Breast cancer in female carriers of ATM gen alterations: outcome of adjuvant radiotherapy

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Aus der Abteilung Strahlentherapie und spezielle Onkologie Direktor: Professor Dr. med. J.-H. Karstens

Medizinische Hochschule Hannover

Breast cancer in female carriers of ATM gen alterations: outcome of adjuvant radiotherapy

Dissertation

Zur Erlangung des Doktorgrades der Medizin In der Medizinischen Hochschule Hannover

Vorgelegt von Esther John

aus Berlin

Hannover, 2005

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Angenommen vom Senat der Medizinischen Hochschule Hannover am 13.02.2007

Gedruckt mit Genehmigung der Medizinischen Hochschule Hannover

Präsident: Prof. Dr. Dieter Bitter-Suermann Betreuer: PD Dr. Michael Bremer

Referent: Prof. Dr. Hans-Joachim Lück Korreferent: Prof. Dr. Matthias Eder

Tag der mündlichen Prüfung: 13.02.2007

Promotionsausschussmitglieder:

Prof. Dr. Johann Karstens Prof. Dr. Geerd-J. Meyer Prof. Dr. Wolfram Knapp

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Inhaltsverzeichnis

Sonderdruck der Originalarbeit : Andreas Meyer, Esther John, Thilo Dörk, Christof Sohn, Johann H. Karstens, Michael Bremer

„ Breast cancer in female carriers of ATM gene alterations: outcome of adjuvant radiotherapy ” Radiother Oncol 2004; 72: 319-323

Zusammenfassung

Publikationen

Lebenslauf

Erklärung nach § 2 Abs. 2 Nrn. 5 und 6

Danksagung

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Breast cancer in female carriers of ATM gene alterations:

outcome of adjuvant radiotherapy

Andreas Meyer

^a,1

, Esther John

^a,1

, Thilo Do¨rk

^b

, Christof Sohn

^b

, Johann H. Karstens

^a

, Michael Bremer

^a,

*

^,2

aDepartment of Radiation Oncology, Medical School Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany

bDepartment of Obstetrics and Gynecology, Medical School Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany Received 2 June 2004; received in revised form 26 June 2004; accepted 2 July 2004

Available online 22 July 2004

Abstract

Background and purpose: We analyzed the clinical outcome of breast cancer patients carrying sequence variants in the ATM gene who received postoperative radiotherapy after breast conservative surgery to test whether an increased cellular radiosensitivity may translate into enhanced tumor cell killing and thereby result in an improvement of the therapeutic ratio.

Patients and methods: We investigated a cohort of 138 breast cancer patients who received adjuvant radiotherapy following breast conservative surgery for T1 and T2 tumors. Genomic DNA samples of these patients had previously been scanned for mutations in the ATM gene. Follow-up data were available in 135 patients, with a median follow-up of 87 months. Local relapse-free, metastasis-free and overall survival were compared between carriers and non-carriers of a sequence variant in the ATM gene.

Results: Twenty patients were found to carry a sequence variant in the ATM gene (truncating, 7; missense, 13). The actuarial 7-year local relapse-free survival of carriers vs. non-carriers were 88 vs. 94% (PZ0.34). Actuarial metastasis-free and overall survival after 7 years were 63 vs. 85% (PZ0.01) and 73 vs. 89% (PZ0.055), respectively. However, the presence of a variant in the ATM gene did not remain a significant discriminator for metastasis-free survival in a multivariate Cox regression analysis (PZ0.068).

Conclusions: Our results do not support the hypothesis that breast cancer patients carrying a sequence variant in the ATM gene differentially benefit from postoperative radiotherapy. These findings have to be verified using larger number of cases to clarify the clinical consequences of sequence variants in the ATM gene.

Keywords:AT heterozygosity; Breast cancer; Adjuvant radiotherapy; Treatment outcome

1. Introduction

Dysfunction of ATM, the gene mutated in ataxia- telangiectasia (A-T), causes hypersensitivity to ionizing radiation, defective cell cycle control and genomic instability due to the impaired repair of DNA double strand breaks [8,10,14]. In A-T heterozygotes there is evidence for at least some effect of the mutated gene manifesting as intermediate radiosensitivity in cell culture[6,11] and an increased risk

of developing cancer, particularly female breast cancer [2,4,15,18].

