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4 Lynch Syndrome 111
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Fig.4.17 Mechanism of action of aspirin in prevention of cancer. Created with Biorender.com
112 P. Edwards and K. J. Monahan
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Fig.4.18 Decision aid regarding taking aspirin [144] © NICE 2020 Lynch syndrome: should I
take aspirin to reduce my chance of getting bowel cancer? Patient decision aid Available from
www.nice.org.uk/guidance/ng151/resources/lynch-syndrome-should-i-take-aspirin-to-reduce-mychance-of-getting-bowel-cancer-pdf-8834927869. All rights reserved. Subject to Notice of rights.
NICE guidance is prepared for the National Health Service in England. All NICE guidance is
subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for
the use of its content in this product/publication
Should aspirin be continued during cancer treatment?
In context of surgical treatment aspirin can increase bleeding and impact on healing. This should be held during surgical resection as per local guidelines. Whilst
on systemic therapy interactions with all regular medications are reviewed and this
should be established and discussed with the treating oncology team. If patients
are on immunotherapy, aspirin does not interact with this. However most toxicity
related to immunotherapy is treated with high dose steroids, the combination can
theoretically have higher GI toxicity and gastric protection is recommended [145].
Should aspirin be taken in older patients with LS?
The ASPREE clinical trial enrolled a healthy, elderly population with mean age 74
in the US and Australia [146]. The primary endpoint was disability-free survival
and participants (n = 19,114) were randomised to receive 100 mg enteric-coated
aspirin (n = 9525) or placebo (n = 9589). Risks of death predominantly caused
by cancer-related death were higher in the aspirin group. This was unexpected,
given previous studies showing protective benefit of aspirin and were unrelated to
cancer-associated haemorrhage. This questions whether cancer biology differs in
the older patient group and therefore aspirin could promote cancer development
and metastasis. Therefore, prophylactic aspirin should not be commenced after age
65 years in people with LS (Table 4.5).
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Tab le 4.5 CRC prevention recommendations of 3 European Societies
ESGE guideline BSG guideline European (EHTG and
Lynch syndrome
diagnostic testing
Age to commence
colonoscopic
surveillance
Colonoscopic
surveillance interval
Technical aspects of
colonoscopy
Surgery – Consideration for
Chemoprophylaxis Aspirin—optimum
All individuals with
CRC diagnosed under
70 should be tested
for LS
MLH1/MSH2:start
aged 25
MSH6/PMS2:start
aged 35
Every 2 years,
consider repeating
within 3 months if
suboptimal
colonoscopy
Routine use of
high-definition
endoscopy systems.
Chromoendoscopy
may be of benefit in
individuals with LS,
although routine use
must be balanced
All CRC should be
tested for LS
MLH1/MSH2:start
aged 25
MSH6/PMS2:start
aged 35
Every 2 years, consider
repeating within
3 months if suboptimal
colonoscopy
High-quality,
high-definition white
light endoscopy.
Chromoendoscopy
(virtual or dye-based)
does not offer a clear
advantage over
high-definition white
light examination
subtotal colectomy in
MLH1/MSH2 (see text)
dose to be established
ESCP) guidelines
All CRC should be
tested for LS
MLH1/MSH2:start
aged 25
MSH6/PMS2: start aged
35
2–3 yearly for MLH1/
MSH2/MSH6 carriers,
for PMS2 5 yearly
surveillance may be
considered. If bowel
prep inadequate
between 6 months and
1 year
Chromoendoscopy may
be considered in the
absence of
high-definition white
light endoscopy or in
centres with low
adenoma detection rates
Consideration for
subtotal colectomy in
MLH1/MSH2 (see text)
Aspirin—optimum dose
to be established
4.10.3 Endometrial Risk Reducing Agents
Data on hormonal therapies; progesterone containing intrauterine devices (IUDs),
combined oral contraceptive pills (OCPs) or oral progestins has been extrapolated
from the general population studies in EC. Here, IUDs have shown to reduce risk
of 50% endometrial cancer, an effect which persists for 5 years after stopping
[147]. The studies within LS have been small but, show a decrease in endometrial
proliferation without proven risk reduction for cancer. There is variation as to how
these treatments are offered across Europe [105] but, despite robust evidence IUDs
are likely having a beneficial effect on women and this should be discussed.
