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Association of mismatch repair status with survival and

response to neoadjuvant chemo(radio)therapy in rectal cancer
Shu-Biao Ye1,9, Yi-Kan Cheng2,9, Lin Zhang3,4,9, Yi-Feng Zou1, Ping Chen3,5, Yan-Hong Deng6, Yan Huang7, Jian-Hong Peng3,8,
Xiao-Jian Wu1 ✉ and Ping Lan 1 ✉

Prior reports have indicated that defective mismatch repair (MMR) has a favorable impact on outcome in colorectal cancer patients
treated with surgery, immunotherapy, or adjuvant chemotherapy. However, the impact of MMR status on response to neoadjuvant
radiotherapy in rectal cancer is not well understood. Here we report that dMMR was associated with improved disease-free survival
(DFS) (P = 0.034) in patients receiving neoadjuvant chemotherapy (NCT). Patients with dMMR tumors who received neoadjuvant
chemoradiotherapy (NCRT) achieved significantly worse DFS (P = 0.026) than those treated with NCT. Conversely, NCRT improved
DFS (P = 0.043) in patients with pMMR tumors, especially for stage III disease with improved DFS (P = 0.02). The presence of dMMR
was associated with better prognosis in rectal cancer patients treated with NCT. NCT benefited patients with dMMR tumors; while
NCRT benefited patients with stage III disease and pMMR tumors. Patients stratified by MMR status may provide a more tailored
approach to rectal cancer neoadjuvant therapy.
npj Precision Oncology (2020)4:26 ; https://doi.org/10.1038/s41698-020-00132-5
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INTRODUCTION for now, these patients receiving NRT or not are determined on
Deficient mismatch repair (dMMR) or microsatellite instability an individual basis, and there is a tremendous demand for
(MSI) is one of the well-established molecular biomarkers in predictive biomarkers to select optimal patients who can benefit
colorectal cancer (CRC) and MSI testing has been recommended the most from NRT. Although immunotherapy alone or
for all CRC patients according to the National Comprehensive combined with conventional therapy are being rapidly devel-
Cancer Network (NCCN) guidelines1 due to its aid in dictating oped for dMMR CRCs16, the predictive value of MMR status in
management2,3. For instance, early-stage colorectal adenocarci- NRT remains undefined in rectal cancer. We therefore aimed to
nomas testing positive for MSI may carry a favorable prognosis investigate the association of MMR status with survival and
and therefore do not require adjuvant chemotherapy3–5. Some response to neoadjuvant chemo(radio)therapy.
studies suggest that these tumors are more prone to be sensitive The new attempts of selective NRT or the omission of NRT that
to 5-FU chemo(radio)therapy, although this finding is controver- have recently emerged in our center (NCT01211210,
sial6–10. Even if a significantly decreased likelihood of pathologic NCT02217020, etc.)17,18 have provided a direct comparison
complete response (pCR) has been demonstrated for dMMR between NCRT and NCT, which is ideal for determining the
patients after chemoradiation6 in the largest sample-sized study, impact of MMR status on response to NRT. This is the first study to
no study has been reported to investigate the association of MMR utilize multicenter data to investigate this issue in locally
status with survival and response to neoadjuvant radiotherapy advanced rectal cancer.
(NRT) with a comparison of patients receiving neoadjuvant
chemotherapy (NCT) with or without radiotherapy.
Neoadjuvant chemoradiotherapy (NCRT) and surgery plus RESULTS
adjuvant chemotherapy is recommended for stage II/III rectal Patient characteristics and associations with MMR status
cancer patients1. Radiotherapy is a crucial component of Patients with dMMR tumors (n = 66) were significantly younger
neoadjuvant care, which has been demonstrated to improve than patients with mismatch repair-proficient (pMMR) tumors
local recurrence-free survival (LRFS) but not overall survival11,12 (n = 949) (Table 1, Supplementary Table 1). NCRT was given in 591
and to be associated with higher rates of related adverse patients (58.2%), whereas 424 patients (41.8%) received NCT. The
events13. Thus, the exploration of different avenues of neoadju- preoperative radiation dose exhibited very minor variability, with
vant therapy, such as the omission of NRT or selective NRT 95.3% receiving 45–50.4 Gy over 5 weeks.
before chemotherapy and total mesorectal excision, is currently For patients with dMMR tumors, although the percentage of
under investigation14,15 (PROSPECT clinical trial, etc.). However, stage III patients in NCT group was higher than NCRT group

1
Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of
Colorectal and Pelvic Floor Diseases, Guangzhou, Guangdong, People’s Republic of China. 2Department of Radiation Oncology, The Sixth Affiliated Hospital, Sun Yat-sen
University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, People’s Republic of China.
3
State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou,
People’s Republic of China. 4Department of Clinical Laboratory, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China. 5Department of VIP Region,
Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China. 6Department of Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong
Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, People’s Republic of China. 7Department of Pathology,
The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases,
Guangzhou, People’s Republic of China. 8Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China. 9These authors
contributed equally: Shu-Biao Ye, Yi-Kan Cheng, Lin Zhang. ✉email: [email protected]; [email protected]

