Lower serum CA125 level,negative vascular invasion,and wild BRAF were strongly associated with better 2-year disease-free survival in patients with stage III colorectal cancer who received adjuvant chemotherapy

Abstract

BACKGROUND:

Adjuvant chemotherapy plays important role in the comprehensive treatment of patients with stage III colorectal cancer. However, there is few molecular markers for predicting the therapeutic effect.

OBJECTIVE:

To identify factors that could predict adjuvant chemotherapy benefits in patients with stage III colorectal cancer.

Methods:

The medical records of 294 patients were reviewed and analyzed using the Kaplan–Meier method and Cox analysis.

RESULTS:

Lower CA125 ( $\leqslant$ 35 u/ml, $P=$ 0.0015) serum levels, stage IIIa ( $P=$ 0.0027), 1-3 positive lymph nodes ( $P=$ 0.0256), negative vascular invasion ( $P=$ 0.0215), lower CA199 ( $\leqslant$ 27 u/ml, $P=$ 0.0038) serum levels, and wild-type BRAF status ( $P=$ 0.0125) were significantly associated with a higher 2-year DFS rate in patients with stage III colorectal cancer. However, in multivariate COX analysis, the association remained significant only for CA125 levels (vs. $\leqslant$ 35 u/ml group, HR 3.341; 95% CI, 1.198–9.316; $P=$ 0.0212), vascular invasion (vs. negative vascular invasion, HR, 2.349; 95% CI, 1.227–4.499; $P=$ 0.01), and BRAF (V600E) (vs. wild Braf, HR, 7.794; 95% CI, 1.867–32.531; $P=$ 0.0049).

CONCLUSION:

Lower CA125 serum levels, negative vascular invasion, and wild-type BRAF status were significantly associated with improved 2-year DFS rates among patient with stage III disease who received adjuvant chemotherapy.

Keywords

CA125 vascular invasion BRAF adjuvant chemotherapy colorectal cancer

1. Background

Figure 1.

The stage distribution of 793 patients with colorectal cancer and the treatment of patients with stage III disease.

Colorectal cancer is the fifth leading cause of cancer deaths, and the incidence of colorectal cancer was approximately 376 new cases per 100000 persons in 2015 in China [1]. Although substantial progress has been made with respect to the treatment of colorectal cancer, many patients will eventually succumb to recurrent disease after resection. Adjuvant therapy for patients with resected colorectal cancer has gained considerable interest [2]. Adjuvant therapy improves relapse-free and overall survival following resection, and the administration of adjuvant treatment is considered the standard of care for patients with high-risk stage II and stage III disease who recover sufficiently post-operatively [3, 4, 5, 6]. Unfortunately, not all patients will benefit from adjuvant chemotherapy, and clinicians are unable to definitively determine which patients harbor micrometastatic disease. So, in clinical practice, adjuvant therapy is administered to large numbers of patients who may have already been rendered disease-free by surgery [7].

Genomic sequencing has revealed that colorectal cancer is a highly heterogeneous disease with different molecular characteristics, and tumor-specific variants affect patient prognoses and outcomes [8, 9]. Therefore, the identification of clinicopathological or molecular characteristics that possess a significant prognostic value could alter the therapeutic outcome. Thus, in this study, we aimed to analyze potential correlations between a series of clinicopathological or molecular biological characteristics and adjuvant chemotherapy benefits to identify markers of adjuvant chemotherapy efficacy in patients with stage III colorectal cancer.

2. Patients and methods

From May 2013 to September 2015, 793 colorectal cancer patients underwent colorectal resection of their primary cancer at the Affiliated Hospital of Jiangnan University (Wuxi No. 4 Hospital), which is the largest cancer hospital in South Jiangsu province, China. The medical records of these colorectal cancer patients were carefully reviewed. Among them, 294 patients were diagnosed with stage III colorectal cancer by pathological findings. The following data were collected retrospectively: age, sex, operation time, tumor location, histological type, differentiation grade, lymphovascular invasion, depth of tumor invasion, positive lymph nodes, tumor deposit (cancerous nodes), stage, preoperative (within 2 weeks prior to the operation) serum tumor markers (AFP, CEA, CA199, CA125, CA724, and ferritin), and gene mutation status (K-ras, N-ras, B-raf, Her-2, Ki-67, ALK, and MMR).

