- Email: [email protected]
Germline Mutations in CDH1 and the Hereditary Diffuse Gastric and Lobular Breast Cancer Syndrome
Annals of Oncology 23 (Supplement 9): ix175–ix177, 2012 doi:10.1093/annonc/mds396
511PD
GERMLINE MUTATIONS IN CDH1 AND THE HEREDITARY DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME
P.R. Benusiglio1, D. Malka2, A. De Pauw3, B. Buecher3, E. Rouleau4, C. Colas5, S. Grandjouan6, M. Blayau7, S. Delaloge8, O. Caron1 1 Clinical Cancer Genetics, Department of Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE, 2Gastrointestinal Oncology, Department of Medical Oncology., Institut Gustave Roussy, Villejuif, FRANCE, 3Cancer Genetics, Institut Curie, Paris, FRANCE, 4Cancer Genetics, Centre Rene Huguenin, Saint-Cloud, FRANCE, 5Cancer Genetics, La Pitie Salpetriere, Paris, FRANCE, 6 Gastroenterology, Hopital Cochin, Paris, FRANCE, 7Molecular Genetics, CHU de Rennes - Hôpital Pontchaillou, Rennes, FRANCE, 8Breast Cancer Unit, Department of Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE
512PD
PORTUGUESE HIGH-RISK BREAST/OVARIAN CANCER: SURVIVAL ANALYSIS
P. Machado1, A. Clara2, A. Mayer3, S. Fragoso1, S. Santos1, A. Luís4, A. Opinião4, J. Parreira5, C. Simões5, F. Vaz4 1 Molecular Biology Research Unit, Portuguese Institute of Oncology of Lisbon, Lisbon, PORTUGAL, 2Medical Oncology, Portuguese Institute of Oncology, Lisbon, PORTUGAL, 3Southern Portuguese Cancer Registry (ROR-SUL),
Introduction: Even if only 5–10% of breast cancer (BC) is due to genetic predisposition (mainly related to BRCA1/2 mutations), its incidence, the high risk of these families and the possible prophylactic interventions make the study of these cases relevant. Scarce data suggest different survival in BRCA1 and BRCA2 associated ovarian cancer (OC). We aimed to analyze the survival of our BRCA1/2 BC and OC survivors. Patients and methods: Review of all BRCA1/2 cancer survivors identified until September 2011. All patients underwent pre and post-test counselling and were pre-screened for the c.156_157insAlu BRCA2 Portuguese founder mutation [Machado et al, 2007]. Negative patients were further analysed by CSCE and MLPA. Date of diagnosis and survival was obtained for 3 BRCA positive patients subgroups: BRCA1, BRCA2 (non c.156_157insAlu) and Alu (c.156_157insAlu). The control group (BRCAwt ) consisted on index patients screened during the same period, who were not BRCA1/2 positive and for whom we found information in the Southern Portuguese Cancer Registry (ROR-Sul). Results: Nine hundred and eighty consecutive index patients were screened and 139 BRCA1/2 positive families were identified: 44 BRCA1 and 95 BRCA2 (44 c.156_157insAlu). A total of 99 BC (88 female + 11 male) and 18 OC were identified in these families. Mean age at diagnosis and overall survival data for the 3 BRCA subgroups and control, regarding BC and OC are resumed in table1. Further clinical characterization (stage, presence of multiple cancers, prophylactic surgeries) is under way. Table1. Overall survival in pts with BC and OC: BRCA1/2 carriers vs wtBRCA1/2. Conclusion: BC was the more frequent type of cancer in these patients and BRCA1/2 carriers show a higher overall survival comparatively to BC pts with wt BRCA (P = 0,0197). The overall survival for OC is better for BRCA2 carriers ((P = 0,0310). OC numbers are small and more follow up of these and future identified carriers are needed. Disclosure: All authors have declared no conflicts of interest.