114 P. Edwards and K. J. Monahan
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4.11 Oncological Management: Radical and Advanced
4.11.1 CRC
Following discovery of MSH2 and MLH1 genes in the 90 s, laboratory models found an intrinsic resistance to DNA damage [14] implying some typical
chemotherapy drugs, which work by causing DNA damage, may be less effective
in these tumours. 5-fluorouracil (5FU) is the backbone for adjuvant chemotherapy
(single agent or combination) for stage II and III CRCs. In vitro studies showed
resistance to 5FU [148, 149] but, several retrospective studies were unable to
address this. Large meta-analysis (IDEA collaboration) [150] have explored the
role of adjuvant chemotherapy notably the SCOT non-inferiority trial of 3 months
of adjuvant chemotherapy versus 6 months of treatment, aiming to reduce long
term toxicity and treatment-related risk of death [151]. This corroborated the suggestion of intrinsic fluoropyrimidine resistance suggesting that adding oxaliplatin
improves overall survival (OS) and disease-free survival (DFS) [152, 153]. In practice, in Europe, in stage II dMMR CRC, adjuvant chemotherapy is not offered due
to the risks outweighing benefits (improved prognosis compared to pMMR) and
stage III dMMR are treated as pMMR with combination treatment rather than 5FU
alone [154].
4.11.2 Immunotherapy; the Basics
Immunotherapy is treatment that utilises the immune system in defence or management of disease [155]. In cancer related to LS, checkpoint inhibitors are used.
Checkpoints form a normal part of the immune system and help our bodies to
recognise what is “self” to protect healthy tissues from an immune response. These
checkpoints activate when a protein on the surface of an immune cell, a T-cell,
binds with a protein on the surface of another cell. This stops the T-cell from
activating and destroying the other cell. This mechanism can allow cancer cells to
evade recognition and death from immune response. Checkpoint inhibitors block
this interaction and allow T-cells to recognise and kill cancer cells (Fig. 4.19). The
commonly targeted checkpoints include CTLA-4 and PD-1 or counterpart PDL1. Due to highly immune infiltrative tumour microenvironment this provides an
optimal target for checkpoint inhibitors [8].
4.11.3 Clinical Trial Data for Use of Immunotherapy in CRC:
Sporadic and Germline
dMMR is a pan-tumour phenotype and the combination of sporadic and germline
cases makes up to 15% of all CRCs. Most of these cases are because of MLH1
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Fig.4.19 Showing the interaction between tumour cells and T cells within our immune system utilising the checkpoints and recognising the cell as “self”, then on the right the checkpoint
inhibitors which allow the T cell to cause tumour cell death. Created with Biorender.com
promoter hypermethylation which can be caused by the characteristically aggressive BRAF V600E mutation. dMMR can be caused by inherited cancer syndromes
like LS (Fig. 4.6).
Utility of immune checkpoint inhibition is important in this group of patients
with dMMR tumours (whether sporadic or germline cause) due to intrinsic
chemotherapy resistance which was proven within neoadjuvant FOXTROT clinical trial subgroup analysis when compared with pMMR tumours. Response rates
in dMMR patients were only 4.7% [156]. There was also disease progression in
29% of dMMR patients and none in pMMR group [157]. For patients with locally
advanced rectal cancer who receive combination chemotherapy and radiotherapy
(chemoradiotherapy) there are risks of disease progression, long term toxicities
related to radiotherapy (bladder/anal sphincter dysfunction, sexual dysfunction)
and pathological response rates are 8.9% in pMMR group and 5.9% in dMMR
group [158].
Clearly in the neoadjuvant setting where there is risk of positive margins and
lymph node metastasis, resistance to treatment can lead to advanced disease,
morbidity and mortality [155–157].
Combining data from 5 clinical trials (including KEYNOTE-016, KEYNOTE164, KEYNOTE-012, KEYNOTE-028, KEYNOTE-158) [159–163] where overall
90 (out of total 149) patients had treatment for advanced MSI-H/dMMR colorectal
cancer, the overall response rate was 39.6% (95% CI 31.7-47.9), responses lasted
6 months or more for 78% of patients who responded to pembrolizumab. This was
116 P. Edwards and K. J. Monahan
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FDA approved in 2017 for use in advanced or unresectable MSI-H or dMMR solid
tumours and represented the first drug to receive tumour site agnostic approval.
CheckMate-142 reviewed treatment naïve advanced or metastatic MSI-H/
dMMR patients with CRC and they were treated with 1st line combination 2
weekly nivolumab (anti-PD-1) and 6 weekly ipilimumab (anti-CTLA4), ORR was
69% (95% CI 53-82) and disease control rate was 84% (95% CI 70.5-93.5).
Median PFS and OS were not reached after follow up of 24.2 months. The effect
was seen regardless of RAS/RAF mutation status. G3/4 treatment related adverse
events occurred in 22% of patients, 13% discontinued [164]. This regime was FDA
approved in 2018.
