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Hereditary Cancer in Clinical Practice
Published in: Hereditary Cancer in Clinical Practice 1/2019

Open Access 01-12-2019 | Breast Cancer | Research

Increased breast cancer risk in women with neurofibromatosis type 1: a meta-analysis and systematic review of the literature

Authors: Lorena P. Suarez-Kelly, Lianbo Yu, David Kline, Eric B. Schneider, Doreen M. Agnese, William E. Carson

Published in: Hereditary Cancer in Clinical Practice | Issue 1/2019

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Abstract

Background

Neurofibromatosis type 1 (NF1) is a cancer predisposing syndrome. Studies suggest that women < 50 years old (y.o.) with NF1 have an increased breast cancer (BC) incidence and BC associated mortality. However, this has not been widely recognized secondary to small study populations.

Methods

A systematic literature review was conducted through database searches for BC and NF1: 3456 articles identified, 166 reviewed, 58 used for descriptive analysis and 4 utilized for meta-analysis. Fisher’s exact tests, Kaplan-Meier curves and random-effects meta-analysis models were used for analysis.

Results

Two hundred eighty-six cases of NF1 and female BC were identified with a median age of 46 years at diagnosis; 53% were <  50. Peak age of BC diagnosis was between 34 to 44 years. Women < 50 y.o. presented with more advanced disease vs. those ≥50 (56% vs. 22% stage III-IV, respectively; p = 0.005). Median survival for the entire cohort was 5 years vs. the reported median BC survival of over 20 years in the general population using the SEER database. Median age at BC death was 48.5 years; 64% of deceased patients were <  50. Meta-analysis of a total of 4178 women with NF1 revealed a BC standardized incidence ratio (SIR) of 3.07 (95%CI 2.16–4.38) for women with NF1 vs. the general population. Women < 50 y.o. demonstrated a higher SIR of 5.08 (95%CI 3.77–6.81) compared to 1.92 (95%CI 1.40–2.63) if ≥50 y.o.

