Lozano M, Villar E, Zarcos I, Ramírez C, González-Hermoso C, Jeiranian A, Dowidar N, Schaper C, Buckingham W, Ferree S, Ribelles N, Rodrigo I, Prat AP, Alba E. Prosigna® subtype correlation is a strong predictor of response to neoadjuvant chemotherapy (NAC) in early breast cancer (EBC) study. [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 P3-07-15.

Disease Control, Survival, and Toxicity Outcome After Intensified Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: A Single-Institution Experience

PurposeTo report the long-term follow-up data and determine the toxicity rate concerning patients with locally advanced rectal cancer (LARC) treated with an intensified neoadjuvant treatment regimen. Patients and MethodsPatients with histologically proven stage II to III adenocarcinoma of the rectum were included and treated with a trimodal approach. Intensified neoadjuvant treatment (chemoradiotherapy [CRT]) consisted of radiotherapy (total dose 50.4/54 Gy) and concomitant oxaliplatin (50 mg/m2/week) and 5-fluorouracil (200 mg/m2/5 daily continuous infusion). Surgery was planned 7 to 9 weeks after the end of CRT. Adjuvant chemotherapy was recommended in those patients with lymph node metastasis at diagnosis. ResultsOne hundred patients (median age, 64 years) were eligible. Overall, the 5-year overall survival and disease-free survival (DFS) were 76.4% and 74.5%, respectively. CRT was well tolerated, with only 17% grade 3/4 acute toxicity. Twenty-four patients (24%) had a pathologic complete response (pCR), and only 1 patient had perioperative metastasis. The 5-year DFS were 95.7% and 66.7% for pCR and no-pCR tumor histology, respectively (P = .0275). ConclusionAlthough oxaliplatin is not considered to be a standard treatment, the high 5-year rate of overall survival and DFS, the low severe toxicity rates, and the effective benefit on pCR and perioperative metastasis support an intensified treatment regimen for LARC.

Abstract OT3-1-01: A two-cohort, phase II, cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with HER2-positive, locally advanced, inflammatory, or early breast cancer

Abstract Background: In HER2-positive early breast cancer (BC), neoadjuvant pertuzumab (P) + trastuzumab (T) + docetaxel (D) significantly increased pathologic complete response (pCR) rates compared with T+D (Gianni L, et al. Lancet Oncol 2012); high pCR rates were also seen with P+T in combination with anthracycline- and non-anthracycline-based regimens (Schneeweiss A, et al. Ann Oncol 2013). Neoadjuvant P+T + chemotherapy was well tolerated, with little increased toxicity associated with the addition of P. Although there was a higher rate of cardiac adverse events (AEs), left ventricular systolic dysfunction (LVSD), and left ventricular ejection fraction (LVEF) declines in P+T-containing arms compared with arms without P, these events were generally asymptomatic, reversible, and patients (pts) recovered with no sequelae. No data are available for neoadjuvant P-based regimens that include paclitaxel (Ptx) and dose-dense doxorubicin plus cyclophosphamide (ddAC), despite these being widely used in (neo)adjuvant BC therapy. This study will evaluate the cardiac safety of two anthracycline-based neoadjuvant regimens in combination with P+T. Following surgery, all pts will receive adjuvant P+T. Trial design: In this non-randomized, open-label, phase II study, two parallel cohorts of pts receive different P-based neoadjuvant treatment regimens. In Cohort A, pts receive four 2-weekly cycles of ddAC, followed by 12 doses of weekly Ptx, plus four 3-weekly (q3w) cycles of P+T from the start of Ptx. In Cohort B, pts receive four q3w cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by four q3w cycles of D, plus four q3w cycles of P+T from the start of D. Following surgery, both cohorts receive 13 cycles of P+T. Eligibility: Pts with HER2-positive, locally advanced, inflammatory, or early BC (size >2 cm or >5 mm and node-positive) are eligible if they have a baseline LVEF ≥55% and an ECOG performance status ≤1. Among the exclusion criteria are prior incisional biopsy or excision of the primary tumor, prior systemic or radiation therapy for cancer, and prior chemopreventive agents. Pts are also excluded if they have poorly controlled hypertension, angina requiring medication, a history of congestive heart failure, serious or uncontrolled cardiac arrhythmia requiring treatment, or myocardial infarction within 6 months prior to enrollment. Aims: The primary objective is cardiac safety during the neoadjuvant period, assessed by incidence of symptomatic LVSD and LVEF changes. Secondary objectives include cardiac safety in the adjuvant and post-treatment periods, incidence of all AEs, pCR rate, event-free survival, invasive disease-free survival, and overall survival. Statistical methods: No statistical hypothesis testing will be performed. Safety and efficacy results will be summarized descriptively. A sample size of 200 pts per cohort is expected to provide sufficient data to evaluate the cardiac safety of each regimen with acceptable precision (exact Clopper-Pearson 95% CIs) around the expected rates. Accrual: The first patient in is planned for August 2014. Citation Format: Sandra M Swain, Michael S Ewer, Hannah Douthwaite, Tania Szado, Maeve Waldron-Lynch, Chau Dang. A two-cohort, phase II, cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with HER2-positive, locally advanced, inflammatory, or early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-1-01.