Published in partnership with The Hormel Institute, University of Minnesota

 S.-B. Ye et al.
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(90.5% vs. 68.9%, P = 0.07), downstaging rate was also higher
Table 1. Comparative baseline characteristics for mismatch repair
than NCRT group (81.0% vs. 62.2%, P = 0.163) (Table 2). Only 1
status.
patient (4.8%) received single agent chemotherapy in NCT
Characteristics MMR-proficient, MMR-deficient, P value# group, while 11 patients (24.4%) received single agent
n = 949 n = 66 chemotherapy (P = 0.001) in NCRT group (Table 3), of whom 7
patients (63.6%) had disease recurrence. As for patients with
Sex (%) 0.683 pMMR tumors, compared to the NCT group, patients in the NCRT
Male 653 (68.8) 47 (71.2) group were more likely to have T3/T4 tumors (P = 0.006), and
Age (year, %) <0.001* poorly differentiated (P < 0.001) and distally located tumors (P =
0.001). Nevertheless, the rate of downstaging and pCR were
≤60 570 (60.0) 54 (81.8)
higher (P < 0.001, P = 0.002) and the rate of advanced patholo-
>60 379 (40.0) 12 (18.2) gic stage was lower (P = 0.0017) in NCRT group (Table 2). Such
Comorbidity (%) 0.369 trends were also demonstrated in rectal cancer with pMMR
Yes 218 (23.0) 12 (18.2) tumors and stage III disease (Supplementary Table 2).
No 731 (77.0) 54 (81.8)
BMI (%) 0.234 Association between MMR status and survival
Mean (SD) 22.5 (3.2) 22.0 (3.0) Although MMR status was not a prognostic biomarker in the
Clinical T stage (%) 0.249 whole cohort even after propensity match analysis (Supplemen-
tary Fig. 1), dMMR was associated with improved DFS (HR, 0.117;
T1 1 (0.0) 0 (0)
95% CI, 0.016–0.847; P = 0.034, Fig. 1, Table 4) in NCT group,
T2 15 (1.6) 1 (1.5) whereas no significant correlation between MMR status and DFS
T3 717 (75.6) 44 (66.7) (HR, 1.495; 95% CI, 0.916–2.444; P = 0.108, Fig. 1) was shown in the
T4 216 (22.8) 21 (31.8) NCRT group (Table 4).
Clinical N stage (%) 0.783
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N0 207 (21.8) 16 (24.2) Association between neoadjuvant treatment and survival

N1 473 (49.8) 30 (45.5) Compared to NCT, NCRT was associated with a worse DFS (HR,
N2 269 (28.3) 20 (30.3)
10.580; 95% CI, 1.333–83.974; P = 0.026) and DMFS (HR, 8.828;
95% CI, 1.081–72.064; P = 0.042) in rectal cancer patients with
Distance from anal verge 0.126
dMMR tumors (Fig. 2, Table 5) but was correlated with an
(%)
improved DFS (HR, 0.763; 95% CI, 0.587–0.991; P = 0.043) and
≤5 cm 442 (46.6) 38 (57.6) LRFS (HR, 0.403; 95% CI, 0.241–0.673; P = 0.001) in pMMR
>5 and ≤10 cm 453 (47.7) 23 (34.8) patients (Supplementary Fig. 2, Supplementary Tables 3 and 4).
>10 cm 54 (65.7 5 (7.6) For patients with stage III disease and pMMR tumors, the
ypStage (%) 0.137 addition of NRT could achieve better DFS (HR, 0.705; 95% CI,
0–I 318 (33.5) 16 (24.2)
0.525–0.946; P = 0.02) and LRFS (HR, 0.389; 95% CI, 0.220–0.687;
P = 0.001) (Fig. 2, Table 6). Competing risk estimate also showed
II–III 631 (66.5) 50 (75.8)
the similar trends in patients with dMMR tumors, pMMR or
pCR (%) 60 (6.3) 6 (9.1) 0.387 pMMR with stage III disease (Supplementary Fig. 3). No benefit
Differentiation (%) 0.090 from the addition of NRT was shown in patients with stage II
Well 167 (17.6) 17 (25.8) disease and pMMR tumors. However, compared to T3N0 disease,
Moderately 652 (68.7) 36 (54.5) T4N0 disease was associated with worse LRFS in these subsets of
patients receiving NCT (HR, 8.108; 95% CI, 1.798–36.559; P =
Poorly 105 (11.1) 11 (16.7)
0.006), whereas there was no correlation between T disease and
NS 25 (2.6) 2 (3.0) LRFS in NCRT group (Supplementary Fig. 4).
Neoadjuvant radiotherapy 0.090
(NRT) (%)
Association of treatment and survival in cohort without pCR
Yes 546 (57.5) 45 (68.2)
Since the reasons for MMR testing were not provided, and testing
No 403 (42.5) 21 (31.8) may have been performed in patients who did not respond well to
Adjuvant chemotherapy 0.651 neoadjuvant therapy and MMR status could not be determined on
(ACT) (%) the surgical pathological specimen for patients with pCR, we
Yes 815 (85.9) 58 (87.9) reanalyzed the association of MMR status with survival and
No 134 (14.1) 8 (12.1) response to neoadjuvant therapy for remaining patients excluding
Radiotherapy dose, Gy (%) 0.08 those with pCR.
Baseline clinical characteristics of the remaining patients
0 403 (42.5) 21 (31.8)
excluding those with pCR are shown in Supplementary Table 5.
<45 25 (2.6) 4 (6.1) Compared to NCT, NCRT was associated with a significantly
≥45 and <50.4 521 (54.9) 41 (62.1) worse DFS (HR, 11.113; 95% CI: 1.395–88.520, P = 0.023) and
MMR mismatch repair, SD standard deviation, BMI body mass index, NRT
DMFS (HR: 9.296, 95% CI: 1.123–76.934, P = 0.039) in patients
neoadjuvant radiotherapy, pCR pathologic complete response, NS not with dMMR (Supplementary Table 6, Supplementary Fig. 4) but
sure. with an improved LRFS (HR: 0.438, 95% CI: 0.257–0.741, P =
#
Clinicopathological differences between the pMMR and dMMR groups 0.002) in patients with pMMR tumors (Supplementary Table 7).
were compared with the Mann–Whitney U test for continuous variables In the remaining data, for patients with pMMR tumors and stage III
and χ2 test (or Fisher’s exact test, if appropriate) for categorical data. disease, the omission of NRT could achieve worse DFS (HR, 0.731;
*Statistically significant. 95% CI: 0.543–0.985, P = 0.039) and LRFS (HR: 0.423, 95% CI:
0.237–0.754, P = 0.004) (Supplementary Table 8, Supplementary