Conclusions

This systematic literature review and meta-analysis suggests that women with NF1 <  50 y.o. have a five-fold increased risk of BC, present with more advanced disease, and may have an increased BC related mortality. Increased awareness and implementation of recent National Comprehensive Cancer Network early BC screening guidelines for this high-risk patient population is essential. Additional evaluation on the influence of NF1 gene mutations identified in patients undergoing hereditary cancer genetic testing on breast cancer risk in individuals without clinical evidence of NF1 is needed.
Appendix
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Literature
1.
2.
Kallionpää RA, Uusitalo E, Leppävirta J, Pöyhönen M, Peltonen S, Peltonen J. Prevalence of neurofibromatosis type 1 in the Finnish population. Genetics In Medicine. 2018;20(9):1082–6.
3.
4.
Uusitalo E, Leppävirta J, Koffert A, Suominen S, Vahtera J, Vahlberg T, Pöyhönen M, Peltonen J, Peltonen S. Incidence and mortality of Neurofibromatosis: a total population study in Finland. J Investig Dermatol. 2015;135(3):904–6.PubMedCrossRef
5.
Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010;152A(2):327–32.PubMedCrossRef
6.
7.
Korf BR. Neurofibromatosis. In: Dulac O, Lassonde M, Sarnat HB, editors. Handbook of Clinical Neurology. Volume 111, edn: Elsevier; 2013. p. 333–40.
8.
Xu W, Yang X, Hu X, Li S. Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing. Int J Mol Med. 2014;34:53–60.PubMedPubMedCentralCrossRef
9.
Sharif S, Moran A, Huson SM, Iddenden R, Shenton A, Howard E, Evans DGR. Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J Med Genet. 2007;44(8):481–4.PubMedPubMedCentralCrossRef
10.
Walker L, Thompson D, Easton D, Ponder B, Ponder M, Frayling I, Baralle D. A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Br J Cancer. 2006;95(2):233–8.PubMedPubMedCentralCrossRef
11.
Uusitalo E, Rantanen M, Kallionpää RA, Pöyhönen M, Leppävirta J, Ylä-Outinen H, Riccardi VM, Pukkala E, Pitkäniemi J, Peltonen S, et al. Distinctive cancer associations in patients with Neurofibromatosis type 1. J Clin Oncol. 2016;34(17):1978–86.PubMedCrossRef
12.
13.
Evans DGR. What is the malignancy risk in Neurofibromatosis type 1? J Clin Oncol. 2016;34(17):1967–9.PubMedCrossRef
14.
Seminog OO, Goldacre MJ. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study. Br J Cancer. 2012;108:193.PubMedPubMedCentralCrossRef
15.
The Cancer Genome Atlas Network. In: Comprehensive molecular portraits of human breast tumors. vol. 490. Nature: Macmillan Publishers Limited; 2012: 61–70.
16.
Wallace MD, Pfefferle AD, Shen L, McNairn AJ, Cerami EG, Fallon BL, Rinaldi VD, Southard TL, Perou CM, Schimenti JC. Comparative oncogenomics implicates the neurofibromin 1 gene (NF1) as a breast cancer driver. Genetics. 2012;92(2):385–96.CrossRef
17.
Salemis NS, Nakos G, Sambaziotis D, Gourgiotis S. Breast cancer associated with type 1 neurofibromatosis. Breast Cancer. 2010;17:306–9.PubMedCrossRef
18.
19.
Zoller MET, Rembeck B, Oden A, Samuelson M, Angervall L. Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population. Cancer. 1997;79(11):2125–31.PubMedCrossRef
20.
Wang X, Levin AM, Smolinski SE, Vigneau FD, Levin NK, Tainsky MA. Breast cancer and other neoplasms in women with Neurofibromatosis type 1: a retrospective Review of cases in the Detroit metropolitan area. Am J Med Genet Part A. 2012;158A:3061–4.PubMedCrossRef
21.
22.
23.
Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000;283(15):2008–12.PubMedCrossRef
24.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5.CrossRefPubMed
25.
Li Q, Cui L, Tian Y, Cui H, Li L, Dou W, Li H, Wang L. Protective effect of dietary calcium intake on esophageal Cancer risk: a meta-analysis of observational studies. Nutrients. 2017;9(5):510.PubMedCentralCrossRef
26.
27.
28.
29.
30.
31.
32.
Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted? Stat Med. 2002;51(11):1559–73.CrossRef
33.
34.
35.
