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Dramatic Response to Platinum in a Patient with Cancer with a Germline BRCA2 Mutation
Clinical Oncology (2009) 21: 444e447 doi:10.1016/j.clon.2009.04.004
Case Report
Dramatic Response to Platinum in a Patient with Cancer with a Germline BRCA2 Mutation R. Moule*y, A. Sohaibz, R. Eelesxy *Radiotherapy Department, University College Hospital, London NW1 2BU, UK; yCancer Genetics Unit, Royal Marsden NHS Foundation Trust, London SM2 5PT, UK; zDepartment of Radiology, Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK; xTranslational Cancer Genetics Team, The Institute of Cancer Research, Sutton, Surrey SM2 5PT, UK
ABSTRACT: We present a case of dramatic response of poor prognosis cancer in a lady with a germline mutation in the BRCA2 gene who was exposed to platinum containing chemotherapy. She is cancer-free 10 years’ later. Such cases provide clinical scenarios for the basis of trials of platinum-like agents in individuals with BRCA mutations who develop cancer. Moule, R. et al. (2009). Clinical Oncology 21, 444—447 ª 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: BRCA2, cancer, dramatic response, platinum
Introduction Breast cancer affects an increasing number of the population, and is the most common cancer in women. In about 10% of these individuals, there is a strong genetic predisposition to the disease due to the presence of highly penetrant genes [1] predisposing them to an increased risk of carcinoma of the breast, as well as onset at an earlier age. Just under half of such cases are due to a deleterious, germline mutation in the BRCA1 or BRCA2 genes. The presence of these genes also predisposes to an increased risk of other malignancy, most commonly carcinoma of the ovary [2]. Colon and endometrial carcinomas have been reported, but are more commonly associated with BRCA1 [3,4]. BRCA2 mutation carriers are at increased risk of cancers of the prostate, stomach, pancreas, gall bladder, bilary tree, male breast, head and neck, melanoma, and fallopian tube [5,6]. BRCA1-associated breast cancer has a poorer survival outcome and prognosis compared with breast cancer associated with BRCA2. This is, however, difficult to quantify and whether survival from cancer is truly different in BRCA1/ 2 mutation carriers is controversial. There are potential biases in the data due to the requirement for DNA analysis, which is often difficult to obtain unless the individual is alive to give a blood sample. Researchers have tried to overcome this in populations with founder mutations by analysing banked tissue from both living and deceased patients for founder mutations. Such studies have suggested that there is no survival difference in breast cancer patients with and without the Ashkenazi Jewish founder mutations. Certainly there is no suggestion that survival is remarkably improved in carriers of either BRCA1 or BRCA2 mutations [7]. Protein products of the BRCA1 and BRCA2 genes have been implicated in repair of the double-strand DNA damage response to 0936-6555/09/210444þ04 $36.00/0
modification of DNA by certain cytotoxic agents. Laboratory data from in vitro studies in both murine and human cell lines deficient in brca1/2 or BRCA1/2 protein, respectively, report increased sensitivity to agents that induce double-stranded DNA breaks [8]. Abbott et al. [8] used a human pancreatic adenocarcinoma cell line deficient in one copy of the BRCA2 gene that also contained the mutation 6174delT in the remaining copy. Increased sensitivity was seen in cells lacking the BRCA2 gene with reduced ability to repair double-stranded DNA damage induced by not only ionising radiation, but also mitoxantrone, amascarine and etoposide. Similar results occurred with the use of BRCA2 antisense in cells with a full BRCA2 gene compliment. Khanna and Jackson [9], using an embryonic murine cell line, showed that brca1 was required for the repair of cisplatin-induced DNA adducts, and the defective gene therefore increased platinum sensitivity [10]. Further characterisation of chemosensitivity and radiosensitivity within human epithelial ovarian cancer cell lines, obtained from treatment-naive patients, showed higher sensitivity to cisplatin and gamma irradiation in those with a BRCA2 mutation compared with a TP53 mutation [11]. There has been debate surrounding survival and the differential effect of chemotherapy in cancer patients with BRCA1/2 germline mutations. The data have generally been in vitro and extrapolation to the clinical setting has been difficult to find. Currently there are no published prospective studies regarding BRCA1/2 and the use of different chemotherapy regimens with the specific question of differences in response between mutation carriers and non-carriers, although for patients with BRCA1/2-related ovarian cancer, an improved survival and response rate occurs compared with non-carriers, especially if they receive platinum-based chemotherapy [12,13]. Neoadjuvant use of chemotherapy in such hereditary breast cancers has been reported in a small
ª 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
RESPONSE TO PLATINUM OF CANCER WITH GERMLINE BRCA2 MUTATION
cohort of Ashkenazi and French Canadian patients comprising 615 women with underlying BRCA1/2 founder mutations. A differential response was seen in BRCA1/2 mutation carriers compared with non-carriers; the former had a better response leading to both clinical and pathological complete remission, which appeared to be independent of clinical stage [14].