What more do we want from neoadjuvant treatment strategies in rectal cancer?

Radiation therapy (RT) delivered preoperatively has clearly shown to improve local disease control after radical surgery in rectal cancer [1–3]. In fact different options including short-course or long-course regimens have been extensively studied with similar good long-term local disease control [4–6]. Also, the addition of chemotherapy with fluoropyrimidine to radiation led to further improvement in local disease control of these patients [7,8]. At a first glance, the issue of local recurrence in rectal cancer had been solved with widespread introduction of preoperative RT with or without concomitant chemotherapy. So why do we keep searching for alternative treatment options for the already successful neoadjuvant approach? What are we looking for? First of all, the observation that neoadjuvant chemoradiation (CRT) could result in complete tumor eradication, also known as complete pathological response is now considered one of the major advantages of neoadjuvant therapy in patients with rectal cancer [9]. Patients with complete pathological response (pCR) are associated with improved oncological outcomes [10]. Therefore, development of alternative neoadjuvant strategies that could maximize pCR rates is highly desirable. Also, even though increased rates of sphincter preservation have been considered another advantage of the neoadjuvant strategy, none of the randomized studies have demonstrated any superiority in sphincter preservation rates in experimental arms of these studies [11]. However, in select patients with clinical and radiological evidence of pCR (complete clinical response [cCR]), alternative organ-preserving treatment strategies have been suggested [12,13]. Therefore, a substantial increase in pCR and cCR rates could benefit patients by improving oncological outcomes and truly affecting sphincter or even organ preservation rates [9]. Therefore, maximization of pCR/cCR rates is an excellent reason for the search of improved neoadjuvant treatment regimens. But radiation therapy comes at a significant cost for patients, even though some

Role of neoadjuvant treatment regimens for locally advanced pancreatic cancer.

