Katarina Öhrling

Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.

BACKGROUND As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. PATIENTS AND METHODS Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively registered at 12 Nordic hospitals. RESULTS The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus 10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels. CONCLUSIONS Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.

Mismatch repair protein expression is an independent prognostic factor in sporadic colorectal cancer

Abstract Background. Mismatch repair (MMR) status has been reported as a prognostic and predictive factor in sporadic colorectal cancer (CRC). The purpose of this study was to determine the prognostic and predictive value of MMR protein expression in the adjuvant setting. Patients and methods. The MMR status in the primary tumor was retrospectively assessed on paraffin-embedded formalin-fixed samples from 1 006 patients with sporadic CRC (488 stage II and 518 stage III) using immunohistochemical analysis (IHC) of MLH1 and MSH2 expression. The patients were included in adjuvant Nordic trials between 1991 and 1996 randomly assigned to surgery alone or surgery plus adjuvant 5-fluorouracil (5-FU)-based chemotherapy. Data was censored at 120 months after surgery. Results. One hundred fifty-seven patients (15.6%) showed a loss of MMR protein expression (139 MLH1 negative, 15 MSH2 negative and 3 MLH1 and MSH2 negative) and were classified as MMR protein negative. A normal MMR protein expression was found in 849 patients who were defined as MMR protein positive. MMR protein expression was a significant prognostic marker in the entire study group with a better overall survival (OS) among patients with MMR protein negative tumors compared to patients with MMR protein positive tumors (p=0.01). In a multivariate analysis the MMR protein expression was significantly associated with OS, (HR 0.70 [95% CI, 0.40 to 0.99]; p=0.01). The MMR status did not predict survival benefit from adjuvant 5-FU-based chemotherapy. Conclusion. This study reveals that IHC of MLH1 and MSH2 expression can yield important prognostic information but is not a predictive factor for adjuvant 5-FU-based chemotherapy in sporadic CRC.

HER3 expression in patients with primary colorectal cancer and corresponding lymph node metastases related to clinical outcome

AIM To evaluate the expression and prognostic value of the epidermal growth factor receptor HER3 in patients with primary colorectal cancer (CRC) and corresponding lymph node metastases. PATIENT AND METHODS HER3 expression was analysed immunohistochemically (IHC) in primary tumours and in corresponding lymph node metastases from 236 patients with stage II and III CRC. In 58 primary tumours, fluorescence in situ hybridisation (FISH) detection was performed. RESULTS HER3 was detected at high frequency in the cell membrane. Seventy percent of the primary tumours had a high HER3 expression compared to 75% in the lymph node metastases. HER3 expression in the primary tumour was an independent prognostic factor for overall survival in the entire group of patients (p=0.026) and in the subgroup of patients with colon cancer stage II (p=0.030). A high HER3 expression in the primary tumour was associated with worse clinical outcome. The expression of HER3 was homogenous within the primary tumour (r=0.9, p<0.0001) and correlated with the HER3 expression in corresponding lymph node metastases (r=0.6, p<0.0001). No gene amplification with respect to HER3 was seen in primary tumours using FISH analysis. CONCLUSION A high HER3 expression was found in 70% of the primary CRC tumours and in 75% of the corresponding lymph node metastases. HER3 expression in the tumour was an independent prognostic factor, where a high HER3 expression was associated with worse clinical outcome. There was a correlation in HER3 expression between primary tumour and corresponding lymph node metastases.

A Combined Analysis of Mismatch Repair Status and Thymidylate Synthase Expression in Stage II and III Colon Cancer

UNLABELLED This study in 716 colon cancer patients evaluates if a combined instead of a single marker analysis of mismatch repair (MMR) status and thymidylate synthase (TS) expression could individualize the treatment decision. The results indicate that a combined analysis of MMR status and TS expression can improve prediction of response to adjuvant 5-fluorouracil (5-FU)-based chemotherapy in stage III colon cancer. BACKGROUND Colon cancer with mismatch repair deficiency and low TS expression has been associated with an improved prognosis. Data also indicate that MMR proficient colon cancer with high TS expression has a better response to adjuvant 5-FU-based chemotherapy. This study evaluates if a combined analysis of MMR status and TS expression in colon cancer can add prognostic value and better predict response to adjuvant 5-FU-based chemotherapy. The potential relationship between MMR status and TS expression is also investigated. PATIENTS AND METHODS This study includes a subgroup of 716 patients with colon cancer out of 2224 stage II and stage III colorectal cancer patients enrolled in Nordic trials randomized to surgery alone or surgery plus adjuvant 5-FU-based chemotherapy. After immunohistochemical analysis of tumor MMR status and TS expression the patients were divided into 4 groups. RESULTS There was a nonsignificant difference in overall survival between group 1 (patients with deficient MMR tumors with low TS) and group 4 (patients with proficient MMR tumors expressing high TS). When comparing group 1 and group 4 patients treated with surgery alone a trend to better overall survival was found in group 1, P=.06. In group 4, stage III patients had a significantly improved survival when receiving adjuvant 5-FU-based chemotherapy compared with surgery alone, P=.01. No relationship was found between MMR status and TS expression. CONCLUSIONS A combined instead of a single marker analysis of MMR status and TS expression can improve the prediction of response to 5-FU-based chemotherapy in stage III colon cancer.

