Rethinking treatment for non-metastatic deficient mismatch repair colorectal and small bowel cancers

Table 1 Baseline demographic and clinical characteristics of the included patients

Patient	Tumor location	Age (years)	Sex	Medical history	Known lynch	Symptoms
P1	Small bowel	85	Male	Colon cancer (surgery 1990/2015), prostate cancer (2015)	Yex (MSH2)	Asymptomatic
P2	Colon	78	Male	COPD, OSA, moderate pulmonary hypertension, atrial fibrillation, IC-FEr (FE 35%), Moderate exertional dyspnea	No	Asymptomatic
P3	Colon	71	Female	No	No	Constitutional symptoms, malnutrition, and abdominal mass
P4	Colon	77	Female	No	No	Constitutional symptoms, anemia, malnutrition, and abdominal mass
P5	Colon	33	Male	No	No	Anemia
P6	Rectum	36	Female	First-degree lynch syndrome (MSH6)	Yes (MSH6)	Progressive weight loss and a change in bowel habits
P7	Rectum	37	Male	Grade III astrocytoma (surgery 2008/2010)	No	Rectal bleeding and a change in bowel habits
P8	Rectum	48	Female	No	No	Rectal bleeding and a change in bowel habits

COPD: Chronic obstructive pulmonary disease; OSA: Severe obstructive sleep apnea; IC-FEr (FE 35%): Heart failure with reduced ejection fraction (left ventricular ejection fraction 35%).

Table 2 Baseline imaging, endoscopic, and histopathological findings

	CT/MRI	PET/CT	Colonoscopy	Biopsy	IHC
P1	Concentric mural thickening with ulceration and locoregional involvement	Increased metabolic activity	-	-	-
P2	No histopathological findings	Focal hypermetabolic deposit near the hepatic flexure of the colon	Flat elevated lesion with central ulceration, irregular morphology, and a disorganized glandular pattern	ADC	dMMR phenotype (loss of MLH1 and PMS2 expression)
P3	Locally advanced colon cancer, with a necrotic lymph node mass adjacent to the ileocolic region and infiltration into the abdominal wall musculature	-	A mass at the hepatic flexure with extensive, deep ulceration	Poorly differentiated ADC	dMMR phenotype (loss of MLH1 and PMS2 expression) BRAF V600E mutation
P4	Circumferential wall thickening involving the cecum and ascending colon up to the hepatic flexure, with extension into the pericolic fat and ileocolic lymphadenopathy	-	Extensive ulcerated mass from the cecum to the hepatic flexure, involving the ileocecal valve and approximately 75% of the circumference	Poorly differentiated ADC	dMMR (loss of PMS2 expression) BRAF V600E mutation
P5	Wall thickening of the cecum with ileocolic lymphadenopathy	-	Nodular mass at the ileocecal valve involving approximately 75% of the circumference	Moderately differentiated ADC	dMMR (loss of MSH2 and MSH6 expression)
P6	Tumor located 9 cm from the anal verge, staged as cT3bN1b, with EMVI and a threatened CRM (< 1 mm)	Rectal mural thickening with regional lymphadenopathy and no other areas of uptake	Ulcerated lesion extending from 7 to 12 cm from the anal verge	ADC	dMMR (loss MSH6 expression)
P7	Lower rectal cancer staged as cT3b cN1a	-	Ulcerated, eroded tumor located 3-4 cm from the anal verge, involving approximately 50% of the circumference without stenosis	ADC	After CRT and first consolidation CT: DMMR phenotype (loss of PMS2 expression)
P8	Tumor staged as T3bcN2b, located 6 cm from the anal verge, with EMVI positive, threatened CRM < 2 mm, and no lateral lymph nodes	Rectal tumor with no other findings	Stenosing rectal tumor located 9 cm from the anal verge	ADC	After CRT: DMMR (MSH2-, MSH6-)

EMVI: Extramural vascular invasion; CRM: Circumferential resection margin; CT: Computed tomography; MRI: Magnetic resonance imaging; PET/CT: Positron emission tomography/computed tomography; IHC: Immunohistochemical; ADC: Adenocarcinoma; CRT: Chemoradiotherapy; dMMR: Deficient mismatch repair.

Table 3 Immune checkpoint inhibitor regimen, immune-related adverse events, treatment response, and subsequent management (surgery or watch-and-wait)

	ICI treatment (agent, dose, number of cycles)	ir-AEs	Treatment response	Subsequent management	AP	Actual situation	Follow-up (months)
P1	Pembrolizumab 2 mg/kg every 21 days, 18 cycles	No	Complete radiological resolution of the mural thickening	W&W	-	Asymptomatic, alive	12 meses
P2	Pembrolizumab 2 mg/kg every 21 days, 10 cycles	Hospitalized for respiratory infection and heart failure exacerbation	Complete radiological and endoscopic response, with no evidence of tumor	W&W	-	Asymptomatic, alive	4 meses
P3	Nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks. 4 (N + I) + 4 (N)	No	Radiological improvement with reduction in tumor size	Laparoscopic right hemicolectomy	ypT0N0 (0/28 lymph nodes)	Asymptomatic, alive
P4	Pembrolizumab 2 mg/kg every 21 days, 5 cycles	No	Decreased in size; reduction in the size of the necrotic pathological lymph node adjacent to the tumor	Robotic right hemicolectomy	ypT0N0 (0/60 lymph nodes)	Asymptomatic, alive
P5	Pembrolizumab2 mg/kg every 21 days, 4 cycles	No	Resolution of the wall thickening in the blind section with persistent lymphadenopathy and a slight increase in metabolism	Robotic right hemicolectomy	ypT0N0 (0/30 lymph nodes)	Asymptomatic, alive
P6	Dostarlimab 500 mg every 3 weeks, 9 cycles	No	Complete clinical response on DRE, colonoscopy, CT and PET/CT	W&W	-	Asymptomatic, alive	27 meses
P7	Dostarlimab 500 mg every 3 weeks, 9 cycles (after CRT + XELOX1)	No	Complete clinical response (CCR) on DRE, colonoscopy (scar in the rectum with good endoscopic appearance), and MRI	W&W	-		22 meses
P8	Dostarlimab 500 mg every 3 weeks, 9 cycles (after CRT)	No	Endoscopic stenosis without malignancy	Robot-assisted TME	ypT0N0 (tumor regression 0/4)	Asymptomatic, alive	20 meses

W&W: Watch & wait; TME: Total mesorectal excision; ir-AEs: Immune-related adverse events; CRT: Chemoradiotherapy; ICI: Immune checkpoint inhibitor; CT: Computed tomography; MRI: Magnetic resonance imaging; PET/CT: Positron emission tomography/computed tomography; AP: Anatomical pathology; DRE: Digital rectal examination.