444 Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality worldwide. Lymph node involvement and resection margin status play important roles in predicting relapse. Resectable disease occurs in only 15–20% of total patients who present with PDAC. Unfortunately, margin involvement (R1) occurs in 70–80% of these patients. Emerging evidence has shown that the use of neoadjuvant chemotherapy and localised radiotherapy to downsize the tumours and increase the margin clearance (R0) rate may improve the overall survival of PDAC patients.We report a neoadjuvant therapy approach in the non-clinical trial setting of our large, tertiary cancer centre. Methods: We prospectively collected the outcome data and toxicity of 53 patients diagnosed with borderline resectable or initially non-resectable PDAC between 2012 and 2014. These patients received either FOLFIRINOX (FFX) or Gemcitabine/Capecitabine (GemCap) combination chemotherapies. Following restaging by computed tomography (CT), the patients proceeded to preo-operative 5-FU-based chemo-radiotherapy, immediate resection or subsequent palliativetherapies. Results: The median age was 65 (range 30 – 79) at PDAC diagnosis. Sixty-one percent (n=32) were male with the commonest anatomical location being the head of the pancreas (58%, n=31). The median follow up for survivors is 13.7 months (range: 5.3–24.4). The median overall survival was 18.3 months (95%, CI: 12.0–24.5). There was no statistical difference between overall survival in patients receiving FFX and GemCap chemotherapies. The margin clearance rate (R0) was 36% (4/11) in patients who proceeded to resection after neoadjuvant chemotherapy alone. The rate was 100% (4/4) in patients who received additional chemoradiation prior to surgery. Conclusions: This case series reveals that neoadjuvant therapy improved survival of patients with PDAC. In addition, we showed an increase in the R0 resection rate in patients who underwent chemoradiation prior to surgery. Further work is ongoing but based on historical data we believe that this neoadjuvant approach may lead to a long term survival benefit.

Neoadjuvant B and N Safe and Effective with D and H in HER2-Positive Breast Cancer

Neoadjuvant treatment regimens resulting in high pathologic complete response (pCR) rates are needed for patients with HER2-positive breast cancer because they are correlated with favorable prognoses. Although N in combination with H is highly effective in HER2-positive breast cancer, this regimen is unsuitable because of high cardiotoxicity. The Phase 2 Study of Neoadjuvant Trastuzumab+Docetaxel+Non-pegylated Liposome-Encapsulated Doxorubicin (NPLD)±Bevacizumab in HER2-Positive Early Breast Cancer [ABCSG-32; NCT01367028] was conducted to evaluate the cardiotoxicity and efficacy of N and B in combination with DH in the neoadjuvant treatment of early HER2-positive breast cancer.