Abstract C38: Marker-defined perivascular cells predict prognosis and response to treatment

Background : Studies in experimental models have implied perivascular cells (PC) as regulators of multiple aspects of tumor biology, including tumor growth, metastasis, immune cell activity and response to treatment. However, the extent of inter- and intra-case variability of perivascular cells in clinical samples, and potential of perivascular cells as biomarkers, remain poorly characterized. Methods: We have developed an integrated analytical pipeline to investigate vascular and PC status in clinical samples. The analytical procedure uses double-staining with one endothelial cell marker (CD34) and one of four PC markers; platelet-derived growth factor receptor-alpha and -beta (PDGFR-α, PDGFR-β;), smooth muscle α actin (ASMA) and desmin. Digital image-analyses are subsequently used to quantitate PC-related metrics including intensity of marker expression in perivascular areas, and fraction of marker-covered vessels. The approach has been applied to multiple cohorts of clinically well-annotated tumor collections from three cancer types; colorectal cancer (CRC), ovarian cancer (OC) and renal cell cancer (RCC). Results: Analyses of PC status uncovered previously un- recognized independent and heterogeneous expression of the analyzed perivascular markers on different levels (perivascular cells, vessels and tumors). Notably, expression of perivascular markers was largely independent of vessel size and density in all three cancer types. Comparative analyses across tumor types identified differences including e.g. higher abundance of PDGFR-β; positive perivascular cells in CRC. A comparison of perivascular status in matched primary tumors and distant metastases uncovered a large degree of dis-concordance of most vascular characteristics except perivascular PDGFR-β; (CRC and OC cohorts). Importantly, this finding implies that vascular status in metastases cannot, in general, be predicted by analyses of primary tumors. Efforts to uncover the basis for inter-case variations in PC status of CRC revealed strong associations between tumor PDGFR-β; PC status and both PC status in adjacent normal tissue and BRAF status, but not RAS mutations. These findings suggest both host features and cancer mutations as determinants of PC characteristics. Concerning relationships between PC features and survival, we observed significant associations between high perivascular PDGFR-β; status and shorter survival in OC and RCC. These associations remain significant in multivariate analyses including standard clinicopathological characteristics. Impact on response to chemotherapy (CT) treatment was analyzed in both early stage and metastatic CRC. Ongoing analyses indicate that low perivascular PDGFR-βdefines a sub-group with shorter survival in the CT-treated group. Explorative analyses of a small set of bevacizumab-treated metastatic CRC also demonstrated significantly shorter progression free survival in the subset with low perivascular PDGFR-β expression. Conclusion: Digital-image-analyses-supported quantifications of PC features in three different tumor types have revealed heterogeneous expression of PC markers in a manner independent of vessel density and vessel size. Host characteristics and oncogenic status have been identified as candidate determinants of perivascular PDGFR-β; status in CRC. Notably, perivascular PDGFR-β; was identified as a novel independent predictor of survival in OC, RCC and CRC. Treatment-stratified analyses in CRC also implied perivascular PDGFR-β; as a determinant of benefit of chemotherapy and VEGF-directed anti-angiogenic drugs. Citation Format: Sara corvigno, artur mezheyeuski, Magnus Frodin, Maja Bradic Lindh, Tormod Kyrre Guren, Per Pfeiffer, H. Elin Kure, Tone Ikdahl, Eva Skovlund, Kjell Magne Tveit, Kristian Pietras, Anna Portyanko, Ina Hrynchyk, David Edler, Anca Dragomir, friedrik Ponten, Jan Mulder, Camilla Qvortrup, Maria Hallstrom, Katarina Ohrling, G. Bea A. Wisman, Elisabeth Avall-Lundqvist, Martin Johansson, Ulrika Harmenberg, Hans Nijman, Per Sandstrom, Hanna Dahlstrand, Halfdan Sorbye, Bengt Gimelius, Ate Van Der Zee, Lars Egevad, Arne Ostman. Marker-defined perivascular cells predict prognosis and response to treatment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C38.