While excessive toxicity has not been observed among A-T heterozygous patients who were treated by radiotherapy for malignancies [1,21] their increased cellular radiosensitivity may render tumor cells more susceptible to the cell killing effect of ionizing radiation potentially leading to an enhanced therapeutic ratio [7,17]. Recently, first evidence has been provided of a differential benefit of adjuvant radiotherapy on disease-free survival in carriers of ATM gene mutations with early breast cancer [17]. We therefore analyzed the clinical outcome of a hospital-based cohort of breast cancer patients carrying variants in the ATM gene compared to non-carriers following postoperative adjuvant radiotherapy.

doi:10.1016/j.radonc.2004.07.010

Radiotherapy and Oncology 72 (2004) 319–323

www.elsevier.com/locate/radonline

* Corresponding author.

1Equally contributing authors.

2Presented at the 8th International Wolfsberg Meeting 2004 in Ermatingen, Switzerland.

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2. Materials and methods

2.1. Patients and molecular genetic analysis

Between 1995 and 2002 genomic DNA samples had been collected from a large unselected hospital-based series of 1000 breast cancer patients receiving radiotherapy at our department[5]. Verbal and written informed consent was obtained from all participating patients before blood sample collection, and the study has been approved by the local ethical committee.

Mutation screening of genomic DNA samples has been described in detail elsewhere[5]. The whole ATM coding sequence had been analyzed from a core group of 192 consecutive breast cancer patients. One hundred and thirty four of these patients had received adjuvant radiotherapy following breast conservative surgery for T1 and T2 tumors.

Additionally, four patients from the whole series who had subsequently been identified by screening to carry a truncating mutation in the ATM gene (splicing mutation 1066-6T/G, frameshift deletion 3801delG,Table 1) were included into our present follow-up study as well. Three patients were excluded due to missing follow-up data, thus finally 135 patients were included in this analysis. Bilateral breast cancer was diagnosed in twelve patients including 4 patients with synchronous bilateral disease.

2.2. Radiotherapy and follow-up

Postoperative radiotherapy was delivered with 6 MV photons (10 MV photons in 2 patients) using opposed tangential portals. Whole breast dose ranged from 45 to 54 Gy (median dose: 54 Gy, single dose 1.7–1.8 Gy) followed by an electron boost (10 Gy) to the tumor bed in 5 patients resulting in total doses equal to or below 60 Gy.

Clinical data were obtained retrospectively by evaluation of all patients’ records of radiation therapy including

the radiation oncologist’s records on follow-up visits 6 and 12 weeks postirradiation. Follow-up data were in part provided by the regional cancer follow-up registry. All patients being alive at the time of data analysis were contacted by phone. Additional information was obtained from the following gynecologist or general practitioner. An analysis of acute and late radiation related toxicity in our A-T heterozygous breast cancer patients has been reported in detail elsewhere[1].

2.3. Statistical analysis

Statistical analysis was performed using a commercially available software package (SPSS win 11.5). Tests for differences between carriers and non-carriers were performed using chi-square tests for categorical factors (two to three categories) and the one-way ANOVA test for continuous variables (age, dose, follow-up). All events were measured from the time of diagnosis. The following end points were analyzed and compared between carriers and non-carriers: local relapse-free survival; metastasis-free survival, with metastases defined as distant failure (beyond local or nodal failure); and overall survival, with death from any cause defined as event. The actuarial rates were calculated by the product-limit method of Kaplan and Meier, and the differences were compared using the log- rank test. A multivariate step-wise Cox proportional regression analysis was used to identify significant prognostic factors for the clinical end points analyzed. The following parameters were included in the analysis: age, total dose delivered, T-stage, nodal status, grading, hormonal receptor status, use of adjuvant chemo- or endocrine therapy and presence or absence of a variant in the ATM gene.

3. Results

Our study cohort consisted of 135 breast cancer patients who were classified as (i) carriers of an ATM truncating mutation or potentially relevant ATM missense variant, (ii) carriers of a frequent amino acid polymorphism at aspartate codon 1853, or (iii) non-carriers. Because of the intrinsic difficulties to classify ATM missense variants, an ATM missense mutation had to match one of the following criteria to qualify for the first patient group (subsequently referred to as carriers): a proven impairment of ATM function in vitro [13], an association with increased cellular radiosensitivity [6,11,13], or an association with breast cancer [3,5,9,19,20]. Twenty patients were included as carriers of a sequence alteration in the ATM gene that qualified for the first group: 7 patients carried A-T causing truncating mutations and 13 patients carried possibly relevant missense substitutions. Two patients were identified to carry more than one variant in the ATM gene (Table 1).