Jackson AH. Three cases of multiple neurofibromatosis with malignant degeneration. J Nerv Ment Dis. 1933;78(6):581–96.CrossRef
36.
Hudson LH, Cox TR. Simultaneous neurofibrosarcoma of the breast and back in von Recklinghausen's disease. Am J Surg. 1956;92(3):476–9.PubMedCrossRef
37.
Singleton AO. The surgical aspects of multiple neurofibromatosis. Am Surg. 1970;36(7):451–4.PubMed
38.
Lima JB, Smith P. Sipple’s syndrome (pheochromocytoma and thyroid carcinoma) with bilateral breast carcinoma. Am J Surg. 1971;121(6):732–5.PubMedCrossRef
39.
Jain SP. von Recklinghausen's disease presenting as the neurofibrosarcoma of the female breast. J Indian Med Assoc. 1974;63(11):366–8.PubMed
40.
Taylor WI. Neurofibromatosis (Recklinghausen's disease) with gastrointestinal and uterine manifestations: report of a case. J Am Osteopath Assoc. 1974;74(1):39–42.PubMed
41.
McMillan MD, Edwards JL. Bilateral mandibular metastasis. Oral Surg Oral Med Oral Pathol. 1975;39(6):959–66.PubMedCrossRef
42.
Sorensen SA, Mulvihill JJ, Nielsen A. Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N Engl J Med. 1986;314(16):1010–5.PubMedCrossRef
43.
Huson SM, Harper PS, Compston DA. Von Recklinghausen neurofibromatosis. A clinical and population study in south-East Wales. Brain. 1988;111:1355–81.PubMedCrossRef
44.
El-Zawahary MD, Farid M, El-Latif AA, Horeia H, El-Gindy M, Twakal G. Breast lesions in generalized neurofibromatosis: breast cancer and cystosarcoma phylloides. Neurofibromatosis. 1989;2(2):121–4.
45.
Sanchis DV, Vazquez Albaladejo C. Von Recklinghausen’s neurofibromatosis. Eur J Surg Oncol. 1992;18(2):202–3.
46.
Aramideh M, de Ongerboer Visser BW, Holstege G, Majoie CB, Speelman JD. Blepharospasm in association with a lower pontine lesion. Neurology. 1996;46(2):476–8.PubMedCrossRef
47.
Malas S, Krawitz HE, Sur RK, Uijs RR, Nayler SJ, Levin CV. Von Recklinghausen’s disease associated with a primary malignant schwannoma of the breast. J Surg Oncol. 1995;59(4):273–5.PubMedCrossRef
48.
Bhargava AK, Bryan N, Nash AG. Localized neurofibromatosis associated with chronic post-mastectomy lymphoedema--a case report. Eur J Surg Oncol. 1996;22(1):114–5.PubMedCrossRef
49.
Nakamura M, Tangoku A, Kusanagi H, Oka M, Suzuki T. Breast cancer associated with Recklinghausen's disease: report of a case. Nihon Geka Hokan. 1998;67(1):3–9.PubMed
50.
Murayama Y, Yamamoto Y, Shimojima N, Takahara T, Kikuchi K, Iida S, Kondo Y. T1 breast cancer associated with Von Recklinghausen's Neurofibromatosis. Breast Cancer. 1999;6(3):227–30.PubMedCrossRef
51.
McGaughran JM, Harris DI, Donnai D, Teare D, MacLeod R, Westerbeek R, Kingston H, Super M, Harris R, Evans DG. A clinical study of type 1 neurofibromatosis in north West England. J Med Genet. 1999;36(3):197–203.PubMedPubMedCentral
52.
53.
Natsiopoulos I, Chatzichristou A, Stratis I, Skordalaki A, Makrantonakis N. Metaplastic breast carcinoma in a patient with Von Recklinghausen’s disease. Clinical Breast Cancer. 2007;7(7):573–5.PubMedCrossRef
54.
Yamamoto Y, Kanazawa H, Sugihara T. Breast reconstruction in the von Recklinghausen disease patient. Plast Reconstr Surg. 2002;110(1):357–8.PubMedCrossRef
55.
Ceccaroni M, Genuardi M, Legge F, Lucci-Cordisco E, Carrara S, D’Amico F, Greggi S, Scambia G. BRCA1-related malignancies in a family presenting with von Recklinghausen’s disease. Gynecol Oncol. 2002;86:375–8.PubMedCrossRef
56.
Medina-Franco H, Gamboa-Dominguez A, de La Medina AR. Malignant peripheral nerve sheath tumor of the breast. Breast J. 2003;9(4):332.PubMedCrossRef
57.
Satge D, Sasco AJ, Goldgar D, Vekemans M, Rethore M-O. A 23-year-old woman with Down syndrome, type 1 neurofibromatosis, and breast carcinoma. Am J Med Genet. 2004;125A:94–6.PubMedCrossRef
58.
Guran S, Safali M. A case of neurofibromatosis and breast cancer: loss of heterozygosity of NF1 in breast cancer. Cancer Genet Cytogenet. 2005;156(1):86–8.PubMedCrossRef
59.
Posada JG, Chakmakjian CG. Images in clinical medicine. Von Recklinghausen's disease and breast cancer. N Engl J Med. 2005;352(17):1799.PubMedCrossRef
