Крупная долгосрочная база данных о пациентах, страдающих болезнью Гаучера, свидетельствует о возросшем риске лимфомы и миэломы, но не твердых опухолей.

Introduction

Gaucher disease (GD) is one of the two most common lysosomal storage disorders (LSDs) and the first to benefit from safe and effective therapy. The introduction of the placental‐derived, macrophage‐targeted enzyme replacement therapy (ERT) in 1991 1 marked a turning point, not only for GD but also for other LSDs and the broader rare disease field. For patients with non‐neuronopathic GD, early ERT – especially before skeletal complications – has been life‐saving, reducing morbidity 2 to a biweekly intravenous infusion of 1 h or less. 3 , 4 The availability of oral substrate reduction therapy (SRT) today and the future addition of oral enzyme enhancement therapy (EET; pharmacological chaperones) and perhaps even a single injection of gene therapy not only are novel therapeutic modalities aiming at improving the quality of life of patients by the elimination of frequent intravenous infusions but also provide new hope to address the two major unmet needs today in GD, which are the management of neuronopathic GD (types 2 and 3) and the risk of comorbidities, particularly Parkinson's disease (PD) and malignancies.

These comorbidities (separate disorders that are more common in GD compared to the general population) can be either responsive or not responsive to GD‐specific therapy. 5

It is well established that specific therapies for GD (ERT/SRT) do not prevent the development of PD, likely because the underlying mechanism differs. The risk for carriers may even exceed that of patients with GD. 4 In contrast, the association between GD and malignancies remains controversial. 6 Some publications claim that there is a higher risk of cancer for patients with GD, whereas others attribute these findings to biases and argue against a heightened risk. 7 , 8 Regardless, this topic is a cause of major concern for both patients with GD and their family members, 6 and it is not clear if specific therapy for GD might increase or decrease such a risk.

In the current study, we report the cancer risk in a large, single‐centre database of patients with GD over three decades and identify risk factors associated with cancer occurrence.

Methods

The medical records of patients over 20 years old at their last follow‐up at the Gaucher Unit of Shaare Zedek Medical Center (SZMC) from 1990 to December 2023 were reviewed. Data collection included demographic details (date of birth, sex and ethnicity), clinical information (dates of GD diagnosis, GD genotype, initial and most recent visits), and GD‐related management (ERT/SRT and splenectomy). For patients diagnosed with cancer, the date of diagnosis and cancer type were recorded. Each medical record was read in its entirety by one of us (M. Istaiti) to ensure the accuracy and completeness of the data collection without relying on data entry to different charts or registries. The SZMC Institutional Review Board approved the design of this retrospective analysis, and informed consent was waived due to the use of unidentified data and aggregated analysis.

Statistical analysis

Descriptive statistics are presented as frequencies, proportions, mean and standard deviation (SD), or median and range, as appropriate. Proportions or medians were compared across groups using the chi‐squared test for categorical variables and the Wilcoxon test for non‐parametric continuous variables. For patients with more than one primary cancer, only the first cancer was considered for the time‐to‐event analysis.

The standardised incidence ratio (SIR) was used to determine if the occurrence of cancer in patients with GD was higher or lower than expected, based on a comparison with the Israel National Cancer Register (INCR). SIR was calculated by dividing the observed by the expected number of cases with 95% confidence interval (CI). To assess the SIR, we divided our cohort into four periods: 1 January 1990–31 December 1997, 1 January 1998–31 December 2005, 1 January 2006–31 December 2014 and 1 January 2015–31 December 2023. The referral years from the INCR for each period were 1996, 2002, 2010 and 2018 respectively. The person‐years for each period per sex and age group were calculated. The age groups ranged from 20 to over 75, divided into 5‐year intervals. For this analysis, all patients with cancer were included regardless of the time of diagnosis and/or time of follow‐up. To avoid bias in cancer risk related to ethnicity, that is, Jewish versus non‐Jewish, only patients from Jewish ethnicity were included in the SIR analysis. The Mann–Kendall trend test, a non‐parametric test for identifying a monotonic trend in time series data, was applied to assess the trend in SIR over the four time periods.

Cancer‐free survival after the first visit was assessed using Kaplan–Meier methods. The data were censored at the date of cancer diagnosis or the last follow‐up visit. For this analysis, patients diagnosed with cancer before the first visit or followed for less than 6 months were excluded. Cancer incidence rates with 95% CI were calculated, and risk factors for cancer occurrence were studied, including sex, Jewish ethnicity, mild GBA1 genetics, age at GD diagnosis, age at first and last visits, history of splenectomy and GD‐specific therapy. Individuals homozygous for the N370S GBA1 variant (recently referred to as c.1226A>G; p.N409S) were classified as mild, whereas all other GBA1 variants were classified as severe. Patients were classified as treated if the GD‐specific medication was prescribed at least 6 months before the censoring date.