Neoadjuvant chemotherapy in pancreatic cancer: innovative, but still difficult

Sir, We read with great interest the recent article by Alvarez and co-workers reporting the effects of nab-paclitaxel on tumour stroma in pancreatic cancer (Alvarez et al, 2013). The authors should be congratulated on their interesting findings from a translational study that investigated the biological effects of neoadjuvant gemcitabine and nab-paclitaxel in patients with resectable disease. Although the primary study endpoint was to determine the effects of this novel chemotherapy regimen on tumour stroma (including an assessment of collagen content and structure of ‘cancer-associated fibroblasts' (CAF)), some important lessons can be learned from this innovative study regarding the approach of neoadjuvant chemotherapy in localised pancreatic cancer (Heinemann et al, 2013). The investigators enroled 16 patients with histologically or cytologically confirmed resectable or borderline resectable exocrine pancreatic cancer that had received two cycles of gemcitabine/nab-paclitaxel. After chemotherapy, 3 patients had progressive disease and 12 patients were able to proceed to surgical resection. Of note, in the final pathological assessment of the surgical specimen, two study patients in fact had a neuroendorcine cancer and not pancreatic adenocarcinoma. No objective response by RECIST was observed after neoadjuvant chemotherapy; however, half of patients had a CA 19-9 decrease of >75% and a partial metabolic response by FDG-PET imaging. The authors reported a median CA 19-9 pre-treatment value of 2.588 U/dl in their patient population, ranging from 1 to 36.376 U/dl; this would correspond to a median CA 19-9 level of 26 U ml−1 at baseline with a range from 0.01 U ml−1 to 364 U ml−1, respectively (please note: (U/dl) is a very uncommon unit for reporting CA 19-9; the most commonly used unit in the literature is ( U ml−1)) (Boeck et al, 2006). On the basis of the evidence from previous CA 19-9 biomarker studies, significantly elevated CA 19-9 levels before surgical resection may indicate a potential subradiographic systemic disease rather than a localised disease. In a single-centre trial from the USA, 51 out of 262 patients who underwent staging laparoscopy for radiographically resectable pancreatic adenocarcinoma in fact had unresectable disease. In this study, the median pre-operative CA 19-9 value for patients who underwent resection was 131 U ml−1 vs 379 U ml−1 for those patients with unresectable disease (P=0.003). With the use of a receiver operating characteristics curve for pre-operative CA 19-9 value and tumour resectability, the statistically optimal cut-off value was determined to be 130 U ml−1 (Maithel et al, 2008). In concordance, Katz et al (2010) suggested a pre-treatment CA 19-9 cut-off of 149 U ml−1 as a predictor of completing chemoradiation and subsequent pancreaticoduodenectomy in their neoadjuvant study (Ketz et al, 2010). In the light of the fact that ‘… the content of stroma and CAF may change with different cancer stages' (as the authors themselves stated correctly in the Discussion section), one should keep in mind that an appropriate selection of patients with a unique stage of disease thus should be an important issue in novel translational studies. Nevertheless, the data presented are important and highlight an innovative approach to how future translational research should be conducted in pancreatic cancer. However, from a clinical point of view, this small study clearly unbosoms potential pitfalls of neoadjuvant treatment approaches in resectable pancreatic cancer: (1) the difficulty of adequately select patients with a real localised disease, (2) the limitations of obtaining an adequate pre-treatment histological diagnosis and (3) the often missing objective response by RECIST to neoadjuvant chemotherapy. The latter one was already described previously in borderline resectable patients and in fact it may be more appropriate to investigate different clinical methods than conventional CT scan for assessing treatment response to a neoadjuvant treatment regimen (e.g. metabolic response by PET or biochemical response by CA 19-9) (Takahashi et al, 2010; Katz et al, 2012). We thus would recommend including a rigorous histological (no cytological) confirmation of disease before study entry, an assessment of response by different methods other than CT scan and also a CA 19-9 cut-off for patients entering neoadjuvant trials. Such an approach has recently been included in several large phase III adjuvant trials (e.g. RTOG 0848, Prodige 24/Accord 24), mainly by using a post-resection CA 19-9 level of <180 U ml−1 as an inclusion criterion.

Freedom from recurrence after induction cisplatin/5-FU/RT versus carboplatin/paclitaxel/RT in patients with esophageal cancer.

126 Background: The optimal neoadjuvant treatment regimen for esophageal cancer has yet to be defined. Methods: We analyzed a prospective database of esophageal cancer patients treated with cisplatin/5-FU/RT (A) or carboplatin/paclitaxel/RT (B) then esophagectomy. Endpoints were pathologic response (pCR), recurrence, and overall survival. Covariates (age, gender, clinical stage, Charlson comorbidity index (CCI), and ECOG PS) were adjusted via propensity score weighting from logistic regression. Differences in survival curves were compared using weighted Kaplan Meier methods and Wilcoxon tests. Landmark analysis compared differences in outcomes at least six months after surgery. Results: From January 2008 to June 2013, 71 patients received induction RT (50.4 Gy), with 38 and 33 patients in groups A and B, respectively. Patient demographics were similar (Table 1). Operative procedure, R0 resections, and operative complications did not differ (operative mortality 1/71, 1.4%; anastomotic leak rate 10% A vs. 9% B, p=1.0). Median follow-up was 18.2 and 9.1 months for groups A and B, respectively. There was no difference in overall survival (p=0.88) or total number of recurrences (11/38, 29% A vs. 10/33, 30% B). Landmark analysis revealed a difference in recurrence at least 6 months after surgery: time to recurrence was shorter in group B (median time to recurrence 31 mos A vs. 18 mos B, p=0.02). pCR was seen in 13/38 (34%) A and 9/33 (27%) B (p=0.53). In patients with pCR, there was a trend toward more recurrences in group B (2/13, 15% A v 4/9, 44% B, p=0.14). Conclusions: Six months after surgery patients receiving induction carboplatin/paclitaxel/RT had shorter time to recurrence compared to cisplatin/5-FU/RT. In those with pCR a trend towards increased distant recurrences was seen with carboplatin/paclitaxel/RT, which may have less systemic efficacy in esophageal cancer than cisplatin/5-FU/RT. This should be evaluated in larger series. [Table: see text]

Squamous Cell Carcinoma of the Pancreas in a Patient with Germline BRCA2 Mutation-Response to Neoadjuvant Radiochemotherapy.