Case Report The patient presented here has a germline mutation in the BRCA2 gene. She developed breast carcinoma and subsequent adenocarcinoma of the lung. She has an unusual history and a remarkable remission. In May 1988, this woman presented with bilateral breast cancer at the age of 42 years. All histology and imaging, from diagnosis to the present, were reviewed at the Royal Marsden NHS Foundation Trust. Histology from the original right breast lumpectomy showed intraductal and invasive ductal carcinoma and on review grade 1 invasive ductal carcinoma with widespread cribiform ductal carcinoma in situ of intermediate grade was reported. She was treated with right breast mastectomy and axillary node clearance, and left breast lumpectomy. Histology revealed grade 2 invasive ductal carcinoma on the left with widespread intermediate grade ductal carcinoma in situ. The right mastectomy pathology was identical in grade as before, with negative resection margins and no lymph node involvement. All pathological specimens were positive for oestrogen and progesterone receptors. She received postoperative adjuvant radiotherapy of 40 Gy in 10 fractions using cobalt 60 with tangential fields with a 25 Gy iridium boost to the left tumour bed, and was started on tamoxifen 20 mg once a day, which was taken for 5 years. In the interim period she decided to undergo further surgical reconstruction of the right chest wall in 1994, and partial left mastectomy and latissimus dorsi flap reconstruction in 1997. Unfortunately, in March 1998, she developed left mid and lower back pain, with episodes of haemoptysis. Previous
445
radiology from 1996 showed no evidence of chest pathology, and similarly on bone scan, no evidence of metastatic disease. However, a posterioreanterior chest X-ray from June 1998 (Fig. 1a) showed a large mass in the left upper lobe (at the level of left hilum) with surrounding distal collapse. Respiratory review and bronchoscopy showed a narrowing of the left upper lobe bronchus with external compression. Bronchial washings showed atypical squamous cells. Computed tomography showed a 6 3 cm mass based anteriorly to the left lower lobe, extending along the pleura and centrally towards the left hilum (Fig. 2a, straight arrow), with adjacent rib destruction, and infiltration of the anterior chest wall (Fig. 2a). There was a soft tissue mass encasing the left upper lobe bronchus (Fig. 2a, curved arrow) with distal consolidation, and a 2 cm metastatic nodule in the left adrenal gland (Fig. 3a, arrow). Two attempts were made to isolate histology via computed tomography-guided core biopsy. On histological review there was poorly differentiated carcinoma, with focal glandular differentiation with features favouring adenocarcinoma, although pathology initially suggested a squamous appearance. No tissue was available for immunohistochemical staining. Therefore, differentiation from pathology alone between a lung primary and breast metastasis was difficult. However, on review at the Royal Marsden NHS Foundation Trust, the tissue blocks were confirmed as primary bronchogenic carcinoma rather than metastatic breast cancer. After eight cycles of mitomycin, vincristine and cisplatin completed in 1999, repeated scans revealed no evidence of disease recurrence. In March 2000, on computed tomography (Fig. 2b), the left upper lobe region had no evidence of residual disease, there was resolution of the mass previously in the left hilum, chest wall and left adrenal gland, which all appeared normal (Fig. 3b, arrow). Figure 1b also shows this, with resolution of the opacity at the level of the left hilum on chest X-ray. To date (October 2008), there continues to be no evidence of recurrence on all imaging modalities, and she continues to have a complete response and to be well.