Mutational analysis of KRAS, NRAS, and BRAF was performed using genomic DNA extracted from microdissected tumor tissue with the DNA Mini Kit (Qiagen), and the gene mutation status was analyzed using the ADx-ARMS™ mutation test kit (Xiamen, China). The KRAS mutation status was analyzed using Human KRAS Gene 7 Mutations Fluorescence Polymerase Chain Reaction (PCR) Diagnostic Kit (ADx-ARMS™); testing for the BRAFV600E hotspot mutation in exon 15 was performed using Human BRAF (V006E) Gene Mutations Fluorescence Polymerase Chain Reaction (PCR) Diagnostic Kit (ADx-ARMS™); and the NRAS mutation status was analyzed using Human NRAS Gene Mutations Fluorescence Polymerase Chain Reaction (PCR) Diagnostic Kit (ADx-ARMS™). Expression of MMR (MLH1, PMS2, MSH2, and MSH6), Her-2, ALK, and KI-67 was analyzed by immunohistochemistry according to routine methods. These analyses involved an initial hematoxylin and eosin slide review by a pathologist to confirm the diagnosis, to delineate the percentage of tumor present, and to demarcate tumor from normal tissue. Specimens were required to contain at least 50% tumor within the sample.

Figure 2.

Kaplan-Meier analysis of disease free survival in the patients who received or not received adjuvant chemotherapy.

2.1 Statistical analysis

Table 1
2-year DFS estimates according to clinical and pathological characteristics for patients with stage III colorectal cancer after adjuvant chemotherapy (univariable analysis)

	No. ptients	No. events	2-year DFS(%)	SE	Chi-square	p-value
Age
$\leqslant$ 70	184	54	68.99	0.04	0.32	0.57
$>$ 70	42	11	69.90	0.09
Gender
Male	133	33	74.92	0.04	2.62	0.10
Female	93	32	64.44	0.05
T stage
T1–2	22	6	75.03	0.10	0.03	0.87
T3–4	204	59	69.49	0.03
Positive lymph nodes
1–3	155	39	75.02	0.03	4.98	0.02
$\geqslant$ 4	71	26	60.00	0.07
TNM stage
IIIa	46	10	77.77	0.07	11.84	0.002
IIIb	109	25	78.07	0.04
IIIc	71	30	53.56	0.07
Vascular invasion
No	128	29	74.66	0.03	5.28	0.02
Yes	98	36	64.08	0.05
Differentiation grade
Poor or poor-moderate	65	20	65.27	0.07	1.86	0.17
Moderate or moderate-well	161	41	73.51	0.04
Location
Left	174	50	69.96	0.04	0.04	0.84
Right	52	15	70.21	0.07
Cancerous nodes
No	191	54	70.86	0.04	0.39	0.52
Yes	35	11	63.82	0.09
Pathology
Tubular adenocarcinoma	128	28	76.18	0.04	3.28	0.06
Other types	98	37	63.24	0.05
AFP* (ng/ml)
$\leqslant$ 7	197	50	74.05	0.03	0.69	0.40
$>$ 7	3	0	100.00	0.00
CEA (ng/ml)
$\leqslant$ 5	124	28	77.58	0.04	0.82	0.36
$>$ 5	79	22	68.67	0.06
CA199* (u/ml)
$\leqslant$ 27	146	29	79.67	0.04	8.36	0.003
$>$ 27	56	21	59.08	0.07
CA724* (u/ml)
$\leqslant$ 6.9	178	45	73.18	0.04	0.20	0.65
$>$ 6.9	24	5	78.29	0.08
CA125* (u/ml)
$\leqslant$ 35	188	43	75.77	0.03	10.02	0.001
$>$ 35	13	7	46.15	0.14
FER* (ng/ml)
$\leqslant$ 400	196	49	73.58	0.03	0.20	0.65
$>$ 400	6	1	83.33	0.15

Note(*): Tumor markers were done not in all 226 patients, so the analysis was done only in patients who received the serum tumor markers test.