npj Precision Oncology (2020) 26 Published in partnership with The Hormel Institute, University of Minnesota
 S.-B. Ye et al.
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Table 2. Baseline characteristics.

Characteristics MMR-proficient (n = 949) MMR-deficient (n = 66)

NCT (n = 403) NCRT (n = 546) P value# NCT (n = 21) NCRT (n = 45) P value#

Age (year, %) 0.538 0.746

≤60 244 (60.5) 326 (59.7) 18 (85.7) 36 (80.0)
>60 159 (39.5) 220 (40.3) 3 (14.3) 9 (20.0)
Sex (%) 0.419 0.771
Male 283 (70.2) 370 (67.8) 14 (66.7) 33 (73.3)
BMI 0.574 0.741
Mean (SD) 22.4 (3.4) 22.5 (3.0) 21.8 (2.8) 22.0 (3.1)
Comorbidity (%) 0.806 0.738
Yes 91 (22.6) 127 (23.3) 3 (14.3) 9 (20)
Clinical T stage (%) 0.006* 0.356
T1 1 (0.2) 0 (0) 0 (0) 0 (0)
T2 6 (1.5) 9 (1.6) 1 (4.8) 0 (0)
T3 324 (80.4) 393 (72.0) 13 (61.9) 31 (68.9)
T4 72 (17.9) 144 (26.4) 7 (33.3) 14 (31.1)
Clinical N stage (%) 0.058 0.089
N0 100 (24.8) 107 (19.6) 2 (9.5) 14 (31.1)
N1 184 (45.7) 289 (52.9) 13 (61.9) 17 (37.8)
N2 119 (29.5) 150 (27.5) 6 (28.6) 14 (31.1)
Clinical stage (%) 0.039* 0.07
II 100 (24.8) 107 (19.6) 2 (9.5) 14 (31.1)
III 303 (75.2) 439 (80.4) 19 (90.5) 31 (68.9)
Distance from anal verge (%) <0.001* 0.395
≤5 cm 164 (40.7) 278 (50.9) 10 (47.6) 28 (62.2)
>5 and ≤10 cm 198 (49.1) 255 (46.7) 10 (47.6) 13 (28.9)
>10 cm 41 (10.2) 13 (2.4) 1 (4.8) 4 (8.9)
ypStage (%) 0.018* 0.759
0–I 118 (29.3) 200 (36.6) 6 (28.6) 10 (22.2)
II–III 285 (70.7) 346 (63.4) 15 (71.4) 35 (77.8)
*
pCR (%) 14 (3.5) 46 (8.4) 0.002 2 (10.0) 4 (9.0) 0.639
*
Downstaging status (%) 0.003 0.163
Downstaged 266 (66.0) 409 (74.9) 17 (81.0) 28 (62.2)
Same or higher 137 (34.0) 137 (25.1) 4 (19.0) 17 (37.8)
NAR score <0.001* 0.53
Mean (SD) 21.8 (28.3) 18.1 (26.4) 14.8 (8.6) 32.7 (44.4)
Differentiation (%) <0.001* 0.426
Well 93 (23.1) 74 (13.6) 8 (38.1) 9 (20.0)
Moderately 265 (65.8) 387 (70.9) 10 (47.6) 26 (57.8)
Poorly 40 (9.9) 65 (11.9) 3 (14.3) 8 (17.8)
NS 5 (1.2) 20 (3.7) 0 (0) 2 (4.4)
MMR mismatch repair, SD standard deviation, BMI body mass index, NCT neoadjuvant chemotherapy, NCRT neoadjuvant chemoradiotherapy, pCR pathologic
complete response, NAR score neoadjuvant rectal score, NS not sure, 5FU 5-fluorouracil, FOLFOX 5-fluorouracil+oxaliplatin, XELOX xeloda+ oxaliplatin, FOLFOXIRI
5-fluorouracil+oxaliplatin+irinotecan.
#
Clinicopathological differences between the pMMR and dMMR groups stratified by neoadjuvant treatment groups were compared with the Mann–Whitney U
test for continuous variables and χ2 test (or Fisher’s exact test, if appropriate) for categorical data.
*Statistically significant.