Fig. 1 e (a) Posterioreanterior chest X-ray (June 1998) showing a large mass above the left hilum with surrounding collapse. (b) Posterioreanterior chest X-ray (March 2000: post-treatment) showing resolution of opacity at the level of the left hilum.
446
CLINICAL ONCOLOGY
Fig. 2 e Axial images of the thorax: (a) June 1998; (b) post-treatment.
In July 2000 this patient was referred to the Cancer Genetics Department at the Royal Marsden NHS Foundation Trust and screened by DNA analysis from a blood sample. A nonsense BRCA2 mutation was detected in exon 11 (c3058 A OT), which would result in a truncated protein product.
Discussion This case is unusual with respect to the adenocarcinoma of the lung. Presentation with stage 3 disease would place this patient’s 5-year survival at about 15%. She has had a sustained clinical and radiological remission for 10 years. The value of chemotherapy for non-small cell lung cancer has previously
been rated as poor. However, a meta-analysis in 1995 by the Non-Small Cell Lung Cancer Collaborative Group in which data from 9387 patients (7151 deaths) from 52 randomised clinical trials were assessed, with survival as the end point, reported a beneficial effect with platinum chemotherapy-based regimens. However, unlike in this case, this reported benefit was in combination with surgery plus or minus radiotherapy, and therefore the use of chemotherapy alone, as reported here, and its benefit on survival in this situation is more difficult to establish. A further meta-analysis of nine trials involving 1190 patients by the Non-Small Cell Lung Cancer Collaborative Group [15] reported that in advanced metastatic disease, platinum-based chemotherapy provides a survival benefit
Fig. 3 e (a) Axial computed tomography image of a metastatic nodule in the left adrenal gland. (b) Normal left adrenal gland, with resolution of metastasis.
RESPONSE TO PLATINUM OF CANCER WITH GERMLINE BRCA2 MUTATION
compared with best supportive care. This has been confirmed with other platinum-based combination regimens or selected new single agents producing a modest survival advantage, as well as improved quality of life. New agents, such as paclitaxel, docetaxel, vinorelbine, gemcitabine and irinotecan, have shown significant single-agent activity in advanced non-small cell lung cancer. Several randomised trials have evaluated platinum-based combinational treatments and suggested that no one combination is superior when using survival as the primary measure of outcome [16]. In our case the use of mitomycin, vincristine and cisplatin chemotherapy has been very beneficial and has provided a remission and survival that was not initially predicted at diagnosis. Tumours in individuals with germline mutations in BRCA1/2 and their sensitivity to chemotherapy have been investigated. Here we shall concentrate on BRCA2, which is most pertinent. The protein product of this gene mediates repair of double-stranded DNA breaks, which would imply that tumours in patients carrying BRCA2 gene mutations should be more amenable to treatment with chemotherapeutic agents that induce this. In vitro, studies have been undertaken using a human pancreatic adenocarcinoma cell line deficient in one copy of BRCA2. When these cells were exposed to ionising radiation, repair of induced double-stranded DNA breaks was not possible, and therefore cell kill increased [8]. Sensitivity to the double-strand breaks that are induced by agents such as mitoxantrone has been reported in BRCA2 defective cells. Recent National Institute for Health and Clinical Excellence guidelines for BRCA1/2 mutation screening in suspected familial breast cancer have suggested testing if the chance of a BRCA1/2 mutation in the family is at least 20%. There have also been investments in genetics laboratories in the UK through the White Paper in Genetics so that the whole of both genes can be analysed. This will result in the identification of an increasing number of individuals with BRCA1/2 mutations and if the in vitro sensitivity to platinum were