Primary squamous cell carcinoma of the pancreas is a rare malignant neoplasia, accounting for approximately 0.5–2% of all malignant pancreatic tumors. These lesions are characterized by poor prognosis. Here we report on a case of a 57-year-old female patient with known BRCA2 germline mutation presenting with primary squamous cell carcinoma of the pancreas as the only malignancy. The tumor was locally advanced at the first presentation but responded almost completely to neoadjuvant radio-chemotherapy. Our case highlights the facts (i) that pancreatic carcinomas belong to the tumor spectrum of patients with the BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) and (ii) that tumors of the pancreas can represent the first or even the only manifestation of HBOC. Furthermore, this case of a nonkeratinizing squamous cell carcinoma indicates that HBOC-associated carcinomas of the pancreas might be characterized by a broader morphological spectrum than was previously thought. Since BRCA mutations cause deficiency of DNA double-strand breakage repair in tumors, neoadjuvant treatment regimens might become a reasonable option in HBOC-associated pancreatic carcinomas. To our knowledge, this is the first reported case of a primary pancreatic squamous cell carcinoma in a patient with this particular genetic background of BRCA2-associated HBOC.

Abstract 5035: Stable transfection of the osteosarcoma cell line SaOs2, genetically transformed MSCs and osteoblasts with insulin-like growth factor 2 receptor.

Abstract Osteosarcoma (OS) is the most commonly seen primary malignant bone tumor in children and adolescents. With neo-adjuvant chemotherapy and other treatment regimens developed, event-free survival has increased to 70%, but the prognosis remains poor for those patients with unresectable or metastatic tumors or less responsive tumors. Insulin-like growth factor 2 (IGF2) and its receptor (IGF2R) are known to be over-expressed in several cancers including OS and have roles in regulating cellular growth and proliferation. Although IGF2R is thought to be a tumor suppressor, the research results in different experimental systems are variable. Our recent studies have demonstrated that IGF2R is consistently over-expressed, relative to other known transmembrane receptors on the cell surface across, 4 standard and 10 patient-derived OS cell lines. To further elucidate the effects of IGF2R in OS, the OS cell line SaOS2 and two cell lines which were genetically transformed, as follows; mesenchymal stem cells (MSC) and osteoblasts (OB) with human telomerase reverse transcriptase and SV40Tag (MSC-TS and OB-TS) were transformed with IGF2R by lentiviral transfection. Drug resistant colonies were picked up 21 days after selection to obtain stably transfected SaOS2, MSC-TS, and OB-TS cell lines now named, SaI, MSC-TSI and OB-TSI, respectively. After cloning, the highest and the lowest IGF2R expression clones were selected from these different cell lines via real-time PCR and western blot for further analysis. The comparison between the lines and characterizations are underway. Initial results suggest introduction of IGF2R changes the phenotype by enhancing cellular motility. Further studies will be presented and include the following: 1) cell proliferation assays, 2) motility and migration assays, 3) subcutaneous tumorigenicity assays, 4) expression profiling, and 5) differentiation assays. In the context of osteosarcoma introduction of IGF2R enhances motility, which is unexpected given prior expectations based on the non-signaling nature of this receptor. Citation Format: Huayi Qu. Stable transfection of the osteosarcoma cell line SaOs2, genetically transformed MSCs and osteoblasts with insulin-like growth factor 2 receptor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5035. doi:10.1158/1538-7445.AM2013-5035

Assessment of a fully automated high-throughput DNA extraction method from formalin-fixed, paraffin-embedded tissue for KRAS, and BRAF somatic mutation analysis