Fig. 5). Although no benefit from the addition of NRT was shown DISCUSSION
in patients with stage II disease and pMMR tumors, the univariate In locally advanced rectal cancer, NRT is routinely used for
analysis indicated that compared with T3 disease, T4 disease was improving local control12. Clinical trials have so far failed to
associated with worse LRFS in these subsets of patients (HR, 5.403; increase disease-free and overall survival11,12. A pilot study from
95% CI, 1.051–27.786; P = 0.044), whereas there was no correlation Memorial Sloan Kettering Cancer Centre has reported the
between T disease and LRFS in NCRT group (Supplementary potential feasibility of NCT without routine use of radiation
Fig. 6). therapy19 and thus the omission of radiotherapy in the

Published in partnership with The Hormel Institute, University of Minnesota npj Precision Oncology (2020) 26
 S.-B. Ye et al.
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Table 3. Treatment characteristics.

Characteristics MMR-proficient (n = 949) MMR-deficient (n = 66)

NCT (n = 403) NCRT (n = 546) P value# NCT (n = 21) NCRT (n = 45) P value#

Neoadjuvant chemotherapy regimen (%) <0.001* 0.001*

5FU/Xeloda 5 (1.2) 163 (29.9) 1 (4.8) 11 (24.4)
FOLFOX/XELOX 314 (77.9) 360 (65.9) 15 (71.4) 34 (75.6)
FOLFOXIRI 83 (20.6) 0 (0) 5 (23.8) 0 (0)
Others 1 (0.2) 9 (1.6) 0 (0) 0 (0)
NS 0 (0) 14 (2.6) 0 (0) 0 (0)
Adjuvant chemotherapy (%) 0.093 0.702
Yes 355 (88.1) 460 (84.2) 18 (85.7) 40 (88.9)
No 48 (11.9) 86 (15.8) 3 (14.3) 5 (11.1)
5FU 5-fluorouracil, FOLFOX 5-fluorouracil+oxaliplatin, XELOX xeloda+ oxaliplatin, FOLFOXIRI 5-fluorouracil+oxaliplatin+irinotecan, NS not sure.
#
Clinicopathological differences between the pMMR and dMMR groups stratified by neoadjuvant treatment groups were compared with the Mann–Whitney
U test for continuous variables and χ2 test (or Fisher’s exact test, if appropriate) for categorical data.

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pMMR (n = 403) p = 0·034 pMMR (n = 546) p = 0·108
dMMR (n = 21) HR = 0·117 (0·016−0·847) dMMR (n = 45) HR = 1·495 (0·916−2·444)
0 0
0 12 24 36 48 60 72 84 96 0 12 24 36 48 60 72 84 96
No at risk: Time(months) No at risk: Time(months)
pMMR 403 308 196 135 86 52 17 6 2 pMMR 546 482 359 261 183 103 47 11 2
dMMR 21 16 14 11 8 8 5 0 0 dMMR 45 39 30 23 18 13 9 3 0

Fig. 1 Association between MMR status and disease-free survival (DFS) according to neoadjuvant treatment. a DFS in patients with
neoadjuvant chemotherapy alone (NCT) by DNA mismatch repair (MMR) status. b DFS in patients with neoadjuvant chemoradiotherapy
(NCRT) by MMR. dMMR-deficient mismatch repair; pMMR-proficient mismatch repair. HR hazard ratio, CI confidential interval.