Analyses were conducted using R version 2024.04.2 + 764.

Results

SIR in patients with GD versus the general Israeli population

The study included 709 patients with a wide range of ages at diagnosis and at the time of first and last visits (Table 1 ). Sixty‐four (9%) patients were diagnosed with cancer. The most common cancer was breast ( n = 13), followed by B‐cell non‐Hodgkin lymphoma ( n = 9) and colon cancer ( n = 9) (Fig. 1 ). Those diagnosed with cancer were significantly older at the time of GD diagnosis and at the time of first and last visits and had a milder genotype (Table 1 ).

Cancer risk in patients with GD was similar to that of the general Israeli population, with a calculated SIR of 0.9 (95% CI 0.6–1.1). However, there was a trend of increasing SIR across the four time periods, which was not statistically significant ( P = 0.089) (Fig. 2 ). Cancer risk for non‐Hodgkin lymphoma and multiple myeloma (MM) was higher compared to the general Israeli population, 2.19 (1.22–3.16) and 6.45 (4.42–8.48) respectively (Table 2 ).

Cancer diagnosis before or around the first visit

Twenty‐two patients were diagnosed with cancer either before or within 6 months after their initial visit to the Gaucher Unit (Table 3 , panel A). The median (range) age at the time of cancer diagnosis was 48.5 (28–77) years. Fourteen of these cases were diagnosed at a median (range) of 3 (0.5–28) years before the first visit, while eight cases were diagnosed around the time of the first visit (within ± 6 months), six of which were haematological cancers. Four patients had a second primary cancer (breast, colon, pancreas and uterine).

Cancer diagnosis during follow‐up (at least 6 months)

A total of 635 patients were followed for a median (range) of 19 (0.5–33) years, of which 42 were diagnosed with cancer at a median (range) age of 63 (32–88) years (Table 3 , panel B). The most common cancer types were haematological, breast and colon. Four patients had a second primary cancer (breast, colon, pancreas and liver).

The incidence rate of cancer during follow‐up was 3.7 (95% CI 2.6–4.8) events per 1000 person‐years. Cancer risk was associated with age at diagnosis, first and last follow‐up (Table 4 ). Cancer‐free survival analysis was not related to GD‐related treatment (Fig. 3 ).

Discussion

In this study, we examined the incidence of cancer among adult patients with GD. By comparing these results with data from the INCR, we demonstrated that patients with GD do not have an increased overall risk of developing cancer. However, we did observe a higher risk for haematological cancers, such as non‐Hodgkin lymphoma and MM, with nearly half of these cases being diagnosed either before or around the time of the first visit.

Reviewing previous publications on GD and cancer, it becomes evident that ascertainment bias is a key issue. This bias has typically been acknowledged in most older literature reporting comorbidities in patients with rare diseases and concluding their reports with sentences like ‘causal relationship between these two pathologic entities remains speculative’. 9 , 10 Unfortunately, the authors of the first relatively large series did not address this bias at all, and their title, ‘Increased Risk of Cancer in Patients with Gaucher Disease’ (20.8%; 10 out of 48), 7 has been a source of anxiety and concern to any newly diagnosed patient with GD to this day. During the time of that study, there was no specific clinic for GD in that particular hospital, and the majority of the patients with GD and malignancies were actually hospitalised because of cancer or during the evaluation of a haematological malignancy when bone marrow aspiration or biopsy revealed Gaucher cells as an incidental finding. Moreover, the comparative control ( n = 511) was a cohort of individuals, not necessarily sick patients, attending a community family practice.

Twelve years later, in an attempt to tease out this possible relationship, an analysis of 500 patients followed at the SZMC Gaucher Unit data showed a lack of association between GD and malignancies. 8 In the same year, 2005, data from the International Collaborative Gaucher Group (ICGG; n = 2742), the disease registry created by the Genzyme Corporation, supported this finding except for highlighting the increased risk of MM (approximately sixfold). 11 This association was later attributed to the high prevalence of monoclonal gammopathy of undetermined significance (MGUS) 12 , 13 , 14 and possibly related to the development of monoclonal antibodies against the lysolipids of GD. 12 , 13 An increased risk of MM has actually become evident in several additional, relatively large‐scale studies. de Fost et al . in a study from 2006, comparing two cohorts of patients with GD, one from the Netherlands treated with low‐dose ERT and the second from Germany with high‐dose ERT ( n = 131), reported a 12.7‐fold greater risk to develop MM and a 2.7‐fold risk to develop hepatocellular carcinoma (HCC). 15 While the greatest risk of MM might be true, the increased risk of HCC is uncertain and has been shown by the same authors that it could have been related to the higher number of patients who were splenectomised (receiving a blood transfusion before the routine screening for hepatitis C) and to a couple of cases of iron overload. 16