Table 2

Multivariable analysis of prognostic factors for 2-year DFS

Risk factors	HR	95% CI	p-value
Clinical and pathological characteristics
Vascular invasion (Y vs. N)	2.349	1.227–4.499	0.0100*
Stage (IIIa vs. IIIb, IIIc)	2.319	0.982–5.476	0.0550
T stage (T1–2 vs.T3–4)	0.311	0.081–1.197	0.0894
N stage (N1 vs .N2)	0.618	0.207–1.841	0.3874
Cancerous nodes (N vs.Y)	1.276	0.534–3.046	0.5837
Pathology (tubular adenocarcinoma	1.326	0.701–2.508	0.3848
vs. other types)
Location (left vs. right)	0.512	0.214–1.221	0.1311
Differentiation grade (poor or poor-	0.868	0.408–1.844	0.7122
moderate vs. moderate or moderate-well)
Tumor markers
CA125(u/ml) ( $>$ 35 vs. $\leqslant$ 35)	3.341	1.198–9.316	0.0212*
CEA(ng/ml) ( $>$ 5 vs. $\leqslant$ 5)	0.921	0.450–1.884	0.8208
CA199 (u/ml) ( $>$ 27 vs. $\leqslant$ 27)	1.299	0.627–2.689	0.4815
Gene status
BRAF (mutation vs. wild)	7.794	1.867–32.531	0.0049*
KRAS (mutation vs. wild)	1.229	0.656–2.302	0.5205

HR; Hazard ratio, * $P<$ 0.05.

Table 3

Two-year DFS estimates according to gene status for patients with stage III colorectal cancer after adjuvant chemotherapy (univariable analysis)

	No. patients (a)	No. events	2-year DFS (%)	SE	Chi-square	p-value
KRAS (total)
Wild	115	34	69.84	0.05	0.0016	0.9682
Mutation	91	26	71.57	0.05
KRAS (Gly12Asp)
Wild	163	47	70.40	0.04	0.1394	0.7088
Mutation	33	11	70.82	0.08
KRAS (Gly12Val)
Wild	177	53	70.12	0.04	0.3016	0.5829
Mutation	19	5	73.05	0.12
KRAS (Gly12Ser)
Wild	189	57	69.86	0.04	0.6684	0.4136
Mutation	7	1	85.71	0.13
KRAS (Gly12Cys)
Wild	189	57	69.78	0.04	0.8143	0.3669
Mutation	7	1	85.71	0.13
KRAS (Gly13Asp)
Wild	172	52	70.67	0.04	0.0362	0.8492
Mutation	25	6	69.43	0.11
Braf (V600E)
Wild	202	57	71.50	0.03	6.2333	0.0125
Mutation	5	2	40.00	0.22
Nras
Wild	117	30	70.03	0.05	1.2126	0.2708
Mutation	7	3	57.14	0.19
MSH2 expression
( $-$ )	3	0	100.00	0.00	0.8885	0.3459
( $+$ )	111	30	70.59	0.05
MSH6 expression
( $-$ )	2	0	100.00	0	0.6896	0.4063
( $+$ )	112	30	70.70	0.05
PMS2 expression
( $-$ )	5	1	80.00	0.18	0.0254	0.8734
( $+$ )	109	29	70.93	0.05
MLH1 expression
( $-$ )	9	2	76.19	0.15	0.1316	0.7168
( $+$ )	105	28	70.93	0.05
MMR (b)
dMMR	16	3	79.44	0.11	0.4611	0.4971
pMMR	98	27	69.83	0.05
Her-2/eu
( $-$ )–( $+$ )	89	24	70.11	0.05	1.1960	0.2741
(2 $+$ )–(4 $+$ )	14	2	85.12	0.10
ALK
( $+$ )	2	0	100.00	0.00	0.6010	0.4382
( $-$ )	95	26	69.69	0.05
KI-67 expression
$<$ 80%	45	15	63.30	0.08	1.9080	0.1672
$\geqslant$ 80%	68	14	77.99	0.05