513PD
BRCA STATUS, MOLECULAR PROFILE AND CLINICAL VARIABLES IN PRIMARY BILATERAL BREAST CANCERS: A POPULATION-BASED CANCER REGISTRY STUDY
A. Musolino1, M.A. Bella1, M. Michiara2, P. Zanelli3, N. Naldi1, B. Bortesi1, P. Sgargi2, R. Camisa1, T.M. Neri3, A. Ardizzoni1 1 Medical Oncology Unit, University Hospital of Parma, Parma, ITALY, 2Medical Oncology Unit, University Hospital of Parma and Cancer Registry of Parma Province, Parma, ITALY, 3Medical Genetics Unit, University Hospital of Parma, Parma, ITALY Introduction: Incidence of primary bilateral breast cancer (BBC) is rare and does not exceed 5%. BRCA1/2 mutation carriers diagnosed with breast cancer have a strong life time risk of developing contralateral breast cancer. Objectives To address both the proportion of BBC associated with BRCA1/2 germline mutations and the contribution of germline mutations to the clinical features and outcome of these tumors. Materials and methods: We identified 263 BBC patients (pts) from a cohort of 9585 women with a first primary breast cancer systematically collected by the Cancer Registry of Parma Province from 1978 to 2006. Among these, 55 women, unselected for family history, were subjected to BRCA1/2 testing. In addition, 55 unilateral breast cancer pts, which tested negative for BRCA1/2 mutations, were evaluated as control group. Results: BRCA mutations were detected in 13 (24%) of 55 BBC pts. Family history of breast cancer was identified in 8% of these pts compared with 7% of non-carriers
Table: 512PD Female breast cancer
N Mean age at diagnosis (y) Mean OS (months) N of deaths
BRCA1 33 43,5 107,59 5
BRCA2 20 40,1 145,23 4
Ovarian cancer Alu 35 45,9 144,70 7
BRCAwt 302 78,47 51
BRCA1 2 68,3 40,45 1
BRCA2 8 47,2 57,92 4
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
Alu 8 55,8 86,48 1
BRCAwt 12 64,14 7
Downloaded from http://annonc.oxfordjournals.org/ by guest on April 11, 2016
Background: Germline mutations in the E-cadherin gene (CDH1) are found in up to 48% of families with hereditary diffuse gastric cancer (HDGC), a syndrome characterized by multiple cases of DGC in a family. In 2010, experts updated CDH1 testing criteria and included individuals and families with diagnoses of both DGC and lobular breast cancer (LBC), as an excess of LBC had been observed in HDGC families. We describe the characteristics associated with CDH1 mutations in a group of French patients and show that individuals or families with multiple LBC but no DGC should be offered genetic testing. Methods: We studied all index cases in which a CDH1 mutation had been identified between 2006 and 2011 in the Paris region. Results: We found 17 index cases with a CDH1 mutation, ten males and seven females, age was 17–63. Eight had familial DGC, four had sporadic DGC at a young age, one was a healthy male with two relatives with DGC, and one was a female with LBC and two siblings with DGC. Additionally, three females (18%) with no personal or family history of DGC had suffered from bilateral LBC under age 50. Only one was tested at diagnosis. She was offered prophylactic gastrectomy, and foci of DGC were seen on the surgical specimen. She is now doing well. The two others, who had initial negative BRCA1/2 screening, were only tested for CDH1 mutations years later after they had developed symptomatic DGC. Discussion: Three of our cases were females with bilateral LBC but no personal or family history of DGC. Two of them were only tested for CDH1 mutations once they had developed symptomatic DGC. Prophylactic gastrectomy is now systematically offered to mutation carriers, and these two cases would have been spared highly-lethal, symptomatic DGC, had they benefited from preventive surgery. The 2010 CDH1 testing criteria should be expanded and include cases or families with multiple LBC but no DGC. More precisely, any patient or family with multiple LBC under age 50 should be tested for CDH1 mutations, as carriers are offered life-saving surgery and adapted breast surveillance. Finally, we propose for consideration the name “hereditary diffuse gastric and lobular breast cancer” to define the cancer susceptibility syndrome associated with mutations in CDH1. Disclosure: All authors have declared no conflicts of interest.
Portuguese Institute of Oncology of Lisbon, Lisbon, PORTUGAL, 4Medical Oncology, Breast Cancer Risk Evaluation Clinic, Instituto Português de Oncologia de Lisboa, Lisbon, PORTUGAL, 5Breast Cancer Risk Evaluation Clinic, Instituto Português de Oncologia de Lisboa, Lisbon, PORTUGAL
abstracts
familial cancer and genetic syndromes
Annals of Oncology
(P = 0.64). Synchronous BBC was significantly rarer in BRCA carriers than in non-carriers. In addition, BRCA-positive pts were younger at diagnosis than BRCA-negative ones. The combination of high histologic grade, ER, PR, and HER2 negativity in both bilateral tumors was more frequent among BRCA-1 positive tumors than BRCA-2 positive and non-BRCA tumors (P < 0.001). Taken collectively, BRCA-positive BBC correlated with triple negative status compared to non-BRCA BBC and unilateral breast cancer controls (P < 0.001). There were no survival differences between BRCA-positive and non-BRCA tumors. Conclusions: Our data show that the combination of BBC occurrence and breast tumor phenotype can provide an efficient model for identifying individuals with high risk for BRCA mutations and support the hypothesis that BBC in BRCA carriers is qualitatively distinct from non-BRCA BBC and from sporadic, unilateral breast cancer. Further studies of incident cases are needed to better define the prognostic value of BRCA mutations. Disclosure: All authors have declared no conflicts of interest.
514P
GASTRIC CANCER IN PORTUGUESE FAMILIES WITH BRCA2 GENE MUTATIONS
Background and objective: BRCA 1/2 are tumor suppressor genes responsible for a high number of hereditary breast and ovarian cancers. BRCA 2 mutations are also associated with higher risk of other cancers: prostate, melanoma, pancreatic, gastric and bile duct cancer. BRCA2 mutations are more frequent than BRCA1 mutations in Portugal and GC has, historically, a high incidence in this country. Our objective was to analyze the frequency and characteristics of GC in confirmed BRCA2 Portuguese families. Methods: Retrospective analysis of all BRCA2 families registered in our Clinic. All cases of GC, on the mutated side of the family, for 3 consecutive generations, were registered. The control group consisted of breast cancer families with standard risk of breast cancer (FSRBC) (with probability <5% of BRCA mutation by BRCAPRO). GC cases in both groups were compared using the Fisher’s exact test. Results: Of 119 families with BRCA 2 mutation analyzed, 35 families (29.4%) had reported cases of GC. Of these 35 families, 24 had one case of GC, 10 had two cases and one family had seven cases. A total of 51 GC cases were found: 20 females (39%) and 31 males (61%) with a median age at diagnosis of 60 years (28–80 yrs). Pathological confirmation was available in 5 cases (4 adenocarcinoma, 1 neuroendocrine). Two cases of GC were diagnosed in BRCA2 pts who were breast cancer survivors and 1 in a healthy woman previously submitted to prophylactic adnexectomy. These 35 families had 19 different BRCA2 mutations, 15 C.156_157insAlu (Portuguese founder mutation). No difference between the frequency of GC in families with C.156_157insAlu mutation and in other BRCA2 families was observed. In the control group of 163 families, only 19 (12%) had cases of GC (1 case in 18 families and 2 cases in 1 family). The median age was 61 years (range 52–76). The frequency of GC in BRCA 2 families was higher compared with the frequency in FSRBC, odds ratio 3.0 CI (1.7–5.3), p < 0, 0001. Conclusion(s): BRCA2 mutations are associated with a higher risk of GC compared with FSRBC. The Portuguese founder mutation was not associated with higher prevalence of GC compared to the other BRCA 2 mutations. Since GC has already a high incidence in our country, we believe this data supports the need for GC screening in BRCA2 pts. Disclosure: All authors have declared no conflicts of interest.
