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Every thing about lynch syndrome and its criteria and NICHE trail

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Lynch syndrome is a hereditary cancer-predisposition syndrome caused by pathogenic variants in DNA mismatch-repair genes. A complete discussion includes:
  1. Genetics and pathogenesis
    • MLH1, MSH2, MSH6, PMS2, and EPCAM-related MSH2 silencing
    • Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H)
  2. Cancer spectrum and risks
    • Colorectal and endometrial cancer
    • Ovarian, gastric, small-bowel, urinary-tract, pancreatic, biliary-tract, brain, and sebaceous skin tumors
    • Gene-specific risk differences
  3. Who should be suspected
    • Young-onset colorectal or endometrial cancer
    • Multiple Lynch-associated cancers
    • Family-history patterns
    • Universal tumor screening with MMR immunohistochemistry or MSI testing
  4. Diagnostic criteria and testing algorithm
    • Amsterdam II criteria
    • Revised Bethesda guidelines
    • PREMM5 and related prediction tools
    • Interpretation of MMR IHC patterns
    • MSI testing, BRAF V600E and MLH1 promoter methylation
    • Germline testing and “Lynch-like” tumors
  5. Surveillance and prevention
    • Colonoscopy intervals and starting ages
    • Gynecologic surveillance and risk-reducing hysterectomy with bilateral salpingo-oophorectomy
    • Screening for upper GI, urinary tract, pancreas, and skin where appropriate
    • Aspirin chemoprevention and CAPP2 evidence
    • Cascade testing of relatives
  6. Treatment implications
    • Surgical choices in colorectal cancer
    • Prognostic value of dMMR/MSI-H status
    • Immune-checkpoint inhibitors for advanced disease
    • Fertility and counseling issues
  7. NICHE trial
    • NICHE-1 and NICHE-2 design
    • Neoadjuvant nivolumab plus ipilimumab in resectable, locally advanced dMMR colon cancer
    • Pathologic complete response and major pathologic response
    • Safety, limitations, and what this does and does not yet mean for routine practice
    • Relation to newer organ-preservation approaches in dMMR rectal cancer
Which section should I cover in detail first?
  1. Criteria and diagnostic algorithm
  2. Surveillance and prevention
  3. NICHE trial in detail
  4. Exam-focused complete notes

Summarize the NICHE-1 and NICHE-2 trial results

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NICHE-1 NICHE-2 trial results neoadjuvant immunotherapy dMMR colon cancer published

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dMMR colon cancer neoadjuvant immunotherapy

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PMID: 32251400

Reading Article

PMID: 38838311

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https://dailyreporter.esmo.org/esmo-congress-2024/gastrointe…

NICHE-1

Design: Exploratory phase II study of operable, nonmetastatic colon cancer. Patients received short-course neoadjuvant immune-checkpoint blockade before surgery: one dose of ipilimumab plus two doses of nivolumab. It included both dMMR/MSI-H and pMMR/MSS tumors.

Main results

GroupPathologic responseMajor pathologic response (MPR)Pathologic complete response (pCR)
dMMR tumors20/20, 100%19/20, 95%12/20, 60%
pMMR tumors4/15, 27%3/15, 20%0% pCR reported
  • MPR means ≤10% viable tumor remaining at resection.
  • pCR means no viable tumor cells in the surgical specimen.
  • Treatment was feasible: all patients underwent radical surgery without treatment-related surgical delay.
  • This established that early dMMR colon cancers can be extraordinarily sensitive to PD-1 plus CTLA-4 blockade, in contrast with pMMR tumors, where benefit was much less consistent.
Published report: Chalabi et al., Nature Medicine 2020, NICHE-1 results [PMID: 32251400].

NICHE-2

Design: Larger, single-arm phase II study in previously untreated, nonmetastatic, locally advanced dMMR colon cancer. The regimen was again one dose of ipilimumab plus two doses of nivolumab before planned surgical resection. It was designed primarily to assess safety and 3-year disease-free survival.

Main published results

Among 115 enrolled patients, 111 were evaluable for efficacy:
  • Timely surgery: 113/115 (98%) had surgery on time, defined as no treatment-related delay exceeding 2 weeks.
  • Severe immune-related adverse events: 5/115 (4%) had grade 3-4 events.
  • No patient discontinued treatment because of toxicity.
  • Any pathologic response: 109/111 (98%)
  • Major pathologic response: 105/111 (95%)
  • Pathologic complete response: 75/111 (68%)
  • At the published median follow-up of 26 months, there were no recurrences.
The primary publication is Chalabi et al., New England Journal of Medicine 2024, NICHE-2 report [PMID: 38838311].