In 2023, the ICGG reported updated data, with a smaller cohort relative to 2005 ( n = 2123) due to differences in inclusion criteria and with a different conclusion suggesting a higher incidence of a list of malignancies (liver, kidney, melanoma, and breast) compared to the general population. 17 These findings may be questioned due to the study's inclusion criteria, the reliance on registry reporting, and the choice of the comparison group, that is, the general US population. Notably, the study group consists of 42% of patients from the United States, many of whom are Ashkenazi, which differs significantly from the broader comparison group. A different and less biased approach analysed cancer incidence among 264 patients with GD compared to 3440 matched controls using the electronic database of Israel's second‐largest healthcare provider, Maccabi Healthcare Services. 18 The higher occurrence of cancers in patients with GD in this study was associated with higher performance of cancer screening studies such as colonoscopy and skin screening tests. In a multivariate analysis, only age at index date was associated with cancer risk.

With the introduction of specific therapies for GD, it was speculated that by ameliorating the metabolic consequences of glucocerebroside storage, the risk of related comorbidities would be reduced. In this context, apart from a single report of improvement of myeloma indices, that is, free light chain kappa and free kappa‐to‐lambda ratio, in a patient receiving velaglucerase alfa or in a preclinical animal model of myeloma by eliglustat, 19 , 20 , 21 we and others have not seen a lower cancer risk among the treated patients. 18 Accordingly, prevention of cancer should not be an indication for treatment in patients with otherwise asymptomatic GD.

The current study, which includes over 200 additional patients and more than 20 years of follow‐up data compared to our previous report from 2005, reinforces the conclusion that the overall cancer risk in patients with GD treated at SZMC is comparable to that of the general population of the same ethnicity and country. This important finding is based on a comprehensive review of each patient's medical records, conducted with an unprecedented level of detail that is unlikely to be replicated, even in the era of digital health.

The question why only a small group of patients develop an unusual manifestation of the disease or a specific associated disorder has challenged researchers for a long time, and the possibility of an additional alternative aetiology, whether genetic or environmental, always comes to the table. So far, attempts to identify specific modifier genes that increase the risk for haematological malignancies have not identified clear candidates, apart from a small study suggesting a relationship between the ApaI (rs7975232) polymorphism of the vitamin D receptor and cancer risk. 22 As far as hepatocellular carcinoma is concerned, there are obvious specific risks derived from prior splenectomy (transfusion‐related viral diseases) and iron overload. 16

When considering the study limitations, one might argue that since the cohort is predominantly Ashkenazi Jewish, the results may not be applicable to non‐Jewish patients with GD. However, this argument would hold more weight if we had identified a higher incidence of cancers, such as breast carcinoma, which is more common in this ethnic group due to the high frequency of BRCA1 and BRCA2 mutations. Our findings, however, do not support this claim. Moreover, the mechanisms proposed to explain the higher risk of malignancies in GD are typically linked to various cellular and molecular events driven by activated macrophages, such as chronic inflammation, immune dysregulation and oxidative stress 7 , 17 , 23 – factors associated with glycolipid storage and not believed to be specific to any particular ethnicity. Another limitation is that the median age of our patients is relatively young, less than 50 years. Since the SIR was associated with age, these younger patients tended to attend more follow‐up visits, leading to increased monitoring and exposure to tests that could ultimately result in cancer diagnosis. However, as a trend of increasing SIR across the four time periods was observed, it may be that the effect of GD on cancer risk increases with age.

It is to be hoped that our current report will be used wisely by genetic counsellors and by physicians treating patients with GD to avoid unjustified termination of pregnancies, alleviate anxiety and allow researchers to focus on the more pressing future challenges. These include the development of better and more affordable treatments, particularly for neuronopathic GD, as well as the prevention of GBA1 ‐related PD, which commonly affects both patients and carriers of GD. 24 At the same time, follow‐up care for all patients with GD should include, with regard to solid tumours, all the recommended cancer screening measures with the goal of early detection and prevention. As far as the haematological malignancies are concerned, the routine annual or semi‐annual follow‐up of patients typically includes medical history and physical examination, a broad laboratory testing (including CBC, immunoglobulin profile and markers of inflammation) and imaging, thereby covering the needed tests for early identification of MM or lymphoma.

Conclusions

Compared to the general population in Israel, our study finds no increased cancer risk in patients with GD. However, as our patient group ages, the risk profile may change. Importantly, cancer risk has shown no association with GD therapy status. We believe that the previously perceived rise in cancer cases among patients with GD could be partly attributed to being diagnosed with GD when worked up for diagnosis of cancer and the close and active surveillance of patients followed for a chronic disease like GD. Nonetheless, we recommend incorporating cancer screening and preventive education into the standard care protocol for patients with GD. At the same time, it is important to reduce concerns about cancer risk during GD genetic counselling sessions and when GD is first diagnosed and explained to patients, children and adults alike.

Acknowledgements

The authors acknowledge the support of Ms. Galit Dayan in the validation of the database used in the study.

Data availability statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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