found in vivo this would alter the management of breast cancer in such individuals. In order to investigate this there is a new trial of treatment at first relapse of breast cancer, comparing platinum and taxanes in a crossover study with 2 : 1 randomisation (www.breakthrough.org.uk/researchcentre/clinical_trials/brca_trial). We have presented a patient with germline BRCA2 mutation who has had a remarkable and dramatic response with cisplatin chemotherapy for squamous cell carcinoma of the lung on a background of previous breast cancer. Although evidence-based medicine should optimally be based on randomised controlled trial evidence, this case report provides a clinical scenario that supports the laboratory premise on which the BRCA trial is based. With changes in genetic screening via National Institute for Health and Clinical Excellence guidelines, more individuals will be identified who have such germline mutations, and if the BRCA trial shows that their tumours have an increased sensitivity to platinum, this would alter the chemotherapy regimens offered to such patients and would drive the introduction of genetic testing as part of the oncology care pathway. Acknowledgements. This study was supported by NHS support to the NIHR Biomedical Research Centre at the Royal Marsden NHS Foundation
447
Trust and the Institute of Cancer Research. We should like to thank the patient for permission to publish her case. We should like to acknowledge Dr Bates’ and Dr Blesing’s help with obtaining clinical information. Author for correspondence: R. Eeles, Translational Cancer Genetics Team, Institute of Cancer Research and Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: þ44-208-661-3642; Fax: þ44-208-770-1489; E-mail: [email protected] Received 2 November 2008; received in revised form 28 March 2009; accepted 17 April 2009
References 1 Claus EB, Risch N, Thompson WD. Genetic analysis of breast cancer in the cancer and hormone study. Am J Hum Genet 1991;48:232e242. 2 Ford D, Easton DF, Stratton MR. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 1998;62:676e689. 3 Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA 1 mutation carriers. Lancet 1994;343:692e695. 4 Thompson D, Easton DF, Breast Cancer Linkage Consortium. Cancer incidence in BRCA1 carrier mutations. J Natl Cancer Inst 2002;94:1358e1365. 5 Breast Cancer Linkage Consortium. Cancer risks in BRCA 2 mutations carriers. J Natl Cancer Inst 1999;91:1310e1316. 6 Thompson D, Easton DF, Breast Cancer Linkage Consortium. Variation in cancer risks by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 2001;68(2):410e419. 7 Foulkes WD, Wong N, Brunet JS, Narod SA. BRCA mutations and survival in breast cancer. J Clin Oncol 1998;16(9):3206e3208. 8 Abbott DW, Freeman ML, Holt JT. Double strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J Natl Cancer Inst 1998;90:978e985. 9 Khanna KK, Jackson SP. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 2001;27:247e254. 10 Bhattacharyya A, Ear US, Koller BH, Weichselbaum RR, Bishop DK. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross linking agent cisplatin. J Biol Chem 2000;275:23899e23903. 11 Samouelian V, Maugard CM, Jolicoeur M, et al. Chemosensitivity and radiosensitivity profiles of four new human epithelial ovarian cancer cell lines exhibiting genetic alterations in BRCA2, TGFbeta-RII, KRAS2, TP53, and/or CDKN2A. Cancer Chemother Pharmacol 2004;54:497e504. 12 Foulkes WD. BRCA1 and BRCA2: chemosensitivity, treatment outcomes and prognosis. Fam Cancer 2006;5:135e142. 13 Tan DS, Rothermundt C, Thomas K, et al. BRCAness syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 2008; 26(34):5530e5536. 14 Chappuis PO, Goffin J, Wong N, Ghadirian P, Tonin PN. A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer. J Med Genet 2002;39(8):608e610. 15 Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Br Med J 1995;311:899e909. 16 Socinski MA. Cytotoxic chemotherapy in advanced non-small cell lung cancer. A review of standard treatment paradigms. Cancer Res 2004;10:4210Se4214S.
