Irene Kührer

TP53 genotype but not p53 immunohistochemical result predicts response to preoperative short-term radiotherapy in rectal cancer.

ObjectiveTo evaluate and compare the predictive power of p53 gene analysis versus p53 immunohistochemical staining in terms of response to preoperative short-term radiotherapy using 25 Gy in operable rectal cancer. Summary Background DataRecent studies show that p53 may be a determinant of radiosensitivity being required for induction of apoptosis in case of radiation-induced DNA damage. MethodsPreirradiation biopsy samples of 64 patients with rectal carcinoma were analyzed. Genetic alterations of the p53 gene were detected by complete direct sequencing of exons 2 to 10. Expression of the nuclear phosphoprotein p53 was assessed by immunohistochemical staining. Results were correlated with histopathology of resected specimens and follow-up data, respectively. ResultsMutations of the p53 gene were present in 45% of tumors. Patients with a normal p53 gene had a significant survival advantage. Comparing pre- and postradiotherapy T category, a reduction was seen in patients with normal p53 genotype only. A mutant p53 genotype was highly specific in indicating stable disease concerning T category after irradiation. Protein overexpression was detected in 61%. Overexpression of the p53 protein was not related to survival or response. The concordance between immunohistochemistry and sequencing was only 0.51. ConclusionsThe authors show that downstaging after short-term radiation may occur but is seen in tumors with normal p53 gene only. Moreover, p53 genotype but not p53 immunohistochemistry is predictive for response to preoperative short-term radiotherapy and patient survival.

Growing clinical evidence for the interaction of the p53 genotype and response to induction chemotherapy in advanced non–small cell lung cancer

OBJECTIVE The objective of this study is to establish clinical evidence that the p53 genotype can serve as a predictive marker for response to cisplatin-based induction therapy. METHODS Patients with advanced non-small cell lung cancer who had received neoadjuvant chemotherapy in the context of a prospective phase II trial were analyzed for the p53 genotype of their tumors. Response to induction therapy was then correlated to the p53 genotype as assessed by complete direct DNA sequencing. Patients had received 3 cycles of cisplatin and etoposide, and 1 cycle of simultaneous radiochemotherapy. All 3 treatment components mediate their cytotoxic effect through induction of apoptosis, which is suggested to require an intact p53 gene. In addition, the results from a previously published hypothesis-finding study are updated to demonstrate the consistency of clinical results and summarize currently available clinical evidence. RESULTS In the phase II trial, 35 patients underwent resection after induction chemotherapy, allowing a pathohistologic response assessment. The presence of a mutant p53 genotype was highly indicative of resistance to induction chemotherapy (P < .002). The sensitivity of a mutant p53 genotype to identify nonresponders was 94% (71.3-99.9 confidence interval). A normal p53 gene was significantly associated with radical resection (P < .004) and survival advantage (P = .02). CONCLUSION This is the second clinical evaluation demonstrating a significant relation between p53 genotype and response to induction therapy in non-small cell lung cancer. We conclude that the p53 genotype should be evaluated as a predictive marker for response to induction therapy in prospective randomized protocols.

Risk factors for bilateral testicular germ cell tumors. Does heredity play a role

Twenty‐three bilateral testicular germ cell tumors (four synchronous and 19 sequential tumors) were investigated for potential risk factors. The incidence of maldescensus testis was not found to be higher than in patients with unilateral disease. The histologic findings of the first tumor did not have any effect on the incidence of the second tumor. In 21 patients (four synchronous and 17 sequential tumors), histocompatibility antigens (HLA) were determined; HLA‐B14 was increased significantly in the sequential tumor group. Tendencies toward an increase of HLA‐DR5 and HLA‐DR7 also were found. The HLA‐DR1, HLA‐DR3, and HLA‐DR4 showed a tendency toward a decreased frequency. Therefore genetic factors might be important in the development of sequential bilateral testicular cancers.