preoperative treatment settings is under investigation14. Although rectal cancer patients with preoperative chemoradiotherapy (5086
numerous studies have demonstrated the impact of MMR status patients) from the National Cancer Database (NCDB)6, including
on the response to NCRT6,10,19–22, little is known about how MMR 4450 patients with pMMR tumors and 636 patients with dMMR
influences the outcome in patients with or without radiotherapy in tumors. After propensity matched and case-control analysis,
neoadjuvant treatment. Therefore, the association between MMR dMMR was independently correlated with a reduced pCR rate
status and the outcome of radio-responsiveness has not been well on multivariable analysis, which indicated the potential chemo/
explored. Accordingly, in this large multicenter retrospective study radio-resistant role of dMMR in rectal cancer. Additionally, a
that, to our knowledge, is the first reported to date, we have poorer prognosis of rectal cancer patients with dMMR tumors has
demonstrated that MMR status could serve as a valuable predictor also been reported8. None of these studies has directly compared
to select optimal patients who benefit the most from NRT. patients receiving neoadjuvant treatment with and without
The dMMR patients in our cohort were significantly younger radiotherapy to determine the association of MMR status and
than pMMR patients because at least some of them had Lynch the response to NRT. Our study first showed that NCT had a better
syndrome, similarly to patients in a recent published study22. survival outcome than NCRT in dMMR patients, which was
Similar to colon cancer, dMMR is a significant prognostic factor in consistent with the abovementioned notion of radio(chemo)-
rectal cancer patients receiving NCT. Neoadjuvant (chemo)radio- resistance for dMMR tumors in the neoadjuvant setting24. One
therapy for rectal cancer with dMMR tumors seems to be possible explanation involves the different chemotherapy regi-
radiosensitive19. However, their study only included 29 locally mens (mFOLFOX6 for FOWARC clinical trial and 4–6 cycles of
advanced rectal cancers and had no comparison with pMMR mFOLFOXIRI for FORTUNE clinical trial, respectively) between
patients. Furthermore, Cercek et al. recently reported chemother- NCRT and NCT group. The lower relapse rate mainly from distant
apy resistance for dMMR tumors23, which was inconsistent with control in NCT group may benefit from double or triple-agents
our findings. The main reasons for the distinction might be that a chemotherapy regimen that the vast majority of patients (95.2%)
portion of patients had metastatic disease and a majority of received. Although substantial evidence showed dMMR colon
patients underwent NCRT after receiving initial NCT in their study. cancers do not benefit from adjuvant FU/leucovorin3,4, preliminary
A recent study has evaluated the largest series of locally advanced data indicates that the addition of either oxaliplatin or irinotecan

npj Precision Oncology (2020) 26 Published in partnership with The Hormel Institute, University of Minnesota
 S.-B. Ye et al.
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Table 4. DFS by MMR and neoadjuvant radiotherapy status in univariable and multivariable analysis adjusted for clinical characteristics.

MMR and NRT status No. of patients (n = 1015) 5-year rate (%) Univariable Multivariable
P valuea HR 95% CI P valueb

NCRT 591
dMMR 45 41 0.070 1.495 0.916–2.444 0.108
pMMR 546 66
NCT 424
dMMR 21 92 0.020* 0.117 0.016–0.847 0.034*
pMMR 403 59
dMMR 66
NCRT 45 41 0.036* 10.580 1.333–83.974 0.026*
NCT 21 92
pMMR 949
NCRT 546 66 0.033* 0.763 0.587–0.991 0.043*
NCT 403 59
DFS disease-free survival, dMMR deficient mismatch repair, pMMR proficient mismatch repair, NRT neoadjuvant radiotherapy, NCT neoadjuvant chemotherapy,
NCRT neoadjuvant chemoradiotherapy, HR hazard ratio, CI confidential interval.
*Statistically significant.
a
Univariable survival between these subgroups was compared by using the log-rank test.
b
Cox proportional-hazards regression analysis, which adjusted for clinicopathologic covariates (including age, gender, clinical T or N stage, localization, and
neoadjuvant radiotherapy) were used to calculate P values.

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Distant metastasis-free survival %)

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Disease-free survial(%)

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NCT (n = 21) p = 0·026 NCT (n = 21) p = 0·042
NCRT (n = 45) HR = 10.580 (1·333−83·974) NCRT (n = 45) HR = 8·828 (1·081−72·064)
0 0
0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84
Time(months) Time(months)
No at risk: No at risk:
NCT 21 16 14 11 9 8 5 0 NCT 21 16 14 11 9 8 5 0
NCRT 45 39 30 23 18 13 9 3 NCRT 45 40 33 25 19 14 10 4

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Local recurrence-free survival (%)

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Disease-free survial(%)

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25 25
NCT (n = 301) p = 0·02 NCT (n = 301) p = 0·001
NCRT (n = 439) HR = 0·705 (0·525−0·946) NCRT (n = 439) HR = 0·389 (0.220−0·687)
0 0
0 12 24 36 48 60 72 84 96 0 12 24 36 48 60 72 84 96
Time(months) Time(months)
No at risk: No at risk:
NCT 301 218 139 97 63 36 11 2 1 NCT 301 242 163 114 73 37 12 2 1
NCRT 439 386 293 210 143 77 33 9 1 NCRT 439 408 344 250 171 95 37 9 1

Fig. 2 Association between neoadjuvant treatment and survival according to mismatch repair (MMR) status. a Disease-free survival (DFS),
and b distant metastasis-free survival (DMFS) in patients with deficient MMR (dMMR) by neoadjuvant radiotherapy. c DFS and d Local
recurrence-free survival (LRFS) in patients with stage III disease and proficient MMR (pMMR) tumors by neoadjuvant radiotherapy. NCT
neoadjuvant chemotherapy, NCRT neoadjuvant chemoradiotherapy, HR hazard ratio, CI confidential interval.

