open access: Lynch Syndrome - Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer (Lynch Syndrome)

open access: Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database
 Published Online First 3 June 2016 
 

The assumptions underlying current guidelines for healthcare for patients with LS, to which we have contributed,1 should be replaced by empirical observations whenever possible. However, there is limited empirical information from prospective studies on the outcomes for patients with LS who have survived a first cancer and are receiving continued surveillance according to existing guidelines.4

We designed the present study to address three questions in patients with LS who had survived previous cancer and were at risk of developing subsequent cancers: (i) what was the cumulative incidence of subsequent cancers, (ii) in which organs did subsequent cancers occur and (iii) what was survival following these subsequent cancers?

  Out of the 1273 patients, 392 (31%) had had two or more previous tumours: 268 (21%) had two, 91 (7%) had three, 22 (2%) had four, 9 (1%) had five, one (0.1%) had six and one (0.1%) had seven cancers before inclusion. 

 Patients with previous colon cancer(s) were not at an increased risk for a subsequent colon cancer when compared with those with previous extracolonic cancers

Abstract

Objective Today most patients with Lynch syndrome (LS) survive their first cancer. There is limited information on the incidences and outcome of subsequent cancers. The present study addresses three questions: (i) what is the cumulative incidence of a subsequent cancer; (ii) in which organs do subsequent cancers occur; and (iii) what is the survival following these cancers? 

Design Information was collated on prospectively organised surveillance and prospectively observed outcomes in patients with LS who had cancer prior to inclusion and analysed by age, gender and genetic variants. 

Results 1273 patients with LS from 10 countries were followed up for 7753 observation years. 318 patients (25.7%) developed 341 first subsequent cancers, including colorectal (n=147, 43%), upper GI, pancreas or bile duct (n=37, 11%) and urinary tract (n=32, 10%). The cumulative incidences for any subsequent cancer from age 40 to age 70 years were 73% for pathogenic MLH1 (path_MLH1), 76% for path_MSH2 carriers and 52% for path_MSH6 carriers, and for colorectal cancer (CRC) the cumulative incidences were 46%, 48% and 23%, respectively. Crude survival after any subsequent cancer was 82% (95% CI 76% to 87%) and 10-year crude survival after CRC was 91% (95% CI 83% to 95%). 

Conclusions Relative incidence of subsequent cancer compared with incidence of first cancer was slightly but insignificantly higher than cancer incidence in patients with LS without previous cancer (range 0.94–1.49). The favourable survival after subsequent cancers validated continued follow-up to prevent death from cancer. The interactive website http://lscarisk.org was expanded to calculate the risks by gender, genetic variant and age for subsequent cancer for any patient with LS with previous cancer.

Significance of this study

What is already known on this subject?

• Inherited colorectal cancer may be caused by mismatch repair (MMR) gene variants and is then commonly referred to as Lynch syndrome.
• Patients with Lynch syndrome are at risk for synchronous and metachronous cancers.
• Endoscopic surveillance with removal of adenomas is recommended to prevent colorectal cancer.

What are the new findings?

• This is the first comprehensive prospective study to provide empirically observed data on subsequent cancer incidence and survival in patients with Lynch syndrome who have survived previous cancer.
• The cumulative incidences for any subsequent cancer were 73% for path_MLH1 and 76% for path_MSH2 carriers. The incidence was lower in MSH6 carriers.
• Colorectal cancer occurred frequently despite continued colonoscopic surveillance with removal of adenomas.
• Survival after subsequent cancer was good......
  

  
  ...Prior to inclusion, the 1273 patients had developed 1835 cancers (mean 1.4 per patient), with CRCs accounting for 1161 (63%) of all previous cancers. CRCs represented 83% of cancers diagnosed in males and 49% of the cancers in females. Endometrial (n=296) and ovarian (n=61) cancers accounted for 28% and 6%, respectively, of all previous cancers in females. Urinary tract (n=80), breast (n=46), upper GI tract (n=41) and prostate (n=21) cancers were also frequently reported. The separate diagnoses by gender are given in table 2. Out of the 1273 patients, 392 (31%) had had two or more previous tumours: 268 (21%) had two, 91 (7%) had three, 22 (2%) had four, 9 (1%) had five, one (0.1%) had six and one (0.1%) had seven cancers before inclusion.