KEYNOTE-164 phase II open-label study, pre-treated metastatic MSI-H/
dMMR CRC treated 124 patients with pembrolizumab, this showed an ORR of
33% and grade 3–4 toxicities in 16% of patients [159]. KEYNOTE-177 looked
at pembrolizumab for unresectable/metastatic (also includes locally advanced, risk
of a positive margin), progression-free survival and overall survival primary end
points. ITT analysis showed increase in PFS by 40% compared to SOC (HR 0.60
95% CI 0.45-0.8). This is licensed for use up to 2 years, due to clinical trial
evidence and lack of belief that benefit would be gained beyond this time [165]
(Table 4.6).
Neoadjuvant Space
Recent presentation of NICHE-2 data at ESMO Congress 2022 shows promising results in colon cancer, showing pathologic complete response in 100% of
dMMR tumours treated neoadjuvant with ipilimumab and nivolumab [169]. The
rate of grade 3 or 4 toxicity was only 4%. 3-year DFS is awaited. The NICOLE
study looked at single agent nivolumab in cT3/T4 resectable colon cancer without
selection for MMR/MSI status, 70% patients in nivolumab group showed significant tumour regression and higher levels of CD8- and CD8 + non-inhibitory
T cells [170]. VOLTAGE-A study, phase III Japanese study, compared MSS
and MSI-H group with long course chemoradiotherapy followed by neoadjuvant
immunotherapy, surgical resection and then adjuvant chemotherapy [171]. Both
groups achieved major pathological response.
Studies specific to LS
Due to recent practice changing approvals in dMMR solid tumours, there are resultant bodies of generalised dMMR CRC outcome data however, this is not specific
for LS CRC.
Thirkelsden et al. systemically reviewed the literature to identify patients with
LS within cohorts of several clinical trials with use of one or more of FDA
approved immune checkpoint inhibitors; anti-CTLA-4, anti-PD-1, anti-PD-L1 in
which information was available on clinical outcomes [172]. Overall, this showed
that LS cancer patients may benefit from ICPI therapy however, there was no statistically significant difference in response compared with non-LS patients, further
4 Lynch Syndrome 117
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Tab le 4.6 Summary of immunotherapy treatment options for dMMR CRC patients
Guidelines Neoadjuvant Adjuvant Advanced
NICE
[166]
ESMO
[167]
NCCN
[168]
Nil T1-4, N1-2, M0:
Nil Low risk stage III
Rectal cancer: nivolumab,
pembrolizumab, dostarlimab
CRC T4b:
nivolumab± ipilimumab,
pembrolizumab
Synchronous lung/liver only
metastases CRC:
dostarlimab
Metachronous CRC
metastases (no previous
immunotherapy):
nivolumab± ipilimumab,
pembrolizumab, dostarlimab
CAPOX 3 months,
FOLFOX
3–6 months, single
agent
fluoropyrimidine
6 months
Stage II low/
intermediate risk
–noadjuvant
therapy, high risk
stage II
pT4b—consider
(T1-3, N1):
CAPOX 3 months,
FOLFOX
6 months
High risk stage III
(T4, and/or N2):
CAPOX 6 months,
FOLFOX
6 months
Stage II low/
intermediate risk
–noadjuvant
therapy, high risk
stage II pT4b
– consider
Low risk stage III
(T1-3, N1):
CAPOX 3 months,
FOLFOX
3–6 months
High risk stage III
(T4, N1-2, T any,
N2): CAPOX
3–6 months,
FOLFOX
6 months
Untreated metastatic: 1st line
pembrolizumab
2nd line
ipilimumab-nivolumab (no
previous IO)
Untreated metastatic: 1st line
pembrolizumab
nd
2
line
ipilimumab-nivolumab (no
previous IO)
Locally unresectable/
medically inoperable:
nivolumab± ipilimumab,
pembrolizumab
Metastatic unresectable:
nivolumab± ipilimumab (after
failure of fluoropyrimidine,
oxaliplatin, irinotecan),
pembrolizumab, dostarlimab
research in this area will help to inform decision making. There clearly is variation in response to treatment which may be related to tumour mutational burden,
immunoediting driver mutations (e.g., HLA genes, BM, JAK1, JAK2, PTEN or
TAP1.) and neoantigen presentation.
118 P. Edwards and K. J. Monahan
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4.11.4 Targeted Treatments in LS Associated Gynaecological
Cancers
As with CRCs dMMR gynaecological tumours respond more favourably to
immune therapies, related to high mutational burden. When cancer develops the
tumour can evade the immune system and treatment of these cancer is through
exploitation of the interaction between PD-1 and PDL-1. Within endometrial
cancer the immune checkpoint PD-1 inhibitor pembrolizumab is licenced and
approved by the FDA for use in all dMMR solid tumours and is used via
this indication. Several trials have reviewed use of combination treatment for
advanced or recurrent endometrial cancer pembrolizumab can be combined with
standard chemotherapy for all comers with PFS of 74% in dMMR cohort at
12 months [173]. Another phase III trial, RUBY included 500 patients 23% with
dMMR tumours where patients received chemotherapy/placebo or chemotherapy/
dostarlimab (PD1 inhibitor) showing significantly increased PFS in all comers but,
specifically in dMMR-MSI-H cohort [174]. Gynaecological cancers associated
with LS generally have a favourable response when compared to their sporadic
counterparts.