515P
CLINICAL PRESENTATION IN BRCA1/2 MUTATION CARRIERS: A SINGLE-INSTITUTION EXPERIENCE
A. Fontana1, P. Aretini2, I. Ferrarini1, E. Bona1, I. Stasi1, E. Landucci3, G. Allegrini4, M. Roncella5, M.A. Caligo2, A. Falcone1 1 Oncologia Medica Ii, Polo Oncologico, Ospedale S. Chiara, AOUP, Pisa, ITALY, 2 Divisione di Patologia Dipartimento di Medicina di Laboratorio e Diagnostica Molecolare, Sezione Genetica Oncologica, Pisa, ITALY, 3Polo Oncologico Ospedale S.Chaira, Oncologia Medica I, Pisa, ITALY, 4Oncologia Medica, Ospedale “F. Lotti”, Pontedera, ITALY, 5AOUP S.Chiara, UO Senologia, Pisa, ITALY Background: Genetic testing for BRCA1/2 mutations may be useful for prevention and close surveillance as well for treatments selection in cancer patients. Methods: Between May 2001 and July 2011 we identified 206 BRCA1/2 mutations carriers: 145 (70%) affected and 61 (30%) unaffected. Of the 145 patients 87 (60%) were found to carry a BRCA1 mutation and 58 (40%) BRCA2. One hundred-twenty-four patients (85%) were diagnosed with breast cancer (BC) and
ix | Abstracts
516P
AN AUDIT OF SCREENING FOR LOSS OF MISMATCH REPAIR (MMR) PROTEIN EXPRESSION IN COLORECTAL CANCERS (CRC) IN A TERTIARY REFERRAL CENTRE
K. Cadoo1, S. Noonan1, N. McNicholas1, M.J. Kennedy2 1 Medical Oncology, St. James Hospital, Dublin, Dublin, IRELAND, 2Dept Medical Oncology, St James’s Hospital, Dublin, IRELAND Introduction: Lynch syndrome accounts for 2% of CRC, resulting from germline mutations in DNA MMR genes; MSH2, MLH1, MSH6, PMS2 & PMS1. Mutations in MSH2 & MLH1 account for 85% of cases. It is imperative to identify Lynch syndrome patients to aggressively manage their risks. In 2009, the EGAPP working group recommended consideration of genetic testing in all new CRC. To this end, a number of institutions are reflex testing all CRC for loss of MMR protein expression by immunohistochemistry. This is a screening tool to select patients for germline testing as 15% of sporadic CRC will also demonstrate loss of expression. This approach was adopted in our institution in late 2008, with analysis for loss of MSH2, MLH1, MSH6 & PMS2 expression. This audit reviews the data from 2009–2010. Methods: Patients were identified from CRC database & their records reviewed. Results: There were 271 patients; 9 (3%) had loss of MMR protein expression, 156 (58%) no loss, 106 (39%) not tested. Of the 106 not tested, 38 (36%) had a biopsy only, 15 (14%) had a polypectomy, 11 (10%) had significant response to neo-adjuvant chemoradiation with insufficient tumor for testing at resection, 6 (6%) had other reasons for not testing. 36 (13% of entire cohort) patients were not tested for unclear reasons. Of the 9 who demonstrated loss of expression, median age was 72yr (36–86) & 3 had family history of CRC. 2 patients were referred for genetic assessment, 1 has Lynch syndrome, 1 awaits the outcome of investigations. 1 elderly patient declined referral. Conclusion: This audit highlights the challenges encountered with the initiation of this screening tool. A number of tumors were not tested, in 13% the reason is unclear, these are being reviewed. In 24% (biopsy & polypectomy & neoadjuvant groups) there was insufficient tumor for testing, raising questions about the validity of the screening test. Of the patients identified with loss, only 2 were referred for genetic assessment. In addition, a cohort of this size would expect to identify 5 Lynch patients, these may exist in the group who demonstrated loss of expression but were not appropriately referred or in the group whose tumors were not tested. Following this audit, processes are being put in place to increase the number of tumors tested and to streamline the further management of patients with a positive screening test. Disclosure: All authors have declared no conflicts of interest.