Published in partnership with The Hormel Institute, University of Minnesota npj Precision Oncology (2020) 26
 S.-B. Ye et al.
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Table 5. Survival by neoadjuvant radiotherapy for dMMR patients in univariate and multivariate analysis adjusted for clinical characteristics.

DFS DMFS
#
Hazard ratio (95% CI) P value Hazard ratio (95% CI) P value#

Univariate
NRT
With vs. without 8.657 (1.158–64.700) 0.010* 6.871 (0.146–51.870) 0.030*
Multivariate
NRT
With vs. without 10.580 (1.333–83.974) 0.026* 8.828 (1.081–72.064) 0.042*
Age
>60 yr vs. ≤60 yr 0.844 (0.215–3.309) 0.808 1.001 (0.995–4.2556) 0.994
Sex
Female vs. male 1.102 (0.394–3.081) 0.853 1.300 (0.447–3.778) 0.630
Clinical T stage
T2–3 vs. T4 2.702 (0.967–7.550) 0.058 2.904 (0.934–9.032) 0.065
Clinical N stage
N0 1.000 1.000
N1 1.112 (0.361–3.422) 0.855 1.427 (0.427–4.762) 0.563
N2 3.133 (0.882–11.133) 0.077 3.837 (0.917–16.052) 0.066
Localization
Low 1.000 1.000
Middle 0.295 (0.076–1.141) 0.077 0.160 (0.029–0.888) 0.036*
High 0.212 (0.023–1.945) 0.170 0.226 (0.023–1.963) 0.172
Among 66 patients with dMMR tumors, there were only four local recurrence events; thus, data of local recurrence-free survival were not shown in Table 5.
dMMR deficient mismatch repair, DFS disease-free survival, DMFS distant metastasis-free survival, NRT neoadjuvant radiotherapy, CI confidential interval.
#
Cox proportional-hazards regression analysis was used to calculate P values.
*
Statistically significant.

to FU/leucovorin may overcome this resistance in patients with a lot from the examination of PET/CT in August 20, 2019. Since a
dMMR25,26. Moreover, patients with dMMR tumors underwent subset of dMMR patients has Lynch syndrome who tends to be
single-agent NCRT had strikingly high disease recurrence rate young, omission of radiotherapy can preserve fertility function.
(63.6%), which was consistent with the evidence that dMMR Trial of immunotherapy in dMMR locally advanced rectal cancers is
tumors had resistance to single-agent chemotherapy. Another preparing in our center.
possible explanation may be the association between the well- For rectal cancer patients with pMMR tumors, although more
known frequent occurrence of BRAF mutations in dMMR tumors27 T3/T4 tumors, poor differentiation and distally located tumors
and resistance to NCRT28. were present in the NCRT group, they still achieved higher rates of
These findings raise the attention of clinicians to test MMR pCR, lower neoadjuvant rectal (NAR) score and early ypStage.
status in biopsy specimens, which may guide subsequent More importantly, this subset of patients had a significantly
treatment. Such information could be quite valuable for the improved survival compared with that of NCT group. Such a trend
exploration of neoadjuvant treatment, for instance, the omission has also been demonstrated in patients with pMMR tumors and
of radiotherapy in preoperative treatment settings or selective stage III disease. ypStage and pCR following neoadjuvant therapy
preoperative radiation14,15. Presuming that such resistance to NRT are well-known strong indicators of survival in rectal cancer30–32.
exists in dMMR rectal cancer patients, immunotherapy may Therefore, more patients with pCR and lower ypStage in NCRT
provide a pathway to help navigate this situation and has been group may yield a better treatment outcome. Although there was
shown as an alternative to conditional therapy in three cases in no correlation between NRT and survival in patients with pMMR
our center. A 27 years old male patient and a 61 years old female tumors and stage II disease, T4 disease was significantly correlated
patient were diagnosed with cT4bN2M0 dMMR rectal cancer, both with more local recurrence in the NCT alone group. Thus, our
of whom were case-reported recently29. The first patient received findings strongly recommended neoadjuvant radiation with
six cycles of nivolumab and total mesorectal excision and the fluorouracil-based chemotherapy for stage III and T4N0 diseases
pathologic examination result showed complete response. After in rectal cancer patients with pMMR tumors, which is consistent
the second patient received four cycles of FOFOLXIRI, the primary with the NCCN guidelines1 and European Society for Medical
tumor shrank. Then after eight cycles of nivolumab, she was Oncology (ESMO)33. Total neoadjuvant therapy (TNT), chemor-
diagnosed with a clinical complete response (cCR) by compre- adiotherapy and chemotherapy prior to resection, aims to reduce
hensive examination. The third male patient (Supplementary case the risk of micrometastases and is increasingly used in practice.
report), 35 years, with dMMR tumor was diagnosed with poor Moreover, clinical evidence and phase II clinical trials demon-
differentiate rectal adenoma carcinoma invading peritoneal strated that TNT improved the compliance rates and the incidence
reflection (cT4a-bN1bM0) in January 2018. After chemoradiother- of pCR34,35. Therefore, TNT might be an alternative for pMMR
apy, he had progression of disease with clinical stage cT4BN2M1 patients to achieve higher pCR rate and improve survival.
with lung and retroperitoneal lymph node metastases. After 16 While our study included the largest cohort of patients with
cycles of anti-PD-1 immunotherapy, primary disease and lung stage II–III rectal cancer to explore the impact of MMR status on
metastases were invisible and retroperitoneal lymph nodes shrank selecting patients who can benefit most from NRT and the