(a): Gene test were done not in all 226 patients, so the analysis was done only in patients who received gene test. (b): dMMR (vs. proficient MMR, pMMR) was defined as defective expression of one or more molecular of MSH2, MSH6, MLH1, or PMS2.

The primary endpoint in this analysis was 2-year disease-free survival (DFS). For DFS, an event was defined as the first occurrence of a tumor metastasis, relapse, or death from any cause. Follow-up time was measured from the date of surgery, and DFS was calculated from the date of surgery to the date of disease metastasis, relapse, or death from any cause. To estimate the effect of clinicopathological or molecular characteristics on disease-free survival, Kaplan-Meier curves were plotted and compared using the log-rank test. Statistical significance was set at $p<$ 0.05. The prognostic value of different variables for clinical outcome was assessed by multivariate analysis using the Cox multiple regression model.

3. Results

3.1 Clinical characteristics

A total of 793 patients with colorectal cancer were enrolled in this study. The stage distribution of these patients is presented in Fig. 1. Of the 294 patients with stage III disease, the median age at presentation was 64 years old (range 28–87); 178 patients were male, and 116 were female. Two hundred and twenty-six patients received adjuvant chemotherapy after surgery, 62 patients did not received adjuvant chemotherapy, and 6 patients were lost to follow-up.

3.2 Two-year DFS among patients with or without adjuvant chemotherapy

The 2-year DFS rates among the 226 patients who received adjuvant chemotherapy and the 62 not treated with adjuvant chemotherapy were 70.62% (SE: 0.03) and 51.84% (SE: 0.07), respectively. The 2-year DFS in the adjuvant chemotherapy group was significantly higher than that among patients who did not receive adjuvant chemotherapy ( $P=$ 0.0025) (Fig. 2).

3.3 The effect of clinical and pathological characteristics on adjuvant chemotherapy outcomes

The effects of clinical and pathological characteristics on adjuvant chemotherapy outcomes are listed in Table 1. Stage IIIa ( $P=$ 0.0027), 1–3 positive lymph nodes ( $P=$ 0.0256), and negative vascular invasion ( $P=$ 0.0215) were significantly associated with greater 2-year DFS among patients with stage III colorectal cancer. Other characteristics, including pathology, differentiation grade, and tumor location, were not associated greater 2-year DFS. In multivariate COX analysis, the significant association remained only for vascular invasion, and positive vascular invasion (vs. negative vascular invasion, HR, 2.349; 95% CI, 1.227–4.499; $P=$ 0.01) was strongly associated with lower 2-year DFS, and the statistical significance of disease stage was at boarder level (HR, 2.319; 95% CI, 0.982–5.476; $P=$ 0.0550) (Tables 1 and 2 and Fig. 3a–c).

Figure 3.

The association between clinical and pathological characteristics and DFS in patients with stage III colorectal cancer. A, lymph nodes; B, disease stage; C, vascular invasion; D, CA199; E, CA125; F, BRAF.