517P
THE IMPLEMENTATION OF A MULTIDISCIPLINARY HEREDOFAMILIAL CANCER UNIT CHANGES HEREDITARY CANCER RISK PERCEPTION AMONG ONCOLOGISTS
I. Márquez-Rodas, A.B. Ruperez Blanco, B. Moya, S. Custodio Cabello, S. Pérez Ramírez, M. Cavanagh, D. López-Trabada, S. López-Tarruella, Y. Jerez Medical Oncology, Instituto Investigación Sanitaria Hospital Gregorio Marañón, Madrid, SPAIN Background: A detailed family history and knowing the criteria for hereditary cancer risk are essential for oncology practice, since patients and relatives at risk could benefit from further genetic counseling (GC). The objective of this work is to
Volume 23 | Supplement 9 | September 2012
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M.T.A. Alexandre1, A. Luís2, A. Opinião2, S. Bento3, C. Simões3, J. Parreira3, S. Fragoso4, P. Machado4, S. Santos4, F. Vaz2 1 Medical Oncology, Instituto Português de Oncologia de Lisboa, Lisbon, PORTUGAL, 2Medical Oncology, Breast Cancer Risk Evaluation Clinic, Instituto Português de Oncologia de Lisboa, Lisbon, PORTUGAL, 3Breast Cancer Risk Evaluation Clinic, Instituto Português de Oncologia de Lisboa, Lisbon, PORTUGAL, 4Molecular Biology Research Unit, Instituto Português de Oncologia de Lisboa, Lisbon, PORTUGAL
among them 73 (59%) tested BRCA1-positive and 51 (41%) BRCA2-positive. Bilateral BC was found in 26 (21%) patients (46% BRCA1, 54% BRCA2). Ovarian tumor was identified in 30 (21%) women (83% BRCA1-positive), while 12 (8%) had breast plus ovarian cancer (92% BRCA1-positive). Others tumors (oesophagus, pancreas, thyroid): 3 (2%) patients. Results: We obtained clinical and pathological data from 38 BC patients. Median age: 40 years (range 23–65); male/female: 1/37. Histology: ductal carcinoma 32 (84%) patients, lobular 1 (3%) patient, medullary 2 (5%) patients, in situ carcinoma 3 (8%) patients. Most of the patients showed stage I BC (19 patients; 50%), while 3 (8%) showed a metastatic spread at the time of diagnosis. Overall 18 (47%) patients had triple negative breast cancer (TNBC), 18 (47%) had hormonal receptor (HR) positive disease, 1 (3%) HER2-positive/HR-negative cancer and 1 was not evaluable. Interestingly, 20 patients were younger than 40 years and among them 11 (55%) had TNBC (91% BRCA1-carriers). Twenty-six patients received neoadjuvant/adjuvant treatments (11 anthracycline-taxane; 8 anthracycline-based; 5 CMF and 2 docetaxel-cyclophosphamide). Among the 7 patients treated with neoadjuvant chemotherapy 2 pCR (ypT0N0) and 5 PR were reported. pCRs were observed in 1 TN and 1 HR-positive BRCA1-carriers, both treated with anthracycline-taxane. Metachronous BC was found in 6 (16%) patients with a median time to diagnosis of 12 years (range 5-22). Prophylactic mastectomy was performed in 4 (10%) patients while 6 (16%) underwent prophylactic bilateral salpingo-oophorectomy. Conclusions: Our data seems consistent with previous literature. Interestingly the majority of younger BC patients showed a BRCA1-TN phenotype. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
compare the family history record and the hereditary cancer perception risk according to National Cancer Institute (NCI) criteria before and after the creation of a multidisciplinary heredofamilial cancer unit (HFCU) in our medical oncology service. Methods: We retrospectively analyze the clinical records from new incoming patients of our medical oncology service in two cohorts: Cohort 1, from January 2009 to December 2009 (616 patients, before HFCU creation); and cohort 2, from May 2010 to April 2011 (after HFCU creation, first 312 patients analyzed). Family history record (yes/no) and NCI general hereditary cancer criteria (unusually early age; one or more first-degree relatives affected with the same or a related tumor; synchronous, bilateral or metachronous cancer in the same patient; atypical presentations) were collected. Results were compared using chi- square test. p <0.05 was considered significant.
Results: The table summarizes the results. In cohort 1, 27.9% (172/616) of clinical records contained the family history, while in cohort 2 this percentage increased to 51.6% (116/312), ( p < 0.01). 104/616 (16.8%) patients in cohort 1 and 69/312 (22.1%) in cohort 2, met NCI risk criteria (N.S.) In cohort 1, 13.5% (14/104) of these patients were referred to GC, while in cohort 2 this percentage increased to 45% (31/ 69) ( p < 0.01). Conclusions: The creation of a HFCU significantly increased the quality of family history records and the referral of patients at risk to GC. However, further efforts must be made in order to remark the importance of family history in oncology. Disclosure: All authors have declared no conflicts of interest.
Table: 517P
Family history recorded (YES/NO) NCI criteria (YES/NO) % GC referral GC referral and type of NCI criteria
BEFORE HFCU 172/616 (27.9%) 104/616 (16.8%) 14/104 (13.5%) • Individual: 7/70 (10%) • Familial: 2/26 (8%) • Both: 5/10 (50%)
AFTER HFCU 161/312 (51.6%) 69/312 (22.1%) 31/69 (45%) • Individual: 7/37 (18.9%) • Familial: 13/18 (72%) • Both: 11/14 (78,5%)
p <0.01 N.S <0.01 N.A.