npj Precision Oncology (2020) 26 Published in partnership with The Hormel Institute, University of Minnesota
 S.-B. Ye et al.
7
Table 6. Survival by neoadjuvant radiotherapy for stage III pMMR patients in univariable and multivariable analysis adjusted for clinical
characteristics.

DFS LRFS DMFS

# #
Hazard ratio (95% CI) P value Hazard Ratio (95% CI) P value Hazard Ratio (95% CI) P value#

Univariate
NRT
With vs. without 0.695 (0.525–0.922) 0.010* 0.426 (0.250–0.727) 0.002 0.778 (0.570–1.061) 0.100
Multivariate
NRT
With vs. without 0.705 (0.525–0.946) 0.020* 0.389 (0.220–0.687) 0.001* 0.793 (0.573–1.096) 0.158
Age
>60 yr vs. ≤60 yr 0.990 (0.741–1.325) 0.950 1.060 (0.607–1.848) 0.839 0.904 (0.655–1.247) 0.538
Sex
Female vs. male 1.005 (0.743–1.360) 0.975 0.571 (0.300–1.089) 0.089 1.200 (0.868–1.658) 0.270
Clinical T stage
T2–3 vs. T4 1.442 (0.884–1.714) 0.219 2.078 (1.147–3.767) 0.019* 1.111 (0.769–1.605) 0.576
Clinical N stage
N1 vs. N2 1.442 (1.081–1.924) 0.013* 2.216 (1.279–3.839) 0.005* 1.454 (1.061–1.994) 0.019*
Localization
Low 1.000 1.000 1.000
Middle 0.873 (0.649–1.175) 0.372 0.425 (0.234–0.774) 0.005* 1.017 (0.734–1.408) 0.920
High 1.390 (0.809–2.390) 0.233 0.922 (0.382–2.228) 0.858 1.288 (0.686–2.417) 0.431
pMMR proficient mismatch repair, DFS disease-free survival, LRFS local recurrence-free survival, DMFS distant metastasis-free survival, NRT neoadjuvant
radiotherapy, CI confidential interval.
#
Cox proportional-hazards regression analysis was used to calculate P values.
*Statistically significant.

findings are thought-provoking, these results remain limited by METHODS

the selection bias inherent to any retrospective study and the Patients
lack of validation cohort. Thus, present investigation attempted This retrospective multicenter study from Sun Yat-sen University (SYSU
to reduce bias via multivariable analysis and propensity cohort) included 9686 patients who had histopathologically confirmed
matched analysis36 and lack of validation cohort was due to rectal adenocarcinoma and clinically confirmed locally advanced rectal
the recent exploration of selective radiation and rarity of dMMR cancer treated with neoadjuvant therapy in the Sixth Affiliated Hospital,
in rectal cancer. Thus, further prospective, multicenter, and Sun Yat-sen University and Sun Yat-sen University Cancer Center from
December 2011 to September 2018. Only 1015 patients who had
randomized studies are warranted to validate our findings.
confirmed MMR status by tissue specimens were finally included. Locally
Although we only included stage II–III rectal cancer patients, the advanced tumor was clinically confirmed disease with stage II (T3 to 4N0)
size of each group in dMMR cohort is still close to those or stage III (T1 to 4N1 to 2) with positive node defined as ≥1.0 cm in
reported by other institutions8,37. Moreover, the reasons for diameter on imaging. The inclusion criteria for patients receiving NCT were
MMR testing were not provided, and MMR status could not be as follows: (1) patients from FOWARC clinical trial, (2) patients from
determined in surgical specimen for patients with pCR, which FORTUNE clinical trial and (3) other patients underwent NCT according to
was perhaps the reason for the relatively low pCR rate (NCT may physicians’ discretion and patients’ preference after the publications of
FOWARC clinical trial14,16. A diagram depicting the selection process is
also lead to low pCR rate). Therefore, we reanalyzed the
outlined in Fig. 3. Clinicopathological features were extracted from
remaining patients, excluding those with pCR. Similar findings prospectively maintained colorectal surgery databases (CSDs) and patient
of the impact of MMR status on selective NRT were also shown records, including clinical characteristics, pathologic features, neoadjuvant
in these subsets of patients. Finally, MMR testing was performed treatment, adjuvant treatment and oncologic outcomes. All patients
with IHC staining, which was not the recommended method of signed informed consent before treatment. Our study was approved by the
next generation sequencing (NSG)38 according to the latest Ethics Committee of Sun Yat-sen University, the Sixth Affiliated Hospital
NCCN guidelines. (Ethics Approval Number: 2019ZSLYEC-176) and followed the reporting
In conclusion, this is the first comprehensive study to suggest recommendation of tumor marker studies (REMARK) guidelines39.
that rectal cancer patients with dMMR tumors do not benefit from
NRT, which indicates the probability of immunotherapy in MMR status determination and analysis
neoadjuvant treatment settings for locally advanced rectal cancer All MMR status was performed by immunohistochemistry (IHC) for the
patients with dMMR tumors; whereas improved survival may be proteins MLH1, MSH2, MSH6 and PMS2. The dMMR was defined as the loss
seen in patients with pMMR tumors and stage III disease. Although of expression of one or more MMR proteins by IHC.
IHC staining for MMR proteins was performed on all specimens. ZSGB-Bio
the present study bridges the previous knowledge gaps, we would Solutions SPlink Detection Kits (Zhong Shan Jin Qiao, Beijing, China) and
not advocate altering treatment decisions according to our automated IHC/ISH slide staining instrument (The BenchMark XT platform)
findings unless it is validated by further prospective, multicenter, were used to stain the formalin-fixed, paraffin-embedded, 5-µm sections
randomized, controlled clinical trials. according to the manufacturer’s instructions. Staining was conducted with

