Urban Laffer

SMAD7 is a prognostic marker in patients with colorectal cancer

Chromosomal region 18q21 is frequently deleted in colorectal cancer (CRC) and is associated with poor prognosis. Potential tumor suppressor mechanisms altered by 18q21 deletion include mediation of TGFβ signaling by SMADs. Following the definition of SMAD4 deletion as a negative predictive marker for chemotherapy benefit in patients with CRC, we aimed to evaluate the clinical relevance of the deletion of other SMAD genes clustered in this region: SMAD2 and SMAD7 in 264 CRC biopsies from a previous clinical study. In contrast to SMAD2 deletion, for which no clinical relevance was observed, hazard ratios (HR) in a multivariate analysis associated with SMAD7 deletion [overall survival (OS): HR = 0.43, p = 0.0012; disease‐free survival (DFS): HR = 0.50, p = 0.0033] indicated a favorable outcome for these patients. In addition, SMAD7 duplication had a hazardous effect on survival [OS: HR = 2.10, p = 0.020; DFS: HR = 2.06, p = 0.015]. Moreover, the HRs associated with one additional copy of SMAD7 were 1.76, p = 0.00024 [OS] and 1.64, p = 0.00048 [DFS] respectively, showing a graded effect of SMAD7 on patient outcome depending on gene copy number that suggests a dose‐and‐effect basis. Since SMAD7 blocks TGFβ signaling, these data are consistent with the loss of SMAD7 rendering carcinoma cells more sensitive to cell growth arrest/apoptotic effect of TGFβ, whereas gain of SMAD7 function might result in TGFβ resistance, thereby emphasizing the role of TGFβ in tumor suppression.

DCR3 locus is a predictive marker for 5-fluorouracil-based adjuvant chemotherapy in colorectal cancer

Adjuvant chemotherapy reduces the incidence of distant metastasis and increases survival of patients with colorectal cancer. However, predictive markers are needed to define subsets of patients with stage II and III disease that may benefit from adjuvant treatment. A secreted member of the TNF receptor superfamily, the decoy receptor 3 (DcR3), was reported to be amplified in colorectal cancer as a negative regulator of Fas‐mediated apoptosis. We analyzed DcR3 gene copy number and protein expression in a large series of tumors from a randomized multicenter trial of 5‐fluorouracil/mitomycin C (FU/MMC) adjuvant chemotherapy of the Swiss Group for Clinical Cancer Research (SAKK 40/81), using real‐time quantitative PCR and immunohistochemistry on tumor microarrays. Results of gene status and protein expression of DcR3 were correlated with disease‐free and overall survival of patients. We observed amplification of the DcR3 gene in 185/294 (63%) and overexpression of the DcR3 protein in 163/223 (73%) of colorectal tumors. Multivariate analysis showed no prognostic effect of DcR3 gene amplification and protein overexpression. However, adjuvant chemotherapy was significantly more beneficial in patients with normal DcR3 gene copy number than in patients with amplification (DFS: HR 2.84, 95% CI 1.16–6.98, p = 0.02; OS: HR 3.15, 95% CI 1.19–8.32, p = 0.02), whereas DcR3 protein overexpression did not influence the effect of adjuvant chemotherapy (DFS: HR 1.02, 95% CI 0.65–1.60, p = 0.95; OS: HR 0.95, 95% CI 0.61–1.49, p = 0.83). We conclude that amplification of the 20q13 locus is a predictive marker for adjuvant chemotherapy in colorectal cancer.

Combined copy status of 18q21 genes in colorectal cancer shows frequent retention of SMAD7

Deletions of chromosome band 18q21 appear with very high frequency in a variety of carcinomas, especially in colorectal cancer. Potent tumor suppressor genes located in this region encode transforming growth factor β (TGF‐β) signal transducers SMAD2 and SMAD4, and inactivation of either one leads to impaired TGF‐β‐mediated cell growth/apoptosis. Following the assignment of SMAD7 to 18q21, we first refined the SMAD7 gene position within this region by genetically mapping SMAD7 between SMAD2 and SMAD4. Further, to compare the respective frequencies of genetic alterations of these three SMAD genes in colorectal cancer, we undertook a large‐scale evaluation of the copy status of each of these genes on DNA samples from colorectal tumor biopsy material. Among a subset of 233 DNA samples for which data were available for all four genes, SMAD4, SMAD2, and the nearby gene DCC showed high deletion rates (66%, 64%, and 59%, respectively), whereas SMAD7 was deleted in only 48% of the tumors. Unexpectedly, we found some gene duplications; SMAD7 appears to be more frequently amplified (10%) than the three other genes (4–7%). Compiled data for SMAD genes in each tumor show that the most common combination (26% of all the tumors) consists of the simultaneous deletions of SMAD2 and SMAD4 associated with normal diploidy or even duplication of SMAD7. Since SMAD7 normally counteracts SMAD2 and SMAD4 in TGF‐β signaling, we hypothesize that the tumor might not benefit from simultaneous SMAD7 inactivation, thereby exerting selective pressure to retain or even to duplicate the SMAD7 gene.

Prognostic and predictive relevance of DNAM-1, SOCS6 and CADH-7 genes on chromosome 18q in colorectal cancer

Purpose: Chromosome 18q deletion has been described as a negative prognostic factor in colorectal cancer (CRC). The relationship between its supposed negative prognostic influence and the inactivation of candidate tumor suppressors deleted in colorectal cancer, Smad2 and Smad4 has not been definitively established. The aim of the present study was to evaluate the genetic status of three novel putative tumor suppressors, Cadh-7, DNAX accessory molecule-1 (Dnam-1) and suppressor of cytokine signaling (Socs6) on chromosome 18q and to correlate molecular results with patient survival and benefit from adjuvant chemotherapy. Experimental Design: One hundred and ninety representative patient samples from a randomized multicenter study of the Swiss Group for Clinical Cancer Research of 5-fluorouracil (5-FU)- based adjuvant chemotherapy were screened for the gene copy status of Cadh-7, Socs6 and Dnam-1 using real-time quantitative PCR assay, and the molecular results were correlated with clinical outcome. Results: Loss of gene copy number was found in 26.8, 37.9 and 54.2% for Cadh-7, Dnam-1 and Socs6, respectively. Only Dnam-1 deletion was an independent negative prognostic factor for the 5-year overall survival (OS) in the untreated group of patients (hazard ratio = 2.44; p = 0.01). On the contrary, loss of Cadh-7 gene copy number was a favourable prognostic factor for disease-free survival (hazard ratio = 0.43; p = 0.03) and OS (hazard ratio = 0.29; p = 0.01) in the untreated control population. Furthermore and most importantly, patients with Dnam-1 deletion who received adjuvant chemotherapy had a significantly lower risk of death compared to untreated patients with Dnam-1 deletion (hazard ratio = 0.51; p = 0.05), whereas those with Dnam-1 retention did not derive any benefit from 5-FU-based treatment (hazard ratio = 1.68; p = 0.16). Conclusions: Loss of Dnam-1 gene copy number and retention of Cadh-7 might be indicators of worse prognosis, and Dnam-1 deletion might predict for a beneficial response to adjuvant 5-FU-based chemotherapy in patients with CRC. The confirmation of our findings in large independent randomized studies is needed.

Perioperative and adjuvant chemotherapy in colon cancer : results of SAKK trial 40/93

Dear Editor: The liver is a common site for the development of metastases in colorectal cancer. Since spread from the primary cancer site is believed to happen via the portal vein, attempts have been made to apply chemotherapy via this route in the immediate postoperative period in order to eliminate micrometastases in the liver. Following encouraging reports by others, the Swiss Group for Clinical Cancer Research (SAKK) has performed a large trial (SAKK 40/81) comparing perioperative intraportal adjuvant chemotherapy with 5-fluorouracil (5-FU) and mitomycin C with surgery alone (Swiss Group for Clinical Cancer Research, Lancet 1995). In this randomized multicenter trial, there was a significant survival advantage following perioperative intraportal chemotherapy. In 1987, prior to the analysis of SAKK 40/81, the SAKK initiated a subsequent randomized three-arm trial (SAKK 40/87) which compared among perioperative intraportal chemotherapy, the same intravenous chemotherapy and surgery alone. In 1993, after a significant survival benefit had been shown by the use of adjuvant 5-FU in combination with levamisol (Moertel et al., N Engl J Med 1990), the SAKK initiated a new threearm trial (SAKK 40/93), where all patients received perioperative intraportal or intravenous chemotherapy and were then randomised to additionally receive no further treatment (arm A) or 5-FU 450 mg/m iv bolus weekly for 12 months in combination with levamisol (arm B) or 5-FU 600 mg/m iv bolus for 12 months (arm C). Due to the fact that the previously reported adjuvant treatments with 5-FU and levamisol had been restricted to colon cancer and adjuvant radiochemotherapy by then had been established in rectal cancer, in SAKK 40/93, only colon cancer patients have been included. After 3.5 years and the inclusion of 284 patients, the trial had to be closed because the first results of SAKK 40/87 became available that failed to confirm an advantage of perioperative intraportal chemotherapy over surgery only (Laffer et al., Int J Colorectal Dis epub August 8, 2008). In this letter, we would like to report the results of this prematurely terminated trial, SAKK 40/93. Between September 1993 and May 1997, 284 [one withdrew consent for his data, so only 283 patients were evaluable] out of 1,500 planed patients have been randomized from 24 institutions in Switzerland, Germany, and Luxembourg. Patient eligibility criteria included stages II (pT 3/4, N0, M0) and III (any pT, pN+, M0), potentially curative resection, no previous radioor chemotherapy, normal organ function, and absence of severe concomitant disease. Int J Colorectal Dis (2009) 24:351–352 DOI 10.1007/s00384-008-0577-y

Brusterhaltende Therapie beim Mammakarzinom— Analyse von über 800 in der Region Basel behandelten Patientinnen

ZusammenfassungGrundlagenFast ein Jahrhundert lang stellte die radikale Amputation der Brust das chirurgische Standardverfahren beim Mammakarzinom aller Stadien dar. Weniger mutilierende Verfahren mußten vorerst ihre prognostische Gleichwertigkeit im Rahmen kontrollierter klinischer Studien nachweisen.MethodikNach einem standardisierten Behandlungsprotokoll (Chirurgie, Radiotherapie und Nachkontrolle) wurden in der Region Basel seit 1977 mehr als 1500 Patientinnen mit Mammakarzinom brusterhaltend behandelt. Die vorliegende Arbeit analysiert 832 Frauen, die im Zeitraum von 1977 bis 1990 behandelt und bis 1991 nachkontrolliert wurden.ErgebnisseBei einer medianen Beobachtungszeit von 3,4 Jahren beträgt das geschätzte Gesamtüberleben 91% nach 5 Jahren und 77% nach 10 Jahren. 94% der brusterhaltend behandelten Frauen sind nach 5 Jahren und 86% nach 10 Jahren lokal rezidivfrei. Die lokale Rezidivfreiheit beträgt 97% bei nodal negativen und 89% bei nodal positiven (p=.00008), sowie 96% bei pT1 und 91% bei pT2-Tumoren (p=.08328). Die R0-Resektion beeinflußt in unserem Kollektiv das lokalrezidivfreie Überleben signifikant.SchlußfolgerungenDie brusterhaltende Behandlung beim Mammakarzinom ist im Vergleich zur radikalen Mastektomie prognostisch ein gleichwertiges Verfahren, wenn die Therapie nach dem heute gültigen Standard erfolgt, welcher eine lokale R0-Resektion und Axilladissektion, die obligate, komplementäre Radiotherapie in ausreichender Dosierung und die konsequente Nachkontrolle umfaßt. Abweichungen von diesem Standard-Konzept sollten nur im Rahmen kontrollierter, randomisierter Studien evaluiert werden.SummaryBackgroundDuring almost one century, radical mastectomy has been the treatment of choice for breast cancer patients. Controlled and randomized trials had to prove the equivalence of less radical procedures.MethodsAccording to a standardized treatment protocol, more than 1500 breast cancer patients have been treated conservatively since 1977. This analysis includes 832 treatments carried out between 1977 and 1990 and observed until 1991.ResultsAfter a median follow-up time of 3.4 years, an overall 5-year survival of 91% and a 10-year survival rate of 77% was estimated. At 5 years, 94% of the women remain locally recurrence free and 86% at 10 years respectively. Freedom of local recurrence totals to 97% in patients without (pN0) and to 89% in patients with tumor involvement of the axillary lymph nodes (pN+) (p=.00008), as well as to 96% for pT1 and 91% for pT2-tumors (p=.08328). The local R0-resection significantly influences local recurrence free survival.ConclusionsCompared to radical mastectomies, breast conserving therapy including radical tumorectomy and axillary dissection, complementary radiotherapy and follow-up, has proven to be an equivalent therapeutical alternative for breast cancer patients. Changes in the standard treatment should only be evaluated in randomized trials.

102. Stellenwert der subtotalen Magenresektion beim Magencarcinom

SummaryThe controversy about the extent of resection of gastric cancer has been lasting for decennies. The extreme viewpoints may have become less divergent recently although controlled data are still lacking. As gastrectomy has generally become safer, a somewhat broader indication for it is justified. Subtotal resection is still justified for cancer of the antrum of the intestinal type (Laurén-classification) without evidently involved distant nodes and as long as a clear margin can be expected, furthermore in some advanced disease situations and finally in high risk patients, especially with severe cardiopulmonary handicaps.ZusammenfassungIn der jahrzehntealten Kontroverse um das Resektionsausmass bei Magencarcinom nähern sich in neuerer Zeit die Standpunkte der „Konservativen” und der „Radikalen” etwas. Dies, obwohl Daten kontrollierter Studien noch ausstehen. Eine vorsichtige Erweiterung der Indikation zur Gastrektomie ist deshalb gegeben, weil diese in den vergangenen Jahren allgemein sicherer geworden ist. Beim Antrumcarcinom des intestinalen Typs ohne offensichtlichen Befall tumorferner Lymphknoten und bei gesundem Absetzungsrand am Magen, bei gewissen fortgeschrittenen Tumorstadien und bei ausgesprochenen, vor allem kardiopulmonalen Risikopatienten hat die subtotale Resektion weiterhin ihren Platz.

87. Beeinflussen pathologisch-anatomische Parameter die Rezidivhäufigkeit nach konservativer Mamma-Chirurgie und Strahlentherapie?

Summary201 breast cancer patients (pT1–2, pN0–1) were treated with conservative breast surgery and radiation therapy. 28 (13.9%) treatment failures, — 13 (6.5%) local recurrences, 4 (2.0%) axillary — and 11 (5.5%) distant metastases —, were found overall after a mean follow-up of 47 months. The differences between pT2 and pT1-tumors (20.6% vs 10.5%) and nodal positive versus nodal negative patients (28.1% vs 6.8%) are statisticallv sienificant. No differences were seen regarding histnlnuical features.Zusammenfassung201 Patientinnen mit Mamma-Ca (pT1–2, pN0–1) wurden mit konservativer Brustchirurgie und postoperativer Strahlentherapie prospektiv behandelt. Nach einer mittleren Beobachtungszeit von 47 Monaten fanden sich insgesamt 28 (13,9%) Therapieversager, — 13 (6,5 %) Lokalrezidive, 4 ( 2,0%) axilläre Rezidive und 11 (5,5%) Fernmetastasen. Als statistisch signifikante Risikogruppen fanden wir die pT2-Tumoren (20,6% vs 10,5%) und tumorbefallene Lymphknoten (28,1 % vs 6,8%). Keine signifikanten Unterschiede wurden bezüglich Morphologie und Differenzierungsgrad entdeckt.