Neurofibromatosis type I with breast cancer: not only for women!
- Kuntegowdanahalli Chinnagiriyappa Lakshmaiah†1Email author,
- Anil N Kumar†1,
- Samit Purohit1,
- Belathur Kalegowda Viveka1,
- Kamalakannan Rahul Rajan2,
- Mohammed Abdul Lateef Zameer3,
- Prabhu Namitha4,
- Monika Lamba Saini†5,
- Hatem A AzimJr6 and
- Kamal S Saini†7
© Lakshmaiah et al.; licensee BioMed Central Ltd. 2014
Received: 1 March 2013
Accepted: 28 January 2014
Published: 24 February 2014
The association of neurofibromatosis type I with invasive male breast cancer is a rare clinical entity with only one case in literature reported in 1953. Women with NF1 are at risk of developing breast cancer and men also may be at risk but there is scarce data on the risk and association of NF1 with male breast cancer due to its rarity. Established clinical trials in male breast cancer patients are lacking and the results are extrapolated from female breast cancer patients. The treatment of male breast cancer is followed as per the guidelines of premenopausal female breast cancer and tamoxifen is the hormone treatment in them. Mendes et al suggests that silencing of NF1 gene confers resistance to tamoxifen. Our conclusions are that since NF1 is mutated or deleted in one third of sporadic breast cancers, its role as a molecular driver for treatment has to be further explored.
Male breast cancer is a rare disease and accounts for less than 1% of all breast cancers . Neurofibromatosis type 1 (NF1) or Von Recklinghausen disease is an autosomal dominant condition that leads to multiple benign tumors (neurofibromas) and predisposes to several types of malignancies, including breast cancer. To the best of our knowledge, only 1 case of neurofibromatosis in a male patient with breast cancer has been previously reported in the literature . Here we report another case and discuss the potential role of the NF1 gene in the pathogenesis of these cases.
A 55-year-old male presented to our institution in November 2011 with complaints of multiple skin nodules, brown skin patches since childhood and an enlarging painless lump in the left breast for 2 months. There was no other medical history of relevance including food allergies or drug abuse. There was history of similar skin nodules in his brother and paternal uncle. There was no history of breast, ovary or prostate cancer in the family.
The patient received 6 cycles of adjuvant FEC (fluorouracil 500 mg/m2 q3w, epirubicin 100 mg/m2 q3w, cyclophosphamide 500 mg/m2 q3w) chemotherapy followed by external beam radiotherapy on a cobalt-60 machine with tangential pairs to chest wall and anterior supraclavicular fields of 50 Gy in 25 fractions with 2 Gy per fraction given once a day for 5 weeks.
At present, the patient is receiving tamoxifen 20 mg once daily and is on follow up since 8 months.
NF1 is an autosomal dominant Mendelian syndrome occurring in about 1 in 4000 persons in the general population and has high penetrance but wide variability in expression . It represents a risk factor for the development of various malignancies, including female breast cancer .
According to Knudson’s “two-hit” hypothesis, both alleles have to be inactivated for tumorogenesis to occur. In NF1-associated cancers, the first “hit” is a germline mutation, while the second “hit” is a somatic mutation that occurs either in utero or after birth and results in inactivation of the normal NF1 allele and a consequent loss of neurofibromin function. Both alleles of NF1 need to be inactivated to influence carcinogenesis, but there is emerging evidence that haploinsuficiency or reduced expression may also have a functional impact .
Individuals with NF1 are heterozygous for an NF1 mutation. Mutation in the normal copy of the NF1 gene enhances the risk of cancer among NF1 patients but these mutations may also be observed in sporadic tumors [9, 10].
Women with inherited NF1 deficiency have an increased risk of breast cancer [11, 12]. Some reports implicate spontaneous NF1 loss in breast tumorigenesis [13, 14]. A recent report suggests that females with NF1 have a relative risk of 2.3 (95% confidence interval 1.7 to 2.9) for developing breast cancer compared with a reference cohort . Men also may be at risk (as highlighted by this case report) but there is scarce data on the risk and association of NF1 and male breast cancer due to its rarity .
Silencing NF1 (or other genes including, BAP1, CDK10, NIPBL, PTEN, RARG, SMC3, and UBA3) have been shown to confer tamoxifen resistance in human breast cancer (MCF7) cell lines . Hence tamoxifen, the drug treatment for hormone receptor positive breast cancers, may theoretically be less effective in cancers involving NF1 mutations; however, this needs to be corroborated by clinical evidence.
In conclusion, this report aims to describe a rare presentation of a male patient with NF1 and breast cancer. The NF1 gene is mutated or deleted in a significant proportion of human breast cancers, and its role as a potentially important molecular driver in breast cancers needs to be explored further. One can speculate that drugs blocking the Ras pathway could be useful in breast cancer with NF1 mutations; this hypothesis needs to be tested in a scientifically robust manner.
Informed consent has been obtained from the patient for publication.
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