60.
Stewart DR, Corless CL, Rubin BP, Heinrich MC, Messiaen LM, Kessler LJ, Zhang PJ, Brooks DG. Mitotic recombination as evidence of alternative pathogenesis of gastrointestinal stromal tumours in neurofibromatosis type 1. J Med Genet. 2007;44(1):e61.PubMedPubMedCentralCrossRef
61.
Kawawa Y, Okamoto Y, Oharaski T, Takahashi K, Kohda E. Paget’s disease of the breast in a woman with neurofibromatosis. Clin Imaging. 2007;31(2):127–30.PubMedCrossRef
62.
Hasson DM, Khera SY, Meade TL, Dupont EL, Greenberg HM, Diaz NM, Romilly AP, Cox CE. Problems with the use of breast conservation therapy for breast cancer in a patient with neurofibromatosis type 1: a case report. Breast J. 2008;14(2):188–92.PubMedCrossRef
63.
Invernizzi R, Martinelli B, Pinotti G. Association of GIST, breast cancer and schwannoma in a 60-year-old woman affected by type-1 von Recklinghausen's neurofibromatosis. Tumori. 2008;94(1):126–8.PubMedCrossRef
64.
Alamsamimi M, Mirkheshti N, Mohajery MR, Abdollahi M. Bilateral invasive ductal carcinoma in a woman with neurofibromatosis type 1. Arch Iranian Med. 2009;12(4):412–4.
65.
Hegyi L, Thway K, Newton R, Osin P, Nerurkar A, Hayes AJ, Fisher C. Malignant myoepithelioma arising in adenomyoepithelioma of the breast and coincident multiple gastrointestinal stromal tumours in a patient with neurofibromatosis type 1. J Clin Pathol. 2009;62(7):653–5.PubMedCrossRef
66.
Maheswari UM, Shau SS, Borkar DB, Paul B. An unusual presentation of neurofibromatosis with breast carcinoma. Bombay Hospital J. 2009;51(2):193–202.
67.
Takeuchi H, Hiroshige S, Hashimoto K, Kusumoto T, Yoshikawa Y, Muto Y. Synchronous double tumor of breast cancer and gastrointestinal stromal tumor in a patient with neurofibromatosis type 1: report of a case. Anticancer Res. 2011;31(12):4481–4.PubMed
68.
Evans DGR, O'Hara C, Wilding A, Ingham SL, Howard E, Dawson J, Moran A, Scott-Kitching V, Holt F, Huson SM. Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989. Eur J Hum Genet. 2011;19(11):1187–91.PubMedPubMedCentralCrossRef
69.
70.
Kim ET, Namgung H, Shin HD, Lee SI, Kwon JE, Chang MC, Park DG. Oncologic manifestations of neurofibromatosis type 1 in Korea. J Korean Surg Soc. 2012;82(4):205–2010.PubMedPubMedCentralCrossRef
71.
Zhou Y, Pan B, Mao F, Zhu Q, Huo Z, Wang H, Cai F, Liang Z, Wang C, Zhang Y, et al. A hidden breast lump covered by nipple appendices in a patient with von Recklinghausen disease: a case report and Review of the literature. Clin Breast Cancer. 2012;12(1):71–5.PubMedCrossRef
72.
Zagouri F, Sergentanis TN, Domeyer P, Zografos GC. Neurofibromatosis 1 and breast cancer: be alert. Am Surg. 2012;78(11):E446–7.PubMed
73.
Onitilo AA, Engel JM. A new NF1 variant in a patient with atypical manifestations. Am J Med Genet A. 2013;161A(2):389–92.PubMedCrossRef
74.
Campos B, Balmana J, Gardenyes J, Valenzuela I, Abad O, Fabregas P, Volpini V, Diez O. Germline mutations in NF1 and BRCA1 in a family with neurofibromatosis type 1 and early-onset breast cancer. Breast Cancer Res Treat. 2013;139:597–602.PubMedCrossRef
75.
Jinkala SR, Rajesh NG, Ramkumar A. Basal like carcinoma of breast in patient with neurofibromatosis I: an association or co-existence? Indian J Pathol Microbiol. 2013;56(2):166–8.PubMedCrossRef
76.
Cheuk DK, Chiang AK, Ha SY, Chan GC. Malignancies in Chinese patients with neurofibromatosis type 1. Hong Kong Med J. 2013;19(1):42–9.PubMed
77.
Vivas APM, Bomfin LE, Pinto CA, Nicolau UR, Alves FA. Oral metastasis of metaplastic breast carcinoma in a patient with neurofibromatosis 1. Case Rep Oncol Med. 2014;2014:1–7.
78.
Nogimori M, Yokota K, Sawada M, Matsumoto T, Kono M, Akiyama M. Spindle cell carcinoma of the breast in a patient with neurofibromatosis type 1. Eur J Dermatol. 2014;24(3):397–8.PubMed
79.
Kumar N, Pandey AN, Kumari S, Kishore S. Breast cancer associated with Von Recklinghausen's disease: case report and Review of literature. Indian J Surg Oncol. 2014;5(3):205–7.PubMedPubMedCentralCrossRef