Published in partnership with The Hormel Institute, University of Minnesota npj Precision Oncology (2020) 26
 S.-B. Ye et al.
8
Rectal cancer patients from SYSU cohort (n=9686)

Excluded (n=7633)
Stage IV (n=2031)
Recurrent rectal cancer (n=580)
Not receiving neoadjuvant treatment (n=4536)
Receiving neoadjuvant therapy in stage I (n=21)
Insufficient follow-up data (n=465)

Stage II-III rectal cancer patients receiving

neoadjuvant treatment (n=2053)

Excluded (n=1038)
Not receiving surgery (n=97)
No MMR testing (n=941)

Rectal cancer patients receiving neoadjuvant

treatment with MMR testing (n=1015)

Patients with pMMR tumors (n=949) Patients with dMMR tumors (n=66)

NCRT (n=546) NCT (n=403) NCRT (n=45) NCT (n=21)

Fig. 3 Flowchart depicting the process of patient inclusion. SYSU Sun Yat-sen University, MMR mismatch repair, pMMR proficient mismatch
repair, dMMR deficient mismatch repair, NCRT neoadjuvant chemoradiotherapy, NCT neoadjuvant chemotherapy.

the use of diagnostic antibodies against MLH1 (clone ES05; Zhong Shan Jin between these subgroups was compared by using the log-rank test.
Qiao, Beijing, China, 1:40), MSH2 (clone RED2; Zhong Shan Jin Qiao, Beijing, Moreover, local regional recurrence (LR) and non-LR-associated death,
China, 1:200), MSH6 (clone UMAB258; Zhong Shan Jin Qiao, Beijing, China, and separately DM and non-DM-associated death were considered
1:200) and PMS2 (clone EP51; Zhong Shan Jin Qiao, Beijing, China, 1:40). competing events (statistical analysis of the competing risk estimate is
When nuclear staining was absent from all tumor cells but present in normal shown in Supplementary Appendix). Cox proportional-hazards regres-
epithelial and stroma cells, protein expression was defined as absent (or sion analysis, which adjusted for clinicopathologic covariates (including
abnormal). age, gender, clinical T or N stage, localization, and NRT) was used to
calculate P values, hazard ratios (HRs), and 95% confidence intervals
(CIs). Two-sided P values of <0.05 were defined as statistical significance.
Treatment All statistical analyses were performed using R software (version 3.5.1;
All patients were treated with definitive-intent surgery and NCT. A total of http://www.Rproject.org).
142 patients did not receive adjuvant chemotherapy. 5-FU-based
chemotherapy was delivered concurrently with radiation in forms of
three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated Reporting summary
radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT). The Further information on research design is available in the Nature Research
clinical target volume (CTV) included the lymphatic drainage areas, i.e., Reporting Summary linked to this article.
mesorectal, internal iliac, and presacral lymph nodes. After one cycle of FU-
based chemotherapy (5FU/xeloda or 5FU + oxaliplatin/xeloda + oxalipla-
tin), NCRT was administrated with other cycles 2–4 concurrent with DATA AVAILABILITY
radiotherapy. Afterwards, 500 patients received adjuvant chemotherapy. The data for patients with dMMR tumors is included in the supplementary
information files. Other datasets used and/or analyzed during the current study are
Statistical analysis available from the corresponding author on reasonable request.
The primary endpoint for the present study was disease-free survival
(DFS), defined as the duration from the first day of therapy to the date of Received: 16 April 2020; Accepted: 4 August 2020;
confirmed relapse of disease. DFS was censored at the date of death
from other causes, or the date of the last follow-up visit for disease-free
patients. LRFS, and distant metastasis-free survival (DMFS), (definitions of
LRFS, and DMFS provided in Supplementary Appendix) and ypStage
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