Longer follow-up

At ESMO 2024, updated NICHE-2 follow-up, with a median of 36.5 months after surgery, again reported no disease recurrences. This is highly encouraging, but it was presented as conference data and should be interpreted differently from a mature, randomized phase III comparison. The ESMO update reported that 94% of patients with a pCR also had preoperative circulating tumor DNA clearance.

Bottom line

NICHE-1 provided the proof of concept. NICHE-2 confirmed it in a much larger dMMR colon-cancer cohort:
  • Very high response rate: 98%
  • Very high MPR rate: 95%
  • pCR in approximately two-thirds of patients
  • Low rate of serious immune toxicity: 4%
  • Surgery was rarely delayed
  • No recurrences in the reported follow-up
However, NICHE-2 was not randomized and involved colon cancer, not rectal cancer. It strongly supports neoadjuvant nivolumab plus ipilimumab as an important treatment strategy for locally advanced dMMR colon cancer, but questions remain about the optimal regimen, whether surgery can safely be omitted in selected complete responders, and how it compares directly with standard surgery-based strategies.

Summarize the NICHE-1 and NICHE-2 trial results

Reading File
Reading Article

PMID: 32251400

Reading Article

PMID: 38838311

Searching PubMed

dMMR colon cancer neoadjuvant immunotherapy

Searching the Web

NICHE-2 trial 3 year disease-free survival 2024 results dMMR colon cancer

NICHE-1

Design: Exploratory phase II study of resectable, early-stage colon cancer. Patients received neoadjuvant nivolumab (anti-PD-1, two doses) plus ipilimumab (anti-CTLA-4, one dose) before surgery. It enrolled both dMMR/MSI-H and pMMR/MSS tumors.

Results in dMMR colon cancer

Among 20 evaluable dMMR tumors treated with the combination:
  • Pathologic response: 20/20, 100%
  • Major pathologic response (MPR): 19/20, 95%
    • MPR = ≤10% viable tumor remaining
  • Pathologic complete response (pCR): 12/20, 60%
    • pCR = no viable tumor in the resection specimen
  • All patients underwent surgery without treatment-related delay.
In contrast, pMMR tumors had substantially lower activity: 4/15 (27%) showed a pathological response, with no pCR reported. NICHE-1 provided the proof of concept that short-course dual checkpoint blockade is highly active in localized dMMR colon cancer. Chalabi et al., Nature Medicine 2020.

NICHE-2

Design: Larger, single-arm phase II study of previously untreated, nonmetastatic, locally advanced dMMR colon cancer. The same brief preoperative regimen was used: one dose of ipilimumab plus two doses of nivolumab, followed by surgery.

Published results

Of 115 enrolled patients:
  • Timely surgery: 113/115, 98%
    • Only 2 patients had surgery delayed by more than 2 weeks.
  • Grade 3-4 immune-related adverse events: 5/115, 4%
  • Treatment discontinuations due to toxicity: 0
Among 111 efficacy-evaluable patients:
  • Any pathologic response: 109/111, 98%
  • MPR: 105/111, 95%
  • pCR: 75/111, 68%
At the initial publication, after median follow-up of 26 months, no recurrence had occurred. Chalabi et al., NEJM 2024.
An ESMO 2024 update reported no recurrences at a median 36.5 months after surgery, supporting highly favorable 3-year disease-free outcomes, though these extended data were conference-reported rather than a randomized comparison. ESMO NICHE-2 update.

Take-home comparison

TrialPopulationAny pathologic responseMPRpCR
NICHE-120 evaluable dMMR tumors100%95%60%
NICHE-2111 evaluable locally advanced dMMR tumors98%95%68%
Clinical meaning: NICHE-2 confirmed the striking NICHE-1 signal in a larger dMMR-only cohort: a few weeks of nivolumab-ipilimumab before surgery produced near-universal pathologic response, frequent complete eradication of tumor in the surgical specimen, limited severe toxicity, and no reported recurrences in the available follow-up. However, NICHE-2 was a single-arm phase II trial, so it does not alone establish whether surgery can be safely omitted after clinical response or prove superiority over all standard treatment pathways.
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