80.
Silva AVD, Rodrigues FR, Pureza M, Lopes VG, Cunha KS. Breast cancer and neurofibromatosis type 1: a diagnostic challenge in patients with a high number of neurofibromas. BMC Cancer. 2015;15:183.PubMedPubMedCentralCrossRef
81.
Chaudhry US, Yang L, Askeland RW, Fajardo LL. Metaplastic breast cancer in a patient with Neurofibromatosis. J Clin Imaging Sci. 2015;5(1):1–4.
82.
Khalil J, Afif M, Elkacemi H, Benoulaid M, Kebdani T, Benjaafar N. Breast cancer associated with neurofibromatosis type 1: a case series and review of the literature. J Med Case Rep. 2015;9(61):1–4.
83.
Jeon YW, Kim RM, Lim ST, Choi HJ, Suh YJ. Early-onset breast cancer in a family with Neurofibromatosis type 1 associated with a germline mutation in BRCA1. J Breast Cancer. 2015;18(1):97–100.PubMedPubMedCentralCrossRef
84.
Seo YN, Park YM. Association between Neurofibromatosis type 1 and breast cancer: a report of two cases with a Review of the literature. Case Rep Med. 2015;2015.
85.
Daly MB, Pilarski R, Berry M, Buys SS, Farmer M, Friedman S, Garber JE, Kauff ND, Khan S, Klein C, et al. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2017. 2017;15(1):9–20.
86.
Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). Lancet 2005, 365(9473):1769–1778.
87.
Kurian AW, Hare EE, Mills MA, Kingham KE, McPherson L, Whittemore AS, McGuire V, Ladabaum U, Kobayashi Y, Lincoln SE et al: Clinical Evaluation of a Multiple-Gene Sequencing Panel for Hereditary Cancer Risk Assessment 2014, 32(19):2001–2009.
88.
Easton DF, Pharoah PDP, Antoniou AC, Tischkowitz M, Tavtigian SV, Nathanson KL, Devilee P, Meindl A, Couch FJ, Southey M et al: Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk 2015, 372(23):2243–2257.
89.
Dubov T, Toledano-Alhadef H, Bokstein F, Constantini S, Ben-Shachar S: The effect of parental age on the presence of de novo mutations – Lessons from neurofibromatosis type I 2016, 4(4):480–486.
90.
Yap YS, McPherson JR, Ong CK, Rozen SG, Teh BT, Lee AS, Callen DF. The NF1 gene revisited - from bench to bedside. Oncotarget. 2014;15(5):5873–92.
91.
92.
Lu H-M, Li S, Black MH, Lee S, Hoiness R, Wu S, Mu W, Huether R, Chen J, Sridhar S, et al. Association of Breast and Ovarian Cancers with Predisposition Genes Identified by large-scale SequencingAssociation of breast and ovarian cancers with predisposition genes identified by large-scale SequencingAssociation of breast and ovarian cancers with predisposition genes identified by large-scale sequencing. JAMA Oncology. 2019;5(1):51–7.CrossRefPubMed
93.
Shimelis H, LaDuca H, Hu C, Hart SN, Na J, Thomas A, Akinhanmi M, Moore RM, Brauch H, Cox A, et al. Triple-negative breast Cancer risk genes identified by multigene hereditary cancer panel testing. J Natl Cancer Inst. 2018;110(8):855–62.PubMedCentralCrossRefPubMed
94.
Thompson ER, Rowley SM, Li N, McInerny S, Devereux L, Wong-Brown MW, Trainer AH, Mitchell G, Scott RJ, James PA et al: Panel Testing for Familial Breast Cancer: Calibrating the Tension Between Research and Clinical Care 2016, 34(13):1455–1459.
95.
Evans DG, Howell SJ, Frayling IM, Peltonen J. Gene panel testing for breast cancer should not be used to confirm syndromic gene associations. NPJ Genomic Med. 2018;3:32.CrossRef
96.
Frayling IM, Mautner V-F, van Minkelen R, Kallionpaa RA, Aktaş S, Baralle D, Ben-Shachar S, Callaway A, Cox H, Eccles DM, et al. Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation. J Med Genet. 2018; jmedgenet-2018-105599.
Metadata
Title
Increased breast cancer risk in women with neurofibromatosis type 1: a meta-analysis and systematic review of the literature
Authors
Lorena P. Suarez-Kelly
Lianbo Yu
David Kline
Eric B. Schneider
Doreen M. Agnese
William E. Carson
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Hereditary Cancer in Clinical Practice / Issue 1/2019
Electronic ISSN: 1897-4287
DOI
https://doi.org/10.1186/s13053-019-0110-z

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