Relevant prognostic factors (T-stage, nodal status, grading, hormonal receptor status) and the use of adjuvant

Table 1

Mutations and sequence variants of the ATM gene identified in 20 breast cancer patients with postoperative radiotherapy following breast conservative therapy

ATM gene alteration No. of patients References Truncating

1066-6TOG 5 [2,4,5]

3801delG 2 [12,15]

Missense

S49C 2 [3]

S707P 3 [5,19]

P1054R 3 [6,9]

P1054R-F858L 1 [6]

P1054R/L1420F 1 [9,20]

L1420F 2 [20]

S2592C 1 [5,13]

Citations refer to published evidence for a functional or clinical relevance of the respective ATM gene alteration for ataxia-telangiectasia and/or breast cancer.

A. Meyer et al. / Radiotherapy and Oncology 72 (2004) 319–323 320

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therapies (chemotherapy, endocrine therapy) were not found to be significantly different between carriers and non-carriers (Table 2).

During a median follow-up of 87 months local recur- rences occurred in 8 patients (carriers, 2; non-carriers, 6) and metastases occurred in 22 patients (carriers, 7; non- carriers, 15). Eighteen patients had deceased with all but one death related to breast cancer. The actuarial 7-year local relapse-free survival was 88% in carriers versus 94% in non- carriers (PZ0.34; Fig. 1). Actuarial metastasis-free and overall survival at 7 years were 63 vs. 85% (PZ0.01,Fig. 2) and 73 vs. 89% (PZ0.055), respectively. Actuarial survival rates including the corresponding odds ratios are summar- ized inTable 3. However, in a multivariate step-wise Cox regression analysis the presence of a sequence variant in the ATM gene did not remain an independent variable for prediction of metastasis-free survival (PZ0.068).

A subgroup analysis to determine the effects of particular truncating or missense variants could not be performed due to the small number of patients within each group. We could investigate, however, the effect of a common ATM amino acid polymorphism D1853N (G5557A) which was present in 41 patients (homozygous, nZ4; heterozygous, nZ37)

from the non-carrier group. When we stratified the non- carrier group by D1853N status, no differences in survival rates were observed between the 41 D1853N carriers and the 74 remaining non-carriers.

4. Discussion

It has been postulated that the constitutive presence of an ATM gene mutation may sensitize tumor cells because of their limited capacity to repair radiation-induced DNA damage and thereby possibly enhances the therapeutic ratio of radiotherapy in A-T heterozygous cancer patients due to

Fig. 1. Actuarial local relapse-free survival of carriers (nZ20; broken line) vs. non-carriers (nZ115; solid line) of variants in the ATM gene, calculated by Kaplan–Meier (log-rank test,PZ0.34).

Fig. 2. Actuarial metastasis-free survival of carriers (nZ20; broken line) vs.

non-carriers (nZ115; solid line) of variants in the ATM gene calculated by Kaplan–Meier (log-rank test,PZ0.01).

Table 2

Patients characteristics of carriers vs. non-carriers of variants in the ATM gene

Carriers (nZ20)

Non-carriers (nZ115)

P-value

Age (years) 0.47

Median (range) 58.5 (35–73) 58.0 (27–85)

Follow-up (months) 0.04

Median (range) 76 (16–93) 87 (5–216)

Tumor stage 0.06

T 1 10 (50%) 82 (71%)

T 2 10 (50%) 33 (26%)

Node stage 0.17

Negative 12 (60%) 94 (71%)

Positive 8 (40%) 32 (28%)

Grading 0.16

G1 0 (0%) 10 (9%)

G2 10 (50%) 69 (60%)

G3 10 (50%) 33 (29%)

Unknown 0 (0%) 13 (11%)

Hormonal receptor status

0.06

Positive 20 (100%) 95 (83%)

Negative 0 (0%) 17 (15%)

Unknown 0 (0%) 3 (3%)

Prognostic favorable patients (pT1 pN0 HRC)

8 (40%) 57 (50%) 0.43

Postoperative radiotherapy (Gy)

0.8 Median dose (range) 54 (50.4–54.0) 54 (49.6–60.0)

Chemotherapy 7 (35%) 30 (26%) 0.41

Antihormonal therapy 16 (80%) 67 (58%) 0.07 HR, hormonal receptor.