Preoperative biopsies or imbedded cytological cells will become more and more a primary source of tissue for molecular diagnostic analyses as a result of novel neo-adjuvant treatment regimens for several cancer types. Furthermore there is a growing need to examine metastatic cancer tissue. Hence, nucleic acids need to be reliably isolated and analyzed from small amounts of formalin-fixed and paraffin-embedded (FFPE) tissue. The limited numbers of (tumor) cells in these samples make high quality and sensitive DNA isolation challenging. Also demands for faster turnaround times are growing. Therefore, we evaluated a fully automated DNA/RNA isolation system and compared this with a manual, classical routine molecular pathology method. We compared the quality of the isolates from both tissue cores and micro-dissection for detection of hotspot mutations in KRAS, BRAF applying hydrolysis probe assays. In addition we determined whether the automated method decreases the hands-on-time and turnaround times in routine molecular pathology workflow.In conclusion, the automated method delivers high quality DNA from both small FFPE tissue cores and micro-dissected tissue material. In comparison to classical methods, less than 50% of starting tissue was sufficient as input for micro-dissection. Turnaround times decreased significantly and 50% less hands-on time was needed.

Toward the Non-surgical Management of Locally Advanced Rectal Cancer

Neoadjuvant short-course radiotherapy and long-course chemoradiation (CRT) reduce local recurrence rates when compared to surgery alone and remain widely accepted as standard of care for patients with locally advanced rectal cancer. However, surgery is not without complications and a non-surgical approach in carefully selected patients warrants evaluation. A pathological complete response to CRT is associated with a significant improvement in survival and it has been suggested that a longer time interval between the completion of CRT and surgery increases tumor downstaging. Intensification of neoadjuvant treatment regimens to increase tumor downstaging has been evaluated in a number of clinical trials and more recently the introduction of neoadjuvant chemotherapy prior to CRT has demonstrated high rates of radiological tumor regression. Careful selection of patients using high-resolution MRI may allow a non-surgical approach in a subgroup of patients achieving a complete response to neoadjuvant therapies after an adequate time period. Clearly this needs prospective evaluation within a clinical trial setting, incorporating modern imaging techniques, and tissue biomarkers to allow accurate prediction and assessment of response.

Neoadjuvant cisplatin for head and neck cancer: Simulation of a novel schedule for improved therapeutic ratio

Current clinical studies support the role of neoadjuvant cisplatin administration prior to curative radiotherapy or radio-chemotherapy for advanced head and neck cancer. Nevertheless, based on locoregional control rates the studies indicate that there is need to redesign cisplatin-based schedules for induction chemotherapy, thus the ideal treatment regimen is yet to be established. While the pharmacokinetics/dynamics of daily cisplatin regimens correspond better with the cell cycle properties of head and neck cancers, weekly regimens are more commonly employed in clinics due to lower complications. Yet, the high rates of adverse events induced by current cisplatin schedules often represent a limiting factor in the overall success of the treatment.The aim of the present paper was to model the pharmacodynamic properties of cisplatin and to simulate and compare various neoadjuvant treatment regimens in regards to their effect on tumour control. Treatment simulation was undertaken on a virtual squamous cell carcinoma of the head and neck, previously grown by computer-based probabilistic methods.The model suggests that a novel cisplatin treatment, given every three days is comparable, in regards to tumour control, with the daily administration and more effective than the weekly regimen in neoadjuvant settings. Endpoints were assessed in terms of cell population regrowth after treatment cessation followed by two weeks of unperturbed growth. Simulation of two weeks low-dose daily cisplatin followed by two weeks ‘free growth’ lead to 15% population regrowth, while weekly high-dose cisplatin over three weeks, followed by two weeks unperturbed growth resulted in 52% tumour cell regrowth. The proposed novel schedule of low-dose third-daily cisplatin gives closer tumour regrowth to daily administration (27% versus 15%) than to the weekly regimen (52%) and also similar cell distribution along the cell cycle as the daily one, suggesting therefore comparable response to subsequent treatment.The advantage of using a third-daily drug regimen would be a decrease in normal tissue complication rates compared to daily administration and possibly an increase in tumour control when compared to the ‘conventional’ weekly cisplatin delivery.