Case Report
Dramatic Response to Platinum in a Patient with Cancer with a Germline BRCA2 Mutation R. Moule*y, A. Sohaibz, R. Eelesxy *Radiotherapy Department, University College Hospital, London NW1 2BU, UK; yCancer Genetics Unit, Royal Marsden NHS Foundation Trust, London SM2 5PT, UK; zDepartment of Radiology, Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK; xTranslational Cancer Genetics Team, The Institute of Cancer Research, Sutton, Surrey SM2 5PT, UK
ABSTRACT: We present a case of dramatic response of poor prognosis cancer in a lady with a germline mutation in the BRCA2 gene who was exposed to platinum containing chemotherapy. She is cancer-free 10 years’ later. Such cases provide clinical scenarios for the basis of trials of platinum-like agents in individuals with BRCA mutations who develop cancer. Moule, R. et al. (2009). Clinical Oncology 21, 444—447 ª 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: BRCA2, cancer, dramatic response, platinum
Introduction Breast cancer affects an increasing number of the population, and is the most common cancer in women. In about 10% of these individuals, there is a strong genetic predisposition to the disease due to the presence of highly penetrant genes [1] predisposing them to an increased risk of carcinoma of the breast, as well as onset at an earlier age. Just under half of such cases are due to a deleterious, germline mutation in the BRCA1 or BRCA2 genes. The presence of these genes also predisposes to an increased risk of other malignancy, most commonly carcinoma of the ovary [2]. Colon and endometrial carcinomas have been reported, but are more commonly associated with BRCA1 [3,4]. BRCA2 mutation carriers are at increased risk of cancers of the prostate, stomach, pancreas, gall bladder, bilary tree, male breast, head and neck, melanoma, and fallopian tube [5,6]. BRCA1-associated breast cancer has a poorer survival outcome and prognosis compared with breast cancer associated with BRCA2. This is, however, difficult to quantify and whether survival from cancer is truly different in BRCA1/ 2 mutation carriers is controversial. There are potential biases in the data due to the requirement for DNA analysis, which is often difficult to obtain unless the individual is alive to give a blood sample. Researchers have tried to overcome this in populations with founder mutations by analysing banked tissue from both living and deceased patients for founder mutations. Such studies have suggested that there is no survival difference in breast cancer patients with and without the Ashkenazi Jewish founder mutations. Certainly there is no suggestion that survival is remarkably improved in carriers of either BRCA1 or BRCA2 mutations [7]. Protein products of the BRCA1 and BRCA2 genes have been implicated in repair of the double-strand DNA damage response to 0936-6555/09/210444þ04 $36.00/0
modification of DNA by certain cytotoxic agents. Laboratory data from in vitro studies in both murine and human cell lines deficient in brca1/2 or BRCA1/2 protein, respectively, report increased sensitivity to agents that induce double-stranded DNA breaks [8]. Abbott et al. [8] used a human pancreatic adenocarcinoma cell line deficient in one copy of the BRCA2 gene that also contained the mutation 6174delT in the remaining copy. Increased sensitivity was seen in cells lacking the BRCA2 gene with reduced ability to repair double-stranded DNA damage induced by not only ionising radiation, but also mitoxantrone, amascarine and etoposide. Similar results occurred with the use of BRCA2 antisense in cells with a full BRCA2 gene compliment. Khanna and Jackson [9], using an embryonic murine cell line, showed that brca1 was required for the repair of cisplatin-induced DNA adducts, and the defective gene therefore increased platinum sensitivity [10]. Further characterisation of chemosensitivity and radiosensitivity within human epithelial ovarian cancer cell lines, obtained from treatment-naive patients, showed higher sensitivity to cisplatin and gamma irradiation in those with a BRCA2 mutation compared with a TP53 mutation [11]. There has been debate surrounding survival and the differential effect of chemotherapy in cancer patients with BRCA1/2 germline mutations. The data have generally been in vitro and extrapolation to the clinical setting has been difficult to find. Currently there are no published prospective studies regarding BRCA1/2 and the use of different chemotherapy regimens with the specific question of differences in response between mutation carriers and non-carriers, although for patients with BRCA1/2-related ovarian cancer, an improved survival and response rate occurs compared with non-carriers, especially if they receive platinum-based chemotherapy [12,13]. Neoadjuvant use of chemotherapy in such hereditary breast cancers has been reported in a small
ª 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
RESPONSE TO PLATINUM OF CANCER WITH GERMLINE BRCA2 MUTATION
cohort of Ashkenazi and French Canadian patients comprising 615 women with underlying BRCA1/2 founder mutations. A differential response was seen in BRCA1/2 mutation carriers compared with non-carriers; the former had a better response leading to both clinical and pathological complete remission, which appeared to be independent of clinical stage [14].