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the more rapid growth of tumor cells compared to normal cells[7,17,18]. In accordance with this assumption, Su and Swift recently published evidence for a differential benefit of adjuvant radiotherapy on the clinical outcome in a series of A-T heterozygous breast cancer patients[17]. Among 43 stage I or II breast cancer patients carrying a single A-T mutation they observed a significantly lower relative risk of recurrence in 14 patients receiving postoperative radiotherapy compared to 29 patients receiving no radiotherapy following mastectomy. Excessive radiation related adverse events were not observed. They suggested that tumor cells in A-T carriers possibly were more susceptible to cell killing by ionizing radiation than in non-carriers resulting in an enhanced therapeutic ratio.

We present here, to our knowledge, the first study on the impact of heterozygosity for an ATM gene alteration on clinical outcome in a hospital-based cohort of breast cancer patients who received postoperative radiotherapy following breast conservative therapy. Regarding local control, no difference between carriers and non-carriers could be found, but this was attributable to the small sample size and limited number of events without sufficient power to detect a potential difference.

Although we observed a significantly worse metastasis- free survival in carriers of a variant in the ATM gene this did not remain an independent variable in a multivariate analysis. This observation might reflect a higher genomic instability and thus more rapid progression of tumors in A-T heterozygous breast cancer patients, with metastatic spread occurring early in the course of disease and prior to adjuvant radiotherapy. This hypothesis would also explain the relatively high number of carriers with a positive nodal status (Table 1). It is interesting in this regard that, in a previous study [16], carriers of A-T mutant alleles compared to intrafamilial non-carriers in A-T blood relatives have shown a nearly twofold greater risk for death with cancer being the underlying cause of most excess deaths among carriers, and ischemic heart disease causing the remainder. It was hypothesized that, besides the increased incidence of cancer and ischemic heart disease, a reduced clinical survival due to more rapid disease progression may have contributed to the overall high mortality rates among carriers[16].

Our data presented here may serve as a pilot investigation for prospectively testing the possible impact of A-T heterozygosity on clinical outcome. The findings have to be replicated in a larger number of breast cancer patients identified to be carriers of a candidate mutation in the ATM

gene through large scale screening to allow further insight into the impact of particular sequence variants on clinical outcome in breast cancer patients following adjuvant radiotherapy. In parallel, the functional consequences of some common variants in the ATM gene that are presently debated, need to be better defined before final conclusions can be drawn.

5. Conclusion

In this first follow-up study of a hospital-based series of breast cancer patients, we could not support the hypothesis that breast cancer patients carrying a sequence variant in the ATM gene may differentially benefit from postoperative radiotherapy. These findings have to be verified by a larger number of cases to shed more light on the potential clinical relevance of particular sequence variants in the ATM gene in breast cancer patients.

Acknowledgements

This study was in part supported by the Deutsche Forschungsgemeinschaft (grant No. Do-761/2-1). We like to thank Guenter Unger from the regional cancer follow-up registry of Lower-Saxony (Tumornachsorgeleitstelle KV Niedersachsen) for providing us with useful clinical follow- up data.

References

[1] Bremer M, Klopper K, Yamini P, Bendix-Waltes R, Dork T, Karstens JH. Clinical radiosensitivity in breast cancer patients carrying pathogenic ATM gene mutations: no observation of increased radiation-induced acute or late effects. Radiother Oncol 2003;69:155–60.

[2] Broeks A, Urbanus JH, de Knijff P, et al. IVS10-6TOG, an ancient ATM germline mutation linked with breast cancer. Hum Mutat 2003;

21:521–8.

[3] Buchholz TA, Weil MM, Ashorn CL, et al. A Ser49Cys variant in the ataxia telangiectasia mutated gene that is more common in patients with breast carcinoma compared with population controls. Cancer 2004;100:1345–51.