3.4 The correlation between serum tumor markers and response to adjuvant chemotherapy

The effects of preoperative serum tumor markers on adjuvant chemotherapy are also presented in Table 1. Among patients with stage III colorectal cancer, 38.9% (79/203), 27.7% (56/202), 6.5% (13/201), 11.9% (24/202), 3.0% (6/202), and 1.5% (3/200) of patients exhibited elevated levels of CEA, CA199, CA125, CA724, ferritin, and AFP, respectively (see Table 1). Among these tumor markers, patients with lower CA125 ( $\leqslant$ 35 u/ml) or CA199 ( $\leqslant$ 27 u/ml) serum levels exhibited better 2-year DFS relative to patients with higher CA125 ( $>$ 35 u/ml) or CA199 ( $>$ 27 u/ml) serum levels ( $P=$ 0.0015 for CA125; $P=$ 0.0038 for CA199). Other tumor markers, including AFP, CEA, CA724, and ferritin were not associated with improved 2-year DFS. In multivariate COX analysis, the association remained significant only for CA125 (vs. $\leqslant$ 35 u/ml group, HR 3.341; 95% CI, 1.198–9.316; $P=$ 0.0212), and the association with CA199 lost significance (vs. $\leqslant$ 27 u/ml group; HR, 1.299, 95% CI, 0.627–2.689; $P=$ 0.4815) (Tables 1 and 2 and Fig. 3d and e).

3.5 The effect of gene mutation status on adjuvant chemotherapy response

The effects of gene status on adjuvant chemotherapy are listed in Table 3. KRAS mutation was detected in 44.2% (91/206) of tumors, whereas NRAS and BRAF (V600E) mutations were detected in only 5.6% (7/124) and 2.4% (5/207) of tumors, respectively (see Table 3). Immunohistochemistry examination revealed that loss of MLH1, PMS2, MSH2, or MSH6 protein expression was notable in 7.9% (9/114), 4.4% (5/114), 2.6% (3/114), and 1.8% (2/114) of tumors, respectively (see Table 3). Defective MMR expression (dMMR, defined as loss of expression of one or more MMR proteins) was detected in 14.0% (16/114) of tumors, including loss of MLH1 in 9, PMS2 in 5, MSH6 in 2, and MSH2 in 3 tumors. Over-expression of Her-2 (greater than 2 $+$ ) was detected in 13.6% (14/103) of tumors, and ALK expression was detected in only 2.1% (2/97) of tumors. When taking the mean value of Ki-67 protein expression (80%, range: 20%–95%) as the cut-off value, Ki-67 over-expression was detected in 60.2% (68/113) tumors. Among these molecular characteristics, wild-type BRAF was associated with significantly better 2-year DFS compared with mutated BRAF (V600E) (K-M analysis: 71.5% vs 40.0%, $P=$ 0.0125; COX: vs wild Braf, HR, 7.794, 95% CI, 1.867- 32.531 $P=$ 0.0049); while other mutational markers were not significantly associated with 2-year DFS (see Tables 2 and 3 and Fig. 3f).

4. Discussion

Adjuvant treatment of colon cancer is an important issue in oncology. The successes of fluoropyrimidine and oxaliplatin in adjuvant chemotherapy was two major advances in the past 20 years [10]. In 1995, the International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) study demonstrated that the use of adjuvant fluorouracil and folinic acid significantly improved the clinical outcomes of patients with colorectal cancer compared with observation alone [11]. Furthermore, in 2004, the addition of oxaliplatin to a regimen of fluorouracil and leucovorin was demonstrated to improve the adjuvant treatment of colon cancer [4]. Currently, six months of combination oxaliplatin and fluoropyrimidine is the standard adjuvant treatment in patients with stage III colorectal cancer [2, 3, 12]. However, not all stage III patients will benefit from adjuvant chemotherapy. Therefore, it is very important to identify predictors that can guide the use of adjuvant chemotherapy.

Generally speaking, disease stage remains the best prognostic indicator of the risk of recurrence or metastasis [7]. The colorectal cancer stage is primarily determined by the depth of tumor penetration into the bowel wall and number of involved lymph nodes. In this study, in all stage III patients who received adjuvant chemotherapy, negative vascular invasion ( $P=$ 0.0215), stage IIIa disease ( $P=$ 0.0027) and fewer positive lymph nodes ( $P=$ 0.0256) were significantly associated with higher 2-year DFS rates, whereas the depth of tumor penetration was not associated with 2-year DFS ( $P=$ 0.8716). However, only the predictive effect of vascular invasion was confirmed by multivariate COX analysis.