Downloaded from http://annonc.oxfordjournals.org/ by guest on April 11, 2016
Volume 23 | Supplement 9 | September 2012
doi:10.1093/annonc/mds396 | ix
511PD
GERMLINE MUTATIONS IN CDH1 AND THE HEREDITARY DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME
P.R. Benusiglio1, D. Malka2, A. De Pauw3, B. Buecher3, E. Rouleau4, C. Colas5, S. Grandjouan6, M. Blayau7, S. Delaloge8, O. Caron1 1 Clinical Cancer Genetics, Department of Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE, 2Gastrointestinal Oncology, Department of Medical Oncology., Institut Gustave Roussy, Villejuif, FRANCE, 3Cancer Genetics, Institut Curie, Paris, FRANCE, 4Cancer Genetics, Centre Rene Huguenin, Saint-Cloud, FRANCE, 5Cancer Genetics, La Pitie Salpetriere, Paris, FRANCE, 6 Gastroenterology, Hopital Cochin, Paris, FRANCE, 7Molecular Genetics, CHU de Rennes - Hôpital Pontchaillou, Rennes, FRANCE, 8Breast Cancer Unit, Department of Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE
512PD
PORTUGUESE HIGH-RISK BREAST/OVARIAN CANCER: SURVIVAL ANALYSIS
P. Machado1, A. Clara2, A. Mayer3, S. Fragoso1, S. Santos1, A. Luís4, A. Opinião4, J. Parreira5, C. Simões5, F. Vaz4 1 Molecular Biology Research Unit, Portuguese Institute of Oncology of Lisbon, Lisbon, PORTUGAL, 2Medical Oncology, Portuguese Institute of Oncology, Lisbon, PORTUGAL, 3Southern Portuguese Cancer Registry (ROR-SUL),
Introduction: Even if only 5–10% of breast cancer (BC) is due to genetic predisposition (mainly related to BRCA1/2 mutations), its incidence, the high risk of these families and the possible prophylactic interventions make the study of these cases relevant. Scarce data suggest different survival in BRCA1 and BRCA2 associated ovarian cancer (OC). We aimed to analyze the survival of our BRCA1/2 BC and OC survivors. Patients and methods: Review of all BRCA1/2 cancer survivors identified until September 2011. All patients underwent pre and post-test counselling and were pre-screened for the c.156_157insAlu BRCA2 Portuguese founder mutation [Machado et al, 2007]. Negative patients were further analysed by CSCE and MLPA. Date of diagnosis and survival was obtained for 3 BRCA positive patients subgroups: BRCA1, BRCA2 (non c.156_157insAlu) and Alu (c.156_157insAlu). The control group (BRCAwt ) consisted on index patients screened during the same period, who were not BRCA1/2 positive and for whom we found information in the Southern Portuguese Cancer Registry (ROR-Sul). Results: Nine hundred and eighty consecutive index patients were screened and 139 BRCA1/2 positive families were identified: 44 BRCA1 and 95 BRCA2 (44 c.156_157insAlu). A total of 99 BC (88 female + 11 male) and 18 OC were identified in these families. Mean age at diagnosis and overall survival data for the 3 BRCA subgroups and control, regarding BC and OC are resumed in table1. Further clinical characterization (stage, presence of multiple cancers, prophylactic surgeries) is under way. Table1. Overall survival in pts with BC and OC: BRCA1/2 carriers vs wtBRCA1/2. Conclusion: BC was the more frequent type of cancer in these patients and BRCA1/2 carriers show a higher overall survival comparatively to BC pts with wt BRCA (P = 0,0197). The overall survival for OC is better for BRCA2 carriers ((P = 0,0310). OC numbers are small and more follow up of these and future identified carriers are needed. Disclosure: All authors have declared no conflicts of interest.
513PD
BRCA STATUS, MOLECULAR PROFILE AND CLINICAL VARIABLES IN PRIMARY BILATERAL BREAST CANCERS: A POPULATION-BASED CANCER REGISTRY STUDY
A. Musolino1, M.A. Bella1, M. Michiara2, P. Zanelli3, N. Naldi1, B. Bortesi1, P. Sgargi2, R. Camisa1, T.M. Neri3, A. Ardizzoni1 1 Medical Oncology Unit, University Hospital of Parma, Parma, ITALY, 2Medical Oncology Unit, University Hospital of Parma and Cancer Registry of Parma Province, Parma, ITALY, 3Medical Genetics Unit, University Hospital of Parma, Parma, ITALY Introduction: Incidence of primary bilateral breast cancer (BBC) is rare and does not exceed 5%. BRCA1/2 mutation carriers diagnosed with breast cancer have a strong life time risk of developing contralateral breast cancer. Objectives To address both the proportion of BBC associated with BRCA1/2 germline mutations and the contribution of germline mutations to the clinical features and outcome of these tumors. Materials and methods: We identified 263 BBC patients (pts) from a cohort of 9585 women with a first primary breast cancer systematically collected by the Cancer Registry of Parma Province from 1978 to 2006. Among these, 55 women, unselected for family history, were subjected to BRCA1/2 testing. In addition, 55 unilateral breast cancer pts, which tested negative for BRCA1/2 mutations, were evaluated as control group. Results: BRCA mutations were detected in 13 (24%) of 55 BBC pts. Family history of breast cancer was identified in 8% of these pts compared with 7% of non-carriers
Table: 512PD Female breast cancer
N Mean age at diagnosis (y) Mean OS (months) N of deaths
BRCA1 33 43,5 107,59 5
BRCA2 20 40,1 145,23 4
Ovarian cancer Alu 35 45,9 144,70 7
BRCAwt 302 78,47 51
BRCA1 2 68,3 40,45 1
BRCA2 8 47,2 57,92 4
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
Alu 8 55,8 86,48 1
BRCAwt 12 64,14 7
Downloaded from http://annonc.oxfordjournals.org/ by guest on April 11, 2016