[4] Chenevix-Trench G, Spurdle AB, Gatei M, et al. Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 2002;94:

205–15.

[5] Dork T, Bendix R, Bremer M, et al. Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res 2001;61:7608–15.

Table 3

Actuarial survival rates at 7 years of carriers vs. non-carriers of variants in the ATM gene

Carriers (%) (nZ20) Non-carriers (%) (nZ115) P-value Odds ratio (95% CI)

Local relapse-free survival 88 94 0.34 2.16 (0.43–10.73)

Metastasis-free survival 63 85 0.01 3.05 (1.24–7.51)

Overall survival 73 89 0.055 2.67 (0.94–7.59)

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[6] Gutierrez-Enriquez S, Fernet M, Dork T, et al. Functional consequences of ATM sequence variants for chromosomal radiosensitivity. Genes Chromosomes Cancer 2004;40:109–19.

[7] Kastan MB, Lim DS, Kim ST, Yang D. ATM—a key determinant of multiple cellular responses to irradiation. Acta Oncol 2001;40:686–8.

[8] Khanna KK, Lavin MF, Jackson SP, Mulhern TD. ATM, a central controller of cellular responses to DNA damage. Cell Death Differ 2001;8:1052–65.

[9] Larson GP, Zhang G, Ding S, et al. An allelic variant at the ATM locus is implicated in breast cancer susceptibility. Genet Test 1997;1:

165–70.

[10] Lavin MF, Shiloh Y. The genetic defect in ataxia-telangiectasia. Annu Rev Immunol 1997;15:177–202.

[11] Neubauer S, Arutyunyan R, Stumm M, et al. Radiosensitivity of ataxia telangiectasia and Nijmegen breakage syndrome homozygotes and heterozygotes as determined by three-color FISH chromosome painting. Radiat Res 2002;157:312–21.

[12] Sandoval N, Platzer M, Rosenthal A, et al. Characterization of ATM gene mutations in 66 ataxia telangiectasia families. Hum Mol Genet 1999;8:69–79.

[13] Scott SP, Bendix R, Chen P, Clark R, Dork T, Lavin MF. Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. Proc Natl Acad Sci USA 2002;99:925–30.

[14] Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 2003;3:155–68.

[15] Stankovic T, Kidd AM, Sutcliffe A, et al. ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles:

expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet 1998;62:334–45.

[16] Su Y, Swift M. Mortality rates among carriers of ataxia-telangiectasia mutant alleles. Ann Intern Med 2000;133:770–8.

[17] Su Y, Swift M. Outcomes of adjuvant radiation therapy for breast cancer in women with ataxia-telangiectasia mutations. J Am Med Assoc 2001;286:2233–4.

[18] Swift M, Morrell D, Massey RB, Chase CL. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 1991;

325:1831–6.

[19] Teraoka SN, Malone KE, Doody DR, et al. Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer 2001;92:479–87.

[20] Thorstenson YR, Roxas A, Kroiss R, et al. Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res 2003;63:

3325–33.

[21] Weissberg JB, Huang DD, Swift M. Radiosensitivity of normal tissues in ataxia-telangiectasia heterozygotes. Int J Radiat Oncol Biol Phys 1998;42:1133–6.

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Zusammenfassung

Mutationen im ATM Gen, welche der seltenen autosomal rezessiv vererbten Multisystemerkrankung Ataxia teleangiectatica (AT) zugrunde liegen, führen aufgrund einer gestörten Reparatur von DNA-Doppelstrangbrüchen zu einer erhöhten zellulären Strahlensensibilität und einer genomischen Instabilität. AT- Heterozygote weisen neben der in-vitro zumindest intermediär erhöhten zellulären Strahlensensibilität ein erhöhtes Risiko auf, insbesondere an Brustkrebs zu erkranken. Erste Hinweise auf eine möglicherweise gesteigerte zelluläre Strahlensensibilität auch von Tumorzellen bei AT-Heterozygoten Patienten ergaben sich in einer Analyse von Su und Swift (JAMA 2001;286:

2233-4), in der eine begrenzte Anzahl von AT-heterozygoten Brustkrebspatientinnen ein geringeres relatives Risiko für ein Tumorrezidiv nach adjuvanter Strahlentherapie aufwies.