4.11.5 Toxicities Related to Immune Checkpoint Blockade
Due to the mechanism of action of immune checkpoint inhibitors, the side effect
profile is associated with overactivity of the immune system against healthy tissues due to off-target inflammatory response. These can present in a similar way
to autoimmune conditions and can require pausing of checkpoint inhibitor treatment, topical steroids, short course systemic steroids and less frequently, use of
other immunomodulating agents e.g., infliximab. There are guidelines for management of organ specific toxicities and if concerned this should be discussed with
an oncologist [175]. In a surgical context, high dose steroids impact on ability to
heal and there is higher risk of poor wound healing, infection or anastomotic leak
[176, 177].
4.11.6 Vaccine Based Therapies
These have been developed against neoantigens produced by frameshift mutations
which are predominant in Lynch syndrome [51]. There is recognition that the
host’s immune surveillance of frameshift peptides (FSP) plays an important role
in the prevention of tumour growth and dissemination. Recognition of common
frameshift mutations by shared immunogenic FSP can be performed by detection of immune response in peripheral blood in healthy (cancer-free) LS carriers.
Tumour infiltrating lymphocytes (TIL) from surgically resected tumour samples
have allowed teams to develop candidate proteins for vaccination against MSI
cancer. Phase I/IIa trials have shown safety and immunogenicity of FSP-based
4 Lynch Syndrome 119
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Fig.4.20 Generation of common frameshift protein neoantigens to help guide vaccine development. Created with Biorender.com
vaccine. Kloor et al. developed an FSP based on 4 shared FSP neoantigens identified in mouse models [55, 178]. The development of these vaccines is challenging
due to the wide inter-individual differences in responses to neoantigens as well as
the number of neoantigens proceeded. The Vilar Lab and academic partners have
developed a new viral based vaccine developed from 209 distinct antigens from
tumour associated and mutated neoantigens identified from LS tumours. This is
currently underway in clinical trials [179] (Fig. 4.20).
4.12 Future Directions
There remain many unanswered questions within the optimal management of LS.
1. Diagnosis of LS
Delivery of effective diagnosis is likely to reduce cancer risk by providing opportunities for surveillance, chemoprophylaxis and prophylactic surgery as well as
optimising outcomes for those who are diagnosed with cancer. As effective LS
diagnosis is delivered the pool of patients who may benefit from these interventions. Larger numbers of diagnosed patients will facilitate research and to further
appreciate the spectrum of risk and design effective diagnostic biomarkers for
cancer diagnosis & prevention, and refine clinical risk-reducing interventions.
120 P. Edwards and K. J. Monahan
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2. Diagnostic challenges
As genetic testing becomes more widely available new challenges may be generated, as well as the workload for diagnostic services, for example for unexplained
dMMR cancer following genetic testing, for variants of unknown significance
(VUS). This is particularly important given significant morbidity related to invasive
procedures, recommendations around chemoprophylaxis and possible prophylactic
surgery.
3. Colonoscopy
There is still no optimal screening interval agreed globally for colonoscopy. Given
limited data on quality of colonoscopy in LS, so it is difficult to assess the efficacy
of quality/performance indicators in colonoscopy. An RCT or similar structured
evaluation may be warranted to evaluate the benefit of different approaches to
colorectal surveillance, including personalised intervals, the use of adjuncts and
alternate intervals.
4. Precursors
Given evidence of the three pathways to development of CRC, how do we survey
for submucosal lesions? There may be specific benefit for non-invasive biomarkers
in this population given the risk of more invasive approaches which lack efficacy
and may cause population harm.
5. Treatment
Post-cancer diagnosis rapid genetic diagnosis may inform treatment strategies
including surgical and other oncological approaches. Decisions around extensive
resection will remain nuanced but may be better informed by accurate longitudinal
risk assessment. Advances in immunotherapy, especially with checkpoint inhibition have changed the landscape of treating dMMR solid tumours. The difficulty
arises when treatment stops working - how should we manage disease subsequently
with often tumours being resistant to conventional chemotherapy. There may be a
role for novel chemoprophylactic applications of immunotherapy in CMMRD or
other higher risk LS populations. Vaccines are in development and further data is
required to evaluate whether they are effective in both reducing cancer risk and in
which tumour sites.
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