Background: Germline mutations in the E-cadherin gene (CDH1) are found in up to 48% of families with hereditary diffuse gastric cancer (HDGC), a syndrome characterized by multiple cases of DGC in a family. In 2010, experts updated CDH1 testing criteria and included individuals and families with diagnoses of both DGC and lobular breast cancer (LBC), as an excess of LBC had been observed in HDGC families. We describe the characteristics associated with CDH1 mutations in a group of French patients and show that individuals or families with multiple LBC but no DGC should be offered genetic testing. Methods: We studied all index cases in which a CDH1 mutation had been identified between 2006 and 2011 in the Paris region. Results: We found 17 index cases with a CDH1 mutation, ten males and seven females, age was 17–63. Eight had familial DGC, four had sporadic DGC at a young age, one was a healthy male with two relatives with DGC, and one was a female with LBC and two siblings with DGC. Additionally, three females (18%) with no personal or family history of DGC had suffered from bilateral LBC under age 50. Only one was tested at diagnosis. She was offered prophylactic gastrectomy, and foci of DGC were seen on the surgical specimen. She is now doing well. The two others, who had initial negative BRCA1/2 screening, were only tested for CDH1 mutations years later after they had developed symptomatic DGC. Discussion: Three of our cases were females with bilateral LBC but no personal or family history of DGC. Two of them were only tested for CDH1 mutations once they had developed symptomatic DGC. Prophylactic gastrectomy is now systematically offered to mutation carriers, and these two cases would have been spared highly-lethal, symptomatic DGC, had they benefited from preventive surgery. The 2010 CDH1 testing criteria should be expanded and include cases or families with multiple LBC but no DGC. More precisely, any patient or family with multiple LBC under age 50 should be tested for CDH1 mutations, as carriers are offered life-saving surgery and adapted breast surveillance. Finally, we propose for consideration the name “hereditary diffuse gastric and lobular breast cancer” to define the cancer susceptibility syndrome associated with mutations in CDH1. Disclosure: All authors have declared no conflicts of interest.
Portuguese Institute of Oncology of Lisbon, Lisbon, PORTUGAL, 4Medical Oncology, Breast Cancer Risk Evaluation Clinic, Instituto Português de Oncologia de Lisboa, Lisbon, PORTUGAL, 5Breast Cancer Risk Evaluation Clinic, Instituto Português de Oncologia de Lisboa, Lisbon, PORTUGAL
abstracts
familial cancer and genetic syndromes
Annals of Oncology
(P = 0.64). Synchronous BBC was significantly rarer in BRCA carriers than in non-carriers. In addition, BRCA-positive pts were younger at diagnosis than BRCA-negative ones. The combination of high histologic grade, ER, PR, and HER2 negativity in both bilateral tumors was more frequent among BRCA-1 positive tumors than BRCA-2 positive and non-BRCA tumors (P < 0.001). Taken collectively, BRCA-positive BBC correlated with triple negative status compared to non-BRCA BBC and unilateral breast cancer controls (P < 0.001). There were no survival differences between BRCA-positive and non-BRCA tumors. Conclusions: Our data show that the combination of BBC occurrence and breast tumor phenotype can provide an efficient model for identifying individuals with high risk for BRCA mutations and support the hypothesis that BBC in BRCA carriers is qualitatively distinct from non-BRCA BBC and from sporadic, unilateral breast cancer. Further studies of incident cases are needed to better define the prognostic value of BRCA mutations. Disclosure: All authors have declared no conflicts of interest.
514P
GASTRIC CANCER IN PORTUGUESE FAMILIES WITH BRCA2 GENE MUTATIONS
Background and objective: BRCA 1/2 are tumor suppressor genes responsible for a high number of hereditary breast and ovarian cancers. BRCA 2 mutations are also associated with higher risk of other cancers: prostate, melanoma, pancreatic, gastric and bile duct cancer. BRCA2 mutations are more frequent than BRCA1 mutations in Portugal and GC has, historically, a high incidence in this country. Our objective was to analyze the frequency and characteristics of GC in confirmed BRCA2 Portuguese families. Methods: Retrospective analysis of all BRCA2 families registered in our Clinic. All cases of GC, on the mutated side of the family, for 3 consecutive generations, were registered. The control group consisted of breast cancer families with standard risk of breast cancer (FSRBC) (with probability <5% of BRCA mutation by BRCAPRO). GC cases in both groups were compared using the Fisher’s exact test. Results: Of 119 families with BRCA 2 mutation analyzed, 35 families (29.4%) had reported cases of GC. Of these 35 families, 24 had one case of GC, 10 had two cases and one family had seven cases. A total of 51 GC cases were found: 20 females (39%) and 31 males (61%) with a median age at diagnosis of 60 years (28–80 yrs). Pathological confirmation was available in 5 cases (4 adenocarcinoma, 1 neuroendocrine). Two cases of GC were diagnosed in BRCA2 pts who were breast cancer survivors and 1 in a healthy woman previously submitted to prophylactic adnexectomy. These 35 families had 19 different BRCA2 mutations, 15 C.156_157insAlu (Portuguese founder mutation). No difference between the frequency of GC in families with C.156_157insAlu mutation and in other BRCA2 families was observed. In the control group of 163 families, only 19 (12%) had cases of GC (1 case in 18 families and 2 cases in 1 family). The median age was 61 years (range 52–76). The frequency of GC in BRCA 2 families was higher compared with the frequency in FSRBC, odds ratio 3.0 CI (1.7–5.3), p < 0, 0001. Conclusion(s): BRCA2 mutations are associated with a higher risk of GC compared with FSRBC. The Portuguese founder mutation was not associated with higher prevalence of GC compared to the other BRCA 2 mutations. Since GC has already a high incidence in our country, we believe this data supports the need for GC screening in BRCA2 pts. Disclosure: All authors have declared no conflicts of interest.