Wir untersuchten deshalb erstmals an einem unselektionierten Kollektiv von Patientinnen mit lokal begrenztem Brustkrebs den Krankheitsverlauf in Abhängigkeit von der Trägerschaft einer AT-Genmutation bzw. –variante, welche nach brusterhaltender Therapie eine postoperative adjuvante Strahlentherapie erhalten hatten. Ausgehend von 1000 Brustkrebspatientinnen, die zwischen 1995 und 1999 postoperativ in der Abteilung Strahlentherapie der MHH bestrahlt wurden, lag bei den ersten 192 Patienten eine komplette Analyse der kodierenden ATM-Gensequenz vor. Hiervon wurden 58 Patienten wegen eines lokal fortgeschrittenen Tumorstadiums (T3 und T4 Tumoren), einer primären Fernmetastasierung, einer Ablatio oder einer Bestrahlung erst in der Rezidivsituation ausgeschlossen. Zusätzlich wurden 4 Patientinnen als Träger einer pathogenen ATM-Genmutation, welche im Rahmen von Vorarbeiten identifiziert worden waren, in diese Untersuchung eingeschlossen.

Nach Ausschluß von 3 Patientinnen mit fehlenden Nachsorgedaten wurden

schließlich 135 Patienten in diese Analyse aufgenommen. Die Erhebung der

klinischen Daten und des Krankheitsverlaufs erfolgte retrospektiv durch

Auswertung von Patientenakten und durch Telefonkontakte zu den lebenden

Patientinnen. Weitere Informationen wurden durch Befragung der

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behandelnden Hausärzte, nachsorgenden Gynäkologen bzw. durch Auswertung von Erhebungsbögen der Tumornachsorgeleitstelle der KVN gewonnen. Der mediane Nachbeobachtungszeitraum betrug 87 Monate.

Von den 135 untersuchten Patientinnen wiesen 20 eine pathogene ATM- Genmutation bzw. eine potentiell relevante ATM-Genvariante auf (trunkierend:

7, missense: 13). Zwischen Trägern (n=20) und Nichtträgern (n=115) lagen hinsichtlich der Verteilung relevanter prognostischer Faktoren keine statistisch signifikanten Unterschiede vor. Während der Nachbeobachtungszeit traten bei 8 Patientinnen Lokalrezidive (Träger: 2, Nichtträger: 6) und bei 22 Patienten Fernmetastasen (Träger: 7, Nichtträger: 15) auf. Bis auf eine Patientin waren 18 Patientinnen als Folge der Tumorerkrankung verstorben. Das lokalrezidivfreie Überleben betrug nach 7 Jahren aktuarisch bei Trägern 88%

gegenüber bei Nichtträgern 94% (p=0.34), das metastasenfreie Überleben 63%

gegenüber 85% (p=0.01) und das Gesamtüberleben 73% gegenüber 89%

(p=0.055). In der multivariaten Cox-Regressionsanalyse blieb das Vorliegen einer Mutation bzw. Variante im ATM-Gen jedoch keine unabhängige Variable für die Vorhersage des metastasenfreien Überlebens (p=0.068).

Diese Ergebnisse stützen nicht die Hypothese von einem differentiellen

therapeutischen Benefit der postoperativen Strahlentherapie bei

Brustkrebspatientinnen, welche Träger einer ATM-Genmutation bzw. –variante

sind. Das ungünstigere metastasenfreie Überleben von Trägern einer ATM-

Genmutation kann hingegen Ausdruck eines möglicherweise aggressiveren

Krankheitsverlaufs auf Basis der genomischen Instabilität sein, was zu einer

frühen subklinischen Fernmetastasierung noch vor Durchführung der

postoperativen Bestrahlung führen könnte. Um die mögliche klinische

Bedeutung einer AT-Heterozygotie bei Tumorpatienten weiter aufzuklären, sind

vergleichbare systematische Untersuchungen an größeren Patientenkollektiven

erforderlich. Die Ergebnisse der hier vorgestellten Analyse können hierzu als

Ausgangsbasis dienen.

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Publikationen

Meyer A, John E, Dörk T, Sohn C, Karstens JH, Bremer M: Breast cancer in female carriers of ATM gene alterations: outcome of adjuvant radiotherapy.