The biomarker TP53 divides patients with neoadjuvantly treated esophageal cancer into 2 subgroups with markedly different outcomes. A p53 Research Group study

BACKGROUND Fluorouracil and cisplatin have been used most frequently as neoadjuvant therapy for esophageal cancer. Both drugs are believed to act via a p53-dependent apoptosis pathway. The TP53 gene is frequently mutated in esophageal cancer. OBJECTIVE To test the value of TP53 as a biomarker prognosing outcome in patients with neoadjuvantly treated esophageal cancer. PATIENTS AND METHODS The investigation included 36 patients with primary operable esophageal cancer who were treated neoadjuvantly with cisplatin and fluorouracil. The TP53 genotype was assessed from paraffin-embedded diagnostic tumor biopsies using a standardized gene-specific TP53 sequencing protocol (mark53 kit; mark53 Ltd, Vienna, Austria). RESULTS Mutations in the TP53 gene were present in 50% of tumors. Two-year overall survival rates were 55.6% in patients with a normal TP53 marker status, compared with 16.7% in those with a mutant TP53 gene. In patients with normal TP53, neoadjuvant treatment resulted in significant advantages in terms of tumor-associated survival (P=.0049) and overall survival (P=.0304) compared with those with mutant TP53. The median tumor-associated survival was 34.2 months for patients with normal TP53, compared with 8.9 months for those with mutant TP53. The latter had a 3-fold higher risk of dying (hazard ratio, 3.01; 95% confidence interval, 1.359-6.86). CONCLUSIONS The biomarker TP53 divides esophageal cancer patients into 2 categories with markedly different outcomes: patients with a normal TP53 marker status may experience notable benefits from neoadjuvant chemotherapy with cisplatin/fluorouracil, whereas those with a mutant TP53 marker status appear to be at risk for lack of response.

TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients.

We investigated the hypothesis that the varying treatment efficacy of adjuvant 5-fluorouracil (5FU) in stage III colon cancer is linked to the TP53 mutational status. ABCSG-90 was a prospective randomized trial in which effect of adjuvant 5FU was studied in stage III colon cancer patients. Tumor material of 70% of these patients (389/572) was available for analysis of the biomarker TP53 using a TP53-gene-specific Sanger sequencing protocol. Median follow-up was 88 months. TP53 mutation frequency was 33%. A significant interaction between TP53 status, outcomes and nodal category was found (P = 0.0095). In the N1 category, TP53 wildtype patients had significantly better overall survival than TP53 mutated (81.0% vs. 62.0% overall survival at 5 years; HR = 2.131; 95% CI: 1.344–3.378; P = 0.0010). In the N2 category, the TP53 status did not affect survival (P = 0.4992). In TP53 wildtype patients, the prognostic significance of N category was significantly enhanced (P = 0.0002). In TP53 mutated patients, survival curves of N1 and N2 patients overlapped and nodal category was no longer prognostic. The biomarker TP53 independently predicted effect of adjuvant 5FU in N1 colon cancer patients. TP53 was not predictive in N2 patients, in whom 5FU is known to have no effect.

Carboplatin-Monotherapie bei Seminomen im Stadium I

Zusammenfassung39 Patienten mit einem reinen Seminom des Hodens im Stadium I erhielten eine adjuvante Chemotherapie. Diese wurde als Carboplatin-Monotherapie (400 mg/m2) in 2 ambulant verteilten Infusionen in 4wöchigem Abstand, durchgeführt. Die durchschnittliche Beobachtungszeit beträgt 20 Monate. Alle Patienten sind in Volremission, es trat aber bei einem Patienten ein Relaps auf, der mittels Polychemotherapie (4 Zyklen BEP) behandelt wurde. Wesentliche und gravierende Nebenwirkungen der Therapie bestanden nicht.Summary39 patients with histologically confirmed pure seminoma of the testis (stage I) were treated with single agent carboplatin. 2 cycles of carboplatin 400 mg/m2 were infused i.v. over 1 hour within 4 weeks on an out-patient basis. After a median follow-up of 20 months all patients are in complete remission. I patient relapsed. This patient was treated with 4 cycles of BEP and achieved complete remission. The chemotherapy with carboplatin was well tolerated with no serious side-effects.