515P
CLINICAL PRESENTATION IN BRCA1/2 MUTATION CARRIERS: A SINGLE-INSTITUTION EXPERIENCE
A. Fontana1, P. Aretini2, I. Ferrarini1, E. Bona1, I. Stasi1, E. Landucci3, G. Allegrini4, M. Roncella5, M.A. Caligo2, A. Falcone1 1 Oncologia Medica Ii, Polo Oncologico, Ospedale S. Chiara, AOUP, Pisa, ITALY, 2 Divisione di Patologia Dipartimento di Medicina di Laboratorio e Diagnostica Molecolare, Sezione Genetica Oncologica, Pisa, ITALY, 3Polo Oncologico Ospedale S.Chaira, Oncologia Medica I, Pisa, ITALY, 4Oncologia Medica, Ospedale “F. Lotti”, Pontedera, ITALY, 5AOUP S.Chiara, UO Senologia, Pisa, ITALY Background: Genetic testing for BRCA1/2 mutations may be useful for prevention and close surveillance as well for treatments selection in cancer patients. Methods: Between May 2001 and July 2011 we identified 206 BRCA1/2 mutations carriers: 145 (70%) affected and 61 (30%) unaffected. Of the 145 patients 87 (60%) were found to carry a BRCA1 mutation and 58 (40%) BRCA2. One hundred-twenty-four patients (85%) were diagnosed with breast cancer (BC) and
ix | Abstracts
516P
AN AUDIT OF SCREENING FOR LOSS OF MISMATCH REPAIR (MMR) PROTEIN EXPRESSION IN COLORECTAL CANCERS (CRC) IN A TERTIARY REFERRAL CENTRE
K. Cadoo1, S. Noonan1, N. McNicholas1, M.J. Kennedy2 1 Medical Oncology, St. James Hospital, Dublin, Dublin, IRELAND, 2Dept Medical Oncology, St James’s Hospital, Dublin, IRELAND Introduction: Lynch syndrome accounts for 2% of CRC, resulting from germline mutations in DNA MMR genes; MSH2, MLH1, MSH6, PMS2 & PMS1. Mutations in MSH2 & MLH1 account for 85% of cases. It is imperative to identify Lynch syndrome patients to aggressively manage their risks. In 2009, the EGAPP working group recommended consideration of genetic testing in all new CRC. To this end, a number of institutions are reflex testing all CRC for loss of MMR protein expression by immunohistochemistry. This is a screening tool to select patients for germline testing as 15% of sporadic CRC will also demonstrate loss of expression. This approach was adopted in our institution in late 2008, with analysis for loss of MSH2, MLH1, MSH6 & PMS2 expression. This audit reviews the data from 2009–2010. Methods: Patients were identified from CRC database & their records reviewed. Results: There were 271 patients; 9 (3%) had loss of MMR protein expression, 156 (58%) no loss, 106 (39%) not tested. Of the 106 not tested, 38 (36%) had a biopsy only, 15 (14%) had a polypectomy, 11 (10%) had significant response to neo-adjuvant chemoradiation with insufficient tumor for testing at resection, 6 (6%) had other reasons for not testing. 36 (13% of entire cohort) patients were not tested for unclear reasons. Of the 9 who demonstrated loss of expression, median age was 72yr (36–86) & 3 had family history of CRC. 2 patients were referred for genetic assessment, 1 has Lynch syndrome, 1 awaits the outcome of investigations. 1 elderly patient declined referral. Conclusion: This audit highlights the challenges encountered with the initiation of this screening tool. A number of tumors were not tested, in 13% the reason is unclear, these are being reviewed. In 24% (biopsy & polypectomy & neoadjuvant groups) there was insufficient tumor for testing, raising questions about the validity of the screening test. Of the patients identified with loss, only 2 were referred for genetic assessment. In addition, a cohort of this size would expect to identify 5 Lynch patients, these may exist in the group who demonstrated loss of expression but were not appropriately referred or in the group whose tumors were not tested. Following this audit, processes are being put in place to increase the number of tumors tested and to streamline the further management of patients with a positive screening test. Disclosure: All authors have declared no conflicts of interest.