Radiother Oncol 2004; 72: 319-323

Bremer M, John E, Dörk T, Karstens JH: Breast cancer in women carrying variants in the ATM gene: outcome of adjuvant radiotherapy (RT). Proc. of the International 8th Wolfsberg Meeting on Molecular Radiation Biology Oncology 2004; Vol. 5: 102

Bremer M, John E, Dörk T, Karstens JH: Mammakarzinom bei Trägerinnen

einer ATM-Genveränderung: Behandlungsergebnisse nach postoperativer

Bestrahlung. Strahlenther Onkol 2004; 180, Sondern. 1: 48

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Lebenslauf

Persönliche Daten

Name Esther John

Geburtsdatum 18.02.1980

Geburtsort Berlin-Zehlendorf Familienstand ledig

Eltern Dr. dipl. ing. Hendrik John (Entwicklungsingenieur) Sabine John geb. Schmidt (Hausfrau)

Geschwister Liza-Sarah John (Studentin) Religion evangelisch-lutherisch

Anschrift Werner-Heins-Weg 15, 29336 Nienhagen

Schulbildung

1986- 1990 Grundschule Altencelle

1990- 1992 Orientierungsschule Burgstrasse Celle 1992-1999 Gymnasium Ernestinum Celle

Mai 1999 Abitur

Berufliche Ausbildung

März 2000 Beginn des Studiums der Humanmedizin an der Freien

Universität Berlin

Oktober 2002 Wechsel an die Medizinische Hochschule Hannover August 2002 Ärztliche Vorprüfung

August 2003 Erster Teil der Ärztlichen Prüfung August 2005 Zweiter Teil der Ärztlichen Prüfung November 2006 Dritter Teil der Ärztlichen Prüfung

Seit 01.01.2007 Assistenzärztin in der Abteilung für Anästhesiologie und

Intensivmedizin des AKH Celle

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Famulaturen

Innere Medizin, Abteilung für Gastroenterologie, AK Celle Unfall- und Wiederherstellungschirurie, AK Celle

Strahlentherapie, Medizinische Hochschule Hannover

Augenheilkunde, Praxis für Augenheilkunde Dr. J. Schulze, Celle

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Erklärung nach § 2 Abs. 2 Nrn. 5 und 6

Ich erkläre, dass ich die der Medizinischen Hochschule Hannover zur Promotion eingereichte Dissertation mit dem Titel:

Breast cancer in female carriers of ATM gene alterations:

outcome of adjuvant radiotherapy

in der Abteilung Strahlentherapie und spezielle Onkologie unter Betreuung von Oberarzt PD Dr. med. Michael Bremer, Abteilung Strahlentherapie und spezielle Onkologie der Medizinischen Hochschule Hannover ohne sonstige Hilfe durchgeführt und bei der Abfassung der Dissertation keine anderen als die dort aufgeführten Hilfsmittel benutzt habe.

Ich habe bisher an keiner in- oder ausländischen Medizinischen Fakultät ein Gesuch um Zulassung zur Promotion eingereicht, noch diese oder eine andere Arbeit als Dissertation vorgelegt.

Hannover, den 26.09.2005

Esther John

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Danksagung

Ich danke Herrn Prof. Dr. med. J.-H. Karstens für die Möglichkeit, in seiner Abteilung wissenschaftlich zu arbeiten.

Mein besonderer Dank gilt meinem Doktorvater Oberarzt PD Dr. med. Michael Bremer, der mich immer unterstützt und motiviert hat. Durch sein Engagement und seine Diskussionsbereitschaft hat er mir sehr viel Freude an dieser Arbeit vermittelt und ein Entstehen in dieser Form erst möglich gemacht.

Herzlichen Dank auch Herrn Dr. med. Andreas Meyer für sein Interesse an meiner Arbeit, seine Unterstützung bei der statistischen Arbeit, dem englischen Text und für jedes aufmunternde Wort.

Speziellen Dank an Herrn Dr. Thilo Dörk und seine Mitarbeiter, für die gute Zusammenarbeit und die Bereitstellung der genetischen Daten und der Tumornachsorgeleitstelle der KVN.

Den Mitarbeitern der Strahlentherapie der Medizinischen Hochschule Hannover möchte ich für ihre Hilfsbereitschaft und die freundliche Arbeitsathmosphäre danken.