Case Report The patient presented here has a germline mutation in the BRCA2 gene. She developed breast carcinoma and subsequent adenocarcinoma of the lung. She has an unusual history and a remarkable remission. In May 1988, this woman presented with bilateral breast cancer at the age of 42 years. All histology and imaging, from diagnosis to the present, were reviewed at the Royal Marsden NHS Foundation Trust. Histology from the original right breast lumpectomy showed intraductal and invasive ductal carcinoma and on review grade 1 invasive ductal carcinoma with widespread cribiform ductal carcinoma in situ of intermediate grade was reported. She was treated with right breast mastectomy and axillary node clearance, and left breast lumpectomy. Histology revealed grade 2 invasive ductal carcinoma on the left with widespread intermediate grade ductal carcinoma in situ. The right mastectomy pathology was identical in grade as before, with negative resection margins and no lymph node involvement. All pathological specimens were positive for oestrogen and progesterone receptors. She received postoperative adjuvant radiotherapy of 40 Gy in 10 fractions using cobalt 60 with tangential fields with a 25 Gy iridium boost to the left tumour bed, and was started on tamoxifen 20 mg once a day, which was taken for 5 years. In the interim period she decided to undergo further surgical reconstruction of the right chest wall in 1994, and partial left mastectomy and latissimus dorsi flap reconstruction in 1997. Unfortunately, in March 1998, she developed left mid and lower back pain, with episodes of haemoptysis. Previous
445
radiology from 1996 showed no evidence of chest pathology, and similarly on bone scan, no evidence of metastatic disease. However, a posterioreanterior chest X-ray from June 1998 (Fig. 1a) showed a large mass in the left upper lobe (at the level of left hilum) with surrounding distal collapse. Respiratory review and bronchoscopy showed a narrowing of the left upper lobe bronchus with external compression. Bronchial washings showed atypical squamous cells. Computed tomography showed a 6 3 cm mass based anteriorly to the left lower lobe, extending along the pleura and centrally towards the left hilum (Fig. 2a, straight arrow), with adjacent rib destruction, and infiltration of the anterior chest wall (Fig. 2a). There was a soft tissue mass encasing the left upper lobe bronchus (Fig. 2a, curved arrow) with distal consolidation, and a 2 cm metastatic nodule in the left adrenal gland (Fig. 3a, arrow). Two attempts were made to isolate histology via computed tomography-guided core biopsy. On histological review there was poorly differentiated carcinoma, with focal glandular differentiation with features favouring adenocarcinoma, although pathology initially suggested a squamous appearance. No tissue was available for immunohistochemical staining. Therefore, differentiation from pathology alone between a lung primary and breast metastasis was difficult. However, on review at the Royal Marsden NHS Foundation Trust, the tissue blocks were confirmed as primary bronchogenic carcinoma rather than metastatic breast cancer. After eight cycles of mitomycin, vincristine and cisplatin completed in 1999, repeated scans revealed no evidence of disease recurrence. In March 2000, on computed tomography (Fig. 2b), the left upper lobe region had no evidence of residual disease, there was resolution of the mass previously in the left hilum, chest wall and left adrenal gland, which all appeared normal (Fig. 3b, arrow). Figure 1b also shows this, with resolution of the opacity at the level of the left hilum on chest X-ray. To date (October 2008), there continues to be no evidence of recurrence on all imaging modalities, and she continues to have a complete response and to be well.