517P
THE IMPLEMENTATION OF A MULTIDISCIPLINARY HEREDOFAMILIAL CANCER UNIT CHANGES HEREDITARY CANCER RISK PERCEPTION AMONG ONCOLOGISTS
I. Márquez-Rodas, A.B. Ruperez Blanco, B. Moya, S. Custodio Cabello, S. Pérez Ramírez, M. Cavanagh, D. López-Trabada, S. López-Tarruella, Y. Jerez Medical Oncology, Instituto Investigación Sanitaria Hospital Gregorio Marañón, Madrid, SPAIN Background: A detailed family history and knowing the criteria for hereditary cancer risk are essential for oncology practice, since patients and relatives at risk could benefit from further genetic counseling (GC). The objective of this work is to
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M.T.A. Alexandre1, A. Luís2, A. Opinião2, S. Bento3, C. Simões3, J. Parreira3, S. Fragoso4, P. Machado4, S. Santos4, F. Vaz2 1 Medical Oncology, Instituto Português de Oncologia de Lisboa, Lisbon, PORTUGAL, 2Medical Oncology, Breast Cancer Risk Evaluation Clinic, Instituto Português de Oncologia de Lisboa, Lisbon, PORTUGAL, 3Breast Cancer Risk Evaluation Clinic, Instituto Português de Oncologia de Lisboa, Lisbon, PORTUGAL, 4Molecular Biology Research Unit, Instituto Português de Oncologia de Lisboa, Lisbon, PORTUGAL
among them 73 (59%) tested BRCA1-positive and 51 (41%) BRCA2-positive. Bilateral BC was found in 26 (21%) patients (46% BRCA1, 54% BRCA2). Ovarian tumor was identified in 30 (21%) women (83% BRCA1-positive), while 12 (8%) had breast plus ovarian cancer (92% BRCA1-positive). Others tumors (oesophagus, pancreas, thyroid): 3 (2%) patients. Results: We obtained clinical and pathological data from 38 BC patients. Median age: 40 years (range 23–65); male/female: 1/37. Histology: ductal carcinoma 32 (84%) patients, lobular 1 (3%) patient, medullary 2 (5%) patients, in situ carcinoma 3 (8%) patients. Most of the patients showed stage I BC (19 patients; 50%), while 3 (8%) showed a metastatic spread at the time of diagnosis. Overall 18 (47%) patients had triple negative breast cancer (TNBC), 18 (47%) had hormonal receptor (HR) positive disease, 1 (3%) HER2-positive/HR-negative cancer and 1 was not evaluable. Interestingly, 20 patients were younger than 40 years and among them 11 (55%) had TNBC (91% BRCA1-carriers). Twenty-six patients received neoadjuvant/adjuvant treatments (11 anthracycline-taxane; 8 anthracycline-based; 5 CMF and 2 docetaxel-cyclophosphamide). Among the 7 patients treated with neoadjuvant chemotherapy 2 pCR (ypT0N0) and 5 PR were reported. pCRs were observed in 1 TN and 1 HR-positive BRCA1-carriers, both treated with anthracycline-taxane. Metachronous BC was found in 6 (16%) patients with a median time to diagnosis of 12 years (range 5-22). Prophylactic mastectomy was performed in 4 (10%) patients while 6 (16%) underwent prophylactic bilateral salpingo-oophorectomy. Conclusions: Our data seems consistent with previous literature. Interestingly the majority of younger BC patients showed a BRCA1-TN phenotype. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
compare the family history record and the hereditary cancer perception risk according to National Cancer Institute (NCI) criteria before and after the creation of a multidisciplinary heredofamilial cancer unit (HFCU) in our medical oncology service. Methods: We retrospectively analyze the clinical records from new incoming patients of our medical oncology service in two cohorts: Cohort 1, from January 2009 to December 2009 (616 patients, before HFCU creation); and cohort 2, from May 2010 to April 2011 (after HFCU creation, first 312 patients analyzed). Family history record (yes/no) and NCI general hereditary cancer criteria (unusually early age; one or more first-degree relatives affected with the same or a related tumor; synchronous, bilateral or metachronous cancer in the same patient; atypical presentations) were collected. Results were compared using chi- square test. p <0.05 was considered significant.
Results: The table summarizes the results. In cohort 1, 27.9% (172/616) of clinical records contained the family history, while in cohort 2 this percentage increased to 51.6% (116/312), ( p < 0.01). 104/616 (16.8%) patients in cohort 1 and 69/312 (22.1%) in cohort 2, met NCI risk criteria (N.S.) In cohort 1, 13.5% (14/104) of these patients were referred to GC, while in cohort 2 this percentage increased to 45% (31/ 69) ( p < 0.01). Conclusions: The creation of a HFCU significantly increased the quality of family history records and the referral of patients at risk to GC. However, further efforts must be made in order to remark the importance of family history in oncology. Disclosure: All authors have declared no conflicts of interest.
Table: 517P
Family history recorded (YES/NO) NCI criteria (YES/NO) % GC referral GC referral and type of NCI criteria
BEFORE HFCU 172/616 (27.9%) 104/616 (16.8%) 14/104 (13.5%) • Individual: 7/70 (10%) • Familial: 2/26 (8%) • Both: 5/10 (50%)
AFTER HFCU 161/312 (51.6%) 69/312 (22.1%) 31/69 (45%) • Individual: 7/37 (18.9%) • Familial: 13/18 (72%) • Both: 11/14 (78,5%)
p <0.01 N.S <0.01 N.A.
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Volume 23 | Supplement 9 | September 2012
doi:10.1093/annonc/mds396 | ix