Gastric Cancer: Clinical Aspects, Epidemiology and Molecular Background

The validity and usefulness of the 7th edition of the UICC tumor node metastasis classification in the context of clinical management of gastric cancer are discussed. The most relevant new agent in gastric cancer therapy is trastuzumab for HER2-positive gastric carcinomas. This marks the success of continuous effort of translational research. Trastuzumab, initially applied in palliative settings, is currently being evaluated also in neoadjuvant treatment regimens. Several new meta-analyses support the carcinogenic effect of high salt intake and smoking in the context of Helicobacter pylori infection. Further data have become available on the efficacy of protective agents, acetyl salicylic acid/nonsteroidal anti-inflammatory drugs, and antioxidants. In search for a successful prevention strategy, the focus is on the identification of individuals at high risk who demand screening (testing) and surveillance. Serological assessment of gastric mucosal abnormalities with increased risk for gastric cancer development is extensively studied, and new data are presented from Asia as well as from Europe. New high-throughput techniques combined with bioinformatic vector analysis open the gate to the identification of new potential diagnostic and therapeutic targets. Furthermore, these approaches allow us to elucidate the interplay of bacterial virulence factors and the host's immune response as well as H. pylori-associated alterations of mucosal gene expression.

Guest editor’s introduction: state-of-the-art and current developments in local tumor therapy

Over the last 20 years image-guided tumor therapy experienced a dramatic development. This development is ruled by two facts: (1) continuously improved imaging with respect to tumor detection, therapy monitoring and guidance, as well as post therapy follow-up; and (2) significant advances in the usability and efficacy of minimal-invasive therapeutical techniques and devices. Robust, high resolution and high contrast imaging by ultrasound, computed tomography and magnetic resonance tomography together with the use of contrast agents for the respective imaging modalities is the crucial component of detecting, characterizing, staging, and follow-up in most tumors. Moreover, rapid real-time imaging by ultrasound, projection radiography, CT, and even MRI allow online guidance for the placement of minimal-invasive therapy devices as well as monitoring instant local therapeutic effects. With respect to general oncological and surgical conditions, surgery is the method of choice in the therapy of most tumors. However, overall only 15–30% of patients with malignancies are suitable for a primary surgical therapy with curative intention. Therefore, modern chemotherapies including the wide use of biologicals are considered to be the main columns in adjuvant and neoadjuvant treatment regimens—taking into account that there will be no long-term curative effect in most of the cases. Based on the positive data of surgical resection in patients with limited tumor load and the resulting longterm survival, the concept of local ablative therapy—with and without concomitant chemotherapy—evolved for cases where a surgical treatment is not possible anymore due to medical and/or technical reasons. In general, four basically different ablative local

Improving quality of cancer care through surgical audit

Quality of healthcare is a hot topic and this is especially true for cancer care. New surgical techniques and effective neoadjuvant treatment regimens have significantly improved colorectal cancer outcome. Nevertheless, there seem to be substantial differences in quality of care between European countries, hospitals and doctors. To reduce hospital variation, most initiatives aim on selective referral, encouraging patients to seek care in high-volume hospitals, where cancer care is concentrated to site-specialist multidisciplinary teams. As an alternative to volume-based referral, hospitals and surgeons can also improve their results by learning from their own outcome statistics and those from colleagues treating a similar patient group. European national audit registries in surgical oncology have led to improvements with a greater impact on survival than any of the adjuvant therapies currently under study. Moreover, they offer the possibility to perform research on patient groups that are usually excluded from clinical trials. Nevertheless, between European countries remain differences in outcome and treatment schedules that cannot be easily explained. The European CanCer Organisation (ECCO) has recognised these importances and created the ‘European Registration of Cancer Care’ (EURECCA) framework to develop a European colorectal audit structure. EURECCA will advance future treatment improvements and spread these to all European cancer patients. It provides opportunities to treat elderly and comorbid patients evidence based while it offers an unique insight in social-economical healthcare matters such as the consequences of commercialisation, treatment availability and screening initiatives. As such, ECCO has established the basis for a strong, multidisciplinary audit structure with the commitment to improve cancer care for every European cancer patient.

