Specific cancer rates may differ in patients with hereditary haemorrhagic telangiectasia compared to controls

Abstract

Background: Hereditary haemorrhagic telangiectasia (HHT) is inherited as an autosomal dominant trait, affects ~1 in 5,000, and causes multi-systemic vascular lesions and life-limiting complications. Life expectancy is surprisingly good, particularly for patients over 60ys. We hypothesised that individuals with HHT may be protected against life-limiting cancers.

Methods: To compare specific cancer rates in HHT patients and controls, we developed a questionnaire capturing data on multiple relatives per respondent, powered to detect differences in the four most common solid non skin cancers (breast, colorectal, lung and prostate), each associated with significant mortality. Blinded to cancer responses, reports of HHT-specific features allowed assignment of participants and relatives as HHT-subjects, unknowns, or controls. Logistic and quadratic regressions were used to compare rates of specific cancer types between HHT subjects and controls.

Results: 1,307 participants completed the questionnaire including 1,007 HHT-subjects and 142 controls. The rigorous HHT diagnostic algorithm meant that 158 (12%) completed datasets were not assignable either to HHT or control status. For cancers predominantly recognised as primary cancers, the rates in the controls generally matched age-standardised rates for the general population. HHT subjects recruited through the survey had similar demographics to controls, although the HHT group reported a significantly greater smoking habit. Combining data of participants and uniquely-reported relatives resulted in an HHT-arm of 2,161 (58% female), and control-arm of 2,817 (52% female), with median ages of 66ys [IQR 53-77] and 77ys [IQR 65-82] respectively. In both crude and age-adjusted regression, lung cancers were significantly less frequent in the HHT arm than controls (age-adjusted odds ratio 0.48 [0.30, 0.70], p = 0.0012). Breast cancer prevalence was higher in HHT than controls (age-adjusted OR 1.52 [1.07, 2.14], p = 0.018). Overall, prostate and colorectal cancer rates were equivalent, but the pattern of colorectal cancer was modified, with a higher prevalence in younger HHT patients than controls.

Conclusions: These preliminary survey data suggest clinically significant differences in the rates of lung, breast and colorectal cancer in HHT patients compared to controls. For rare diseases in which longitudinal studies take decades to recruit equivalent datasets, this type of methodology provides a good first-step method for data collection.

Figures

Figure 1

Stratification of diagnostic assignments. Flow chart indicating the application of the Curaçao Criteria to Survey Respondents, stratified by whether they reported themselves as having HHT, and by the presence or absence of a family history.

Figure 2

Validation data of cancer rates in controls. Comparison of age-standardized rates (ASRs) for survey control arm and Globocan ASRs for “More Developed Regions”, 2008. The study data represent cancer cases in 2,817 control participants or relatives, with an average age of 77 ys, and 52% female, and plots the observed/expected ratios presented in Table 2, against the overall frequency of the specified cancer, since variance would be expected to be greater for less common cancers. Data are stratified by whether the cancers are predominantly primary only (navy symbols, black solid line with 95% confidence intervals); or primary and secondary sites (red symbols and red dotted line).

Figure 3

Reported numbers for haematological and solid cancers. Data are illustrated for the most common four cancers and haematological cancers, in 2,166 HHT patients and 2,817 controls (Error bars indicate 95% confidence intervals).

Figure 4

Age-specific prostate cancer rates. Quadratic regression plots for male-only HHT patients and controls. Shaded areas indicate 95% confidence intervals.

Figure 5

Age-specific lung cancer rates. Quadratic regression plots for all HHT patients and controls. Shaded areas indicate 95% confidence intervals. Note primary and secondary lung cancers are not distinguished.

Figure 6

Age-specific liver cancer rates. Quadratic regression plots for all HHT patients and controls. Shaded areas indicate 95% confidence intervals. Note primary and secondary liver cancers are not distinguished.

Figure 7

Age-specific breast cancer rates. Quadratic regression plots for female-only HHT patients and controls. Shaded areas indicate 95% confidence intervals.

Figure 8

Age-specific colorectal cancer rates. Quadratic regression plots for all HHT patients and controls. Shaded areas indicate 95% confidence intervals.

Figure 9

Age-specific rates of all solid, non-skin cancers. Quadratic regression plots for all HHT patients and controls. Data include brain, bladder, breast, cervical, colorectal, kidney, liver, lung, pancreas, prostate, stomach uterus, mouth and oesophageal cancers. Shaded areas indicate 95% confidence intervals.

Figure 10

Age-specific rates of haematological cancers. Quadratic regression plots for all HHT patients and controls. Data include leukaemia, lymphomas and myeloma. Shaded areas indicate 95% confidence intervals.