Turning the tables on surgical oncology: the • Pancho trial unplugged

ZusammenfassungGRUNDLAGEN: Die neoadjuvante Therapie bringt bei Patienten mit Ösophaguskarzinom keine eindeutige Verbesserung des Gesamtüberlebens. Einen deutlichen Überlebensvorteil zeigen allerdings Patienten mit kompletter pathologischer Remission. METHODIK: Dieses Review fasst mehrere retrospektive klinische Studien zusammen, die p53 als potentiellen prädiktiven Marker für das Ansprechen auf Chemotherapie ausweisen. Um den Zusammenhang zwischen p53 und Chemotherapieansprechen auf hohem Evidenzniveau (Level I) zu untersuchen, wurde die • Pancho Studie initiiert. ERGEBNISSE: In der • Pancho Studie wird erstmals – prospektiv randomisiert – untersucht, ob eine Interaktion zwischen p53 und dem Ansprechen auf Chemotherapie besteht. In der vorliegenden Arbeit berichten wir über das • Pancho Studiendesign (Wechselwirkungsdesign), die Fallzahlberechnung, die Studienendpunkte und den Rekrutierungsstatus dieser Multizenter-Studie nach einem Jahr Laufzeit. SCHLUSSFOLGERUNGEN: Die • Pancho Studie testet erstmals in einem geeigneten Design, ob der p53 Genotyp ein valider Marker ist, um wirksame Chemotherapien zu selektieren und damit eine individuelle Krebstherapie zu ermöglichen.SummaryBACKGROUND: In esophageal cancer patients neoadjuvant therapy failed to demonstrate a clear benefit in overall survival. A significant advantage can be seen in patients with complete pathological response. METHODS: This review summarizes the results of retrospective clinical studies suggesting p53 as a predictive marker for chemotherapy response. To advance these findings to level of evidence I the • Pancho trial was initiated. RESULTS: The • Pancho trial represents the first prospective randomized trial testing the interaction between p53 and response to chemotherapy. The special design of the • Pancho trial (interaction design), the sample size considerations, the study endpoints and the 12 months accrual of this nationwide study are reported. CONCLUSIONS: The • Pancho trial evaluates for the first time whether the p53 genotype is qualified to select patients who will respond to certain chemotherapy and to guide cancer therapy.

PART 1 – p53 adapted preoperative radiotherapy for T2 and T3 rectal cancer. A study of the p53 research group

ZusammenfassungGRUNDLAGEN: Die Wirkung der Strahlentherapie beruht auf DNA-Schädigung, wobei das p53 Gen eine wichtige Rolle bei der Induktion des Zelltodes spielt. p53 ist in Tumoren häufig inaktiviert, was eine DNA-Schaden-Induzierte Apoptose verhindert. METHODIK: In der vorliegenden Arbeit werden Aspekte zur Durchführung einer prädiktiven Markerstudie erörtert. Diese Studie ist zur klinischen Umsetzung einer auf p53 als prädiktivem Marker basierenden, individualisierten Krebstherapie erforderlich. ERGEBNISSE: PART 1 ist eine akademische, prospektiv randomisierte klinische Studie, welche sich erstmals mit markeradaptierter Strahlentherapie befasst. Patienten mit Rektumkarzinom Stadium T2/T3, welche für eine präoperative Strahlentherapie geeignet sind, werden in die Studie eingebracht. Das Studiendesign erlaubt die Untersuchung, ob der p53-Genotyp ein valider Marker zur Therapiewahl ist. Eine verlängerte Wartezeit zwischen Bestrahlung und Operation soll die Strahlenwirkung auf den Tumor sichtbar machen. SCHLUSSFOLGERUNGEN: Die Markerstudie ist ausgelegt um auf hohem Evidenzniveau (Level 1) zu zeigen, dass der p53 Genotyp und der Zeitpunkt der Operation prognostische Faktoren sind. Weiters soll der prädiktive Wert des p53 Genotyps als Selektionsmarker für Patienten zur Strahlentherapie evaluiert werden.SummaryBACKGROUND: Cell killing by ionizing radiation is triggered by DNA-damage involving the p53 gene as major player in cell death induction. p53 is frequently inactivated in cancer which prevents apoptosis after extensive DNA-damage. METHOD: We summarize considerations to conduct a predictive marker trial mandatory before clinical application of p53 for individualized therapy. RESULTS: PART 1 is an academic driven prospective randomized trial addressing individualized, marker adapted radiation therapy for the first time. Patients suffering from T2/T3 rectal cancer appropriate for preoperative radiation will be included. The design qualifies the trial to determine the relevance of p53 gene mutation as a marker guiding the choice of therapy. A delay of surgery after radiation is implemented to improve detection of the radiation effect on the tumor. CONCLUSIONS: This predictive marker trial intends to provide the level of evidence I that the p53 genotype and time of surgery are prognostic markers. Furthermore should the predictive value of p53 genotype be evaluated as marker to select patients for preoperative radiation therapy.

TP53 is not a prognostic marker-clinical consequences of a generally disregarded fact: How to bring a biomarker to clinical use

Technological progress within the last 15–20 years has significantly increased our knowledge about the molecular basis of cancer development, tumor progression, and treatment response. As a consequence, a vast number of biomarkers have been proposed, but only a small fraction of them have found their way into clinical use. The aim of this paper is to describe the specific demands a clinically relevant biomarker should meet and how biomarkers can be tested stepwise. We name this procedure the “triple‐R principle”: robustness, reproducibility, and relevance. The usefulness of this principle is illustrated with the marker TP53. Since it is mutated in a broad spectrum of cancer entities, TP53 can be considered a very promising marker. Thus, TP53 has been studied in detail but there is still no explicit consensus about its clinical value. By considering our own experience and reviewing the literature, we demonstrate that a major problem of current biomarker research is disregard of whether the biomarker is prognostic or predictive. As an example, it is demonstrated that TP53 is not a prognostic marker, but rather a purely predictive marker, and that disregard of this fact has made this otherwise strong biomarker appear as not being clinically useful so far.

Surgical management of cancer of the colon

ZusammenfassungGRUNDLAGEN: Die Inzidenz des Kolonkarzinoms hat in den letzten Jahren zugenommen. Ebenso haben sich in den letzten Jahren neue diagnostische und therapeutische Methoden entwickelt. METHODIK: Übersicht zum Management des Kolonkarzinoms. ERGEBNISSE: Die chirurgische Therapie des Kolonkarzinoms bietet bei einer R0-Resektion die einzige Heilungschance. Im fortgeschrittenen Tumorstadium kann die Prognose durch eine Chemotherapie verbessert werden, die Effizienz neoadjuvanter Maßnahmen wurde bisher beim Kolonkarzinom nicht nachgewiesen. Unter dem Gesichtspunkt der intramuralen mikroskopischen Tumorwachstumsausbreitung ist bei den zirkulär wachsenden Kolonkarzinomen ein Sicherheitsabstand von 5 cm ausreichend. Das Ausmaß der Darmresektion wird durch die Resektion der versorgenden Gefäße und das hierdurch definierte Lymphabflussgebiet vorgegeben. Die Prognose des Kolonkarzinoms hängt in erster Linie vom Stadium bei der Diagnosestellung und von der Erfahrung des onkologischen Chirurgen ab. Wichtig für die Prognose sind besonders T-, N- und M-Stadium und das Grading. Die Bedeutung molekularer Marker des Tumorgewebes und des Serums werden derzeit noch diskutiert. SCHLUSSFOLGERUNGEN: Bei radikaler chirurgische Therapie kann auch beim Kolonkarzinom ein gutes onkologisches Ergebnis erzielt werden.SummaryBACKGROUND: The incidence of colon carcinoma has increased during the last years, but novel diagnostic tools have also been developed. METHODS: Review on colon carcinoma. RESULTS: The only chance in the cure of colonic carcinoma is achieved by radical surgery (R0-resection). Prognosis of advanced carcinomas may improve with chemotherapy, although the efficiency of neoadjuvant designs has not yet been confirmed. Taking into account the intramural microscopic tumor spread, a safety margin of 5 cm seems to be sufficient for circumferentially growing tumors. The extent of colonic resection is defined by the resection of the blood vessels as well as its lymphovascular excision. Prognosis of colonic cancer depends on the tumor stage at the time of diagnosis as well as on the experience of the operating surgeon. In addition, TNM stage and tumor grading are very important factors, too, regarding prognosis. The impact of molecular markers of tumor tissue and serum are still being discussed. CONCLUSIONS: Radical surgical resection can yield good results in the treatment of colon carcinoma.