Quality assurance through outcome registration in colorectal cancer: An ECCO initiative for Europe

In recent years there have been significant improvements in outcome of rectal cancer treatment. Both new surgical techniques as well as effective neoadjuvant treatment regimens have contributed to these improvements. It is key to spread these advances towards every rectal cancer patient and to make sure that not only patients who are treated within the framework of clinical trials may benefit from these advancements. Throughout Europe there have been interesting quality programs that have proved to facilitate the spread of up to date knowledge and skills among medical professionals resulting in improved treatment outcome. Nevertheless, between European countries remain differences in outcome and treatment schedules that cannot be easily explained. The European CanCer Organisation (ECCO) has recognised these importances's and created the 'European Registration of Cancer Care' (EURECCA) framework to develop a European colorectal audit structure. EURECCA will advance future treatment improvements and spread these to all European cancer patients. It provides opportunities to treat elderly and comorbid patients evidence based while it offers an unique insight in social-economical healthcare matters. As such, ECCO has established the basis for a strong, multidisciplinary audit structure with the commitment to improve cancer care for every European cancer patient.

Geparquinto: An interim safety analysis of epirubicin/cyclophosphamide followed by docetaxel with or without bevacizumab as neoadjuvant chemotherapy for primary breast cancer patients

e11519^ Background: The GeparQuinto trial is investigating the incorporation of bevacizumab (B), RAD001 (everolimus) for HER2-negative, and lapatinib for HER2-positive patients (pts) into neoadjuvant treatment regimens. As these targeted agents have not yet been adequately tested in combination with epirubicin (E), cyclophosphamide (C), and docetaxel (T) chemotherapy, a run-in phase of the trial was conducted for safety reasons. Methods: Starting in 11/2007, 62 pts received 4 cycles of E: 90 mg/m2 and C: 600 mg/m2, both on day 1 q day 21 followed by 4 cycles of T: 100 mg/m2, day 1 q day 21. Pts were randomized to receive this chemotherapy alone (EC-T, n=32) or concomitantly with B: 15 mg/kg i.v., day 1 q day 21 (ECB-TB, n=30). Main eligibility criteria for this part of the study were: histologically confirmed, HER2-negative, locally advanced breast cancer (cT3 cN+ and cT4), female, and ≥18 years of age with normal cardiac function (LVEF &gt;55%). This interim toxicity analysis was a prerequisite for opening the main phase of the HER2-negative trial part to also include pts with cT2 tumors. Results: 61 pts received all cycles of EC (n=31 EC-T, n=30 ECB-TB), 1 pt discontinued on investigator's decision, 1 pt discontinued after EC due to disease progression. 18 pts received all cycles of T in each of the EC-T and ECB-TB groups. Reasons for discontinuation of T were adverse events (n=2 EC-T, n=1 ECB-TB) or investigator's decision (n=1 EC-T). 17 pts completed all cycles of B. Statistically significant differences in toxicities were only observed for grade 3–4 leucopenia during EC (40.6%) and ECB (70.0%; p=0.024) and for grade 1–4 [grade 3–4] mucositis during T (52.4% [9.5%]) and TB (100% [36.8%]; p&lt;0.001 [p=0.060]). No statistically significantly different levels of other hematological or non-hematological toxicities were reported between the two arms. Conclusions: Addition of B to EC followed by T is feasible with the only increase in toxicity due to leucopenia and mucositis. Based on these data, the main phase of the trial was opened and has included over 450 pts to date. [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .