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

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. Electronic supplementary material The online version of this article (10.1186/s13053-019-0110-z) contains supplementary material, which is available to authorized users.


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Type of study designs used Observational study √ Study population Women with NF1 and controls Reporting of search strategy should include √ Qualifications of searchers (eg, librarians and investigators) The credentials of the investigators are provided in the author list.
√ Search strategy, including time period included in the synthesis and keywords PubMed and PMC from oldest record to December 2015.
Key words: "Neurofibromatoses", "Neurofibromatosis 1", "genes, Neurofibromatosis 1", and "Neurofibromatosis type 1" in combination with "breast neoplasms", "breast cancer", "malignancy", "neoplasm", "tumor", or "cancer." The search was restricted to studies in human beings and publications in English language. √ Effort to include all available studies, including contact with authors The references of all retrieved articles and recent reviews were also manually reviewed. The search was restricted to published studies and abstracts without full text and unpolished studies were excluded. Description of any contact with authors.
No attempt was made to contact any authors.

Reporting of methods should include √
Description of relevance or appropriateness of studies assembled for assessing the hypothesis to be tested The inclusion criteria are presented in the "Study Selection" section.
√ Rationale for the selection and coding of data (eg, sound clinical principles or convenience) The following data from each included study were extracted:   Table 2 Results of sensitivity testing (eg, subgroup analysis) We performed a subgroup analysis based on two age groups (< 50 or ≥ 50 years of age). Given that a small number of studies were included in the meta-analysis, we were selective about what subgroups/other factors to examine. We did not have any drastically different studies that we might have wanted to exclude and check sensitivity of the estimates. √ Indication of statistical uncertainty of findings 95% confidence intervals are presented with all summary effect estimates.

Reporting of discussion should include
Quantitative assessment of bias (eg, publication bias) Quantitative assessment of publication bias was not performed. Publication bias here would arise from either of these cohorts if they are published because of high rates of cancer or other cohorts are not published because of low/normal rates. Since we aren't evaluating a treatment effect, the suppression of null studies is less of a concern here. We also limited ourselves to these 4 studies to avoid potential publication bias from case studies/series. We could make a funnel plot; however, with only 4 studies, it would not be any more informative than the forest plot that we already present. √ Justification for exclusion (eg, exclusion of non-English-language citations) The details of the exclusion of studies are shown in Flow chart.
√ Assessment of quality of included studies Tables 2.

Reporting of conclusions should include √ Consideration of alternative explanations for observed
We discussed that we cannot exclude chance, residual or unmeasured confounding as alternative explanation for our results findings. √ Generalization of the conclusions (ie, appropriate for the data presented and within the domain of the literature review) We discussed that the results of current study suggests that women with NF1 less than 50 years of age have a fivefold increased risk of breast cancer, present with more advanced disease, and may have an increased breast cancer related mortality. √ Guidelines for future research We discussed that a large multi-center, long-term, follow-up prospective study or a national initiative should be conducted to better delineate the true risk of breast cancer in NF1, understand the etiology and natural history of breast cancer in this population, and to determine the optimal screening method and timing to allow for earlier breast cancer diagnosis and decreased breast cancer associated morbidity and mortality in women with NF1. √ Disclosure of funding source The funding information is shown in the text.