Fig. 1 e (a) Posterioreanterior chest X-ray (June 1998) showing a large mass above the left hilum with surrounding collapse. (b) Posterioreanterior chest X-ray (March 2000: post-treatment) showing resolution of opacity at the level of the left hilum.
446
CLINICAL ONCOLOGY
Fig. 2 e Axial images of the thorax: (a) June 1998; (b) post-treatment.
In July 2000 this patient was referred to the Cancer Genetics Department at the Royal Marsden NHS Foundation Trust and screened by DNA analysis from a blood sample. A nonsense BRCA2 mutation was detected in exon 11 (c3058 A OT), which would result in a truncated protein product.
Discussion This case is unusual with respect to the adenocarcinoma of the lung. Presentation with stage 3 disease would place this patient’s 5-year survival at about 15%. She has had a sustained clinical and radiological remission for 10 years. The value of chemotherapy for non-small cell lung cancer has previously
been rated as poor. However, a meta-analysis in 1995 by the Non-Small Cell Lung Cancer Collaborative Group in which data from 9387 patients (7151 deaths) from 52 randomised clinical trials were assessed, with survival as the end point, reported a beneficial effect with platinum chemotherapy-based regimens. However, unlike in this case, this reported benefit was in combination with surgery plus or minus radiotherapy, and therefore the use of chemotherapy alone, as reported here, and its benefit on survival in this situation is more difficult to establish. A further meta-analysis of nine trials involving 1190 patients by the Non-Small Cell Lung Cancer Collaborative Group [15] reported that in advanced metastatic disease, platinum-based chemotherapy provides a survival benefit
Fig. 3 e (a) Axial computed tomography image of a metastatic nodule in the left adrenal gland. (b) Normal left adrenal gland, with resolution of metastasis.
RESPONSE TO PLATINUM OF CANCER WITH GERMLINE BRCA2 MUTATION
compared with best supportive care. This has been confirmed with other platinum-based combination regimens or selected new single agents producing a modest survival advantage, as well as improved quality of life. New agents, such as paclitaxel, docetaxel, vinorelbine, gemcitabine and irinotecan, have shown significant single-agent activity in advanced non-small cell lung cancer. Several randomised trials have evaluated platinum-based combinational treatments and suggested that no one combination is superior when using survival as the primary measure of outcome [16]. In our case the use of mitomycin, vincristine and cisplatin chemotherapy has been very beneficial and has provided a remission and survival that was not initially predicted at diagnosis. Tumours in individuals with germline mutations in BRCA1/2 and their sensitivity to chemotherapy have been investigated. Here we shall concentrate on BRCA2, which is most pertinent. The protein product of this gene mediates repair of double-stranded DNA breaks, which would imply that tumours in patients carrying BRCA2 gene mutations should be more amenable to treatment with chemotherapeutic agents that induce this. In vitro, studies have been undertaken using a human pancreatic adenocarcinoma cell line deficient in one copy of BRCA2. When these cells were exposed to ionising radiation, repair of induced double-stranded DNA breaks was not possible, and therefore cell kill increased [8]. Sensitivity to the double-strand breaks that are induced by agents such as mitoxantrone has been reported in BRCA2 defective cells. Recent National Institute for Health and Clinical Excellence guidelines for BRCA1/2 mutation screening in suspected familial breast cancer have suggested testing if the chance of a BRCA1/2 mutation in the family is at least 20%. There have also been investments in genetics laboratories in the UK through the White Paper in Genetics so that the whole of both genes can be analysed. This will result in the identification of an increasing number of individuals with BRCA1/2 mutations and if the in vitro sensitivity to platinum were found in vivo this would alter the management of breast cancer in such individuals. In order to investigate this there is a new trial of treatment at first relapse of breast cancer, comparing platinum and taxanes in a crossover study with 2 : 1 randomisation (www.breakthrough.org.uk/researchcentre/clinical_trials/brca_trial). We have presented a patient with germline BRCA2 mutation who has had a remarkable and dramatic response with cisplatin chemotherapy for squamous cell carcinoma of the lung on a background of previous breast cancer. Although evidence-based medicine should optimally be based on randomised controlled trial evidence, this case report provides a clinical scenario that supports the laboratory premise on which the BRCA trial is based. With changes in genetic screening via National Institute for Health and Clinical Excellence guidelines, more individuals will be identified who have such germline mutations, and if the BRCA trial shows that their tumours have an increased sensitivity to platinum, this would alter the chemotherapy regimens offered to such patients and would drive the introduction of genetic testing as part of the oncology care pathway. Acknowledgements. This study was supported by NHS support to the NIHR Biomedical Research Centre at the Royal Marsden NHS Foundation
447
Trust and the Institute of Cancer Research. We should like to thank the patient for permission to publish her case. We should like to acknowledge Dr Bates’ and Dr Blesing’s help with obtaining clinical information. Author for correspondence: R. Eeles, Translational Cancer Genetics Team, Institute of Cancer Research and Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: þ44-208-661-3642; Fax: þ44-208-770-1489; E-mail: [email protected] Received 2 November 2008; received in revised form 28 March 2009; accepted 17 April 2009
References 1 Claus EB, Risch N, Thompson WD. Genetic analysis of breast cancer in the cancer and hormone study. Am J Hum Genet 1991;48:232e242. 2 Ford D, Easton DF, Stratton MR. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 1998;62:676e689. 3 Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA 1 mutation carriers. Lancet 1994;343:692e695. 4 Thompson D, Easton DF, Breast Cancer Linkage Consortium. Cancer incidence in BRCA1 carrier mutations. J Natl Cancer Inst 2002;94:1358e1365. 5 Breast Cancer Linkage Consortium. Cancer risks in BRCA 2 mutations carriers. J Natl Cancer Inst 1999;91:1310e1316. 6 Thompson D, Easton DF, Breast Cancer Linkage Consortium. Variation in cancer risks by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 2001;68(2):410e419. 7 Foulkes WD, Wong N, Brunet JS, Narod SA. BRCA mutations and survival in breast cancer. J Clin Oncol 1998;16(9):3206e3208. 8 Abbott DW, Freeman ML, Holt JT. Double strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J Natl Cancer Inst 1998;90:978e985. 9 Khanna KK, Jackson SP. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 2001;27:247e254. 10 Bhattacharyya A, Ear US, Koller BH, Weichselbaum RR, Bishop DK. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross linking agent cisplatin. J Biol Chem 2000;275:23899e23903. 11 Samouelian V, Maugard CM, Jolicoeur M, et al. Chemosensitivity and radiosensitivity profiles of four new human epithelial ovarian cancer cell lines exhibiting genetic alterations in BRCA2, TGFbeta-RII, KRAS2, TP53, and/or CDKN2A. Cancer Chemother Pharmacol 2004;54:497e504. 12 Foulkes WD. BRCA1 and BRCA2: chemosensitivity, treatment outcomes and prognosis. Fam Cancer 2006;5:135e142. 13 Tan DS, Rothermundt C, Thomas K, et al. BRCAness syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 2008; 26(34):5530e5536. 14 Chappuis PO, Goffin J, Wong N, Ghadirian P, Tonin PN. A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer. J Med Genet 2002;39(8):608e610. 15 Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Br Med J 1995;311:899e909. 16 Socinski MA. Cytotoxic chemotherapy in advanced non-small cell lung cancer. A review of standard treatment paradigms. Cancer Res 2004;10:4210Se4214S.