Several serum biomarkers have been proposed as prognostic and/or predictive markers for colorectal cancer. Carcinoembryonic antigen (CEA) is the most routinely used colorectal tumor marker, and it is recommended for prognosis, monitoring response to treatment, and detecting metastatic disease or disease recurrence [13]. High serum CEA is often associated with worse survival [14]. In colorectal peritoneal carcinomatosis following cytoreductive surgery and intraperitoneal chemotherapy, patients with a high serum CEA exhibit a six-fold increase in death risk [15]. However, in this study, in the context of adjuvant chemotherapy for colorectal cancer, CEA levels did not predict adjuvant chemotherapy efficacy in patients with stage III disease.

CA125 is a glycoprotein antigen that was first found to be associated with ovarian cancer [16]. High serum CA125 levels are often associated with a worse prognosis in many types of tumors, including ovarian carcinoma [17], pancreatic adenocarcinoma [18], and colorectal cancer [16]. Furthermore, a study from Japan demonstrated that the CA125 levels could predict the efficacy of FOLFIRI plus bevacizumab as a second-line treatment in metastatic colorectal cancer patients, and low CA125 serum levels ( $<$ 35 u/ml) were associated with better PFS and OS [19]. In this study, univariate and multivariate analysis confirmed that low serum CA125 levels were an independent predictor of better 2-year DFS after adjuvant chemotherapy.

A high preoperative CA19-9 value is a significant predictor of early recurrence and poor prognosis after resection for pancreatic adenocarcinoma [20]. In colorectal cancer, studies have suggested that elevated serum CA 19-9 levels independently predict poor relapse-free survival and overall survival in patients with stage II [21] or stage IV colorectal cancer [22]. In this study, we also observed that stage III colorectal cancer patients with lower preoperative serum CA19-9 levels ( $<$ 27 $\mu$ /ml) were more likely to exhibit a greater 2-year DFS in univariate analysis, but the significance vanished in multivariate analysis.

In the era of precision medicine, clinicians are eager to identify genetic markers to guide the treatment of colorectal cancer. To address this problem, researchers have developed multigene-expression signatures that can be used to identify high-risk colon cancers [23, 24, 25]. Although gene-expression signatures hold promise, there are insufficient data to recommend the use of multigene assays to determine adjuvant therapy [26]. KRAS, NRAS, BRAF, and MMR are the most widely and extensively studied molecules in colorectal cancer. Studies from the USA demonstrate that favorable DFS is observed for dMMR versus proficient MMR in proximal colon cancer [27]. KRAS mutations are significantly associated with a shorter DFS, but this correlation is only observed in patients with wild-type BRAF tumors [28]. In this study KRAS mutations were detected in 44.2% of stage III colorectal tumors, whereas NRAS and BRAF (V600E) mutations were detected in only 5.6% and 2.4% of tumors, respectively. Among these molecules, only wild-type BRAF was significantly associated with better rate 2-year DFS; the MMR, KRAS, and NRAS statuses did not significantly affect the 2-year DFS of patients with stage III colorectal cancer after adjuvant chemotherapy. It is worth noting that the mutation rates of KRAS or BRAF in patients with colorectal cancer differ significantly between China and the United States. The mutation rate of KRAS is approximately 40% in Chinese patients with colon cancer [29] and 35% in American patients [30], and the mutation rate of BRAF in American patients with colon cancer is approximately 3-fold higher than that in Chinese patients, with rates of 14% [30] versus 5% [29], respectively. These differences may partly explain why KRAS or BRAF mutations exhibit different effects on patient prognosis in our study and the study from the United States [28].

In conclusion, this study confirmed a DFS benefit for adjuvant therapy on stage III colorectal cancer and revealed that variables of vascular invasion situation, serum CA125 levels, and BRAF are significantly associated with 2-year DFS. In stage III colorectal disease, patients with lower serum CA125 levels, negative vascular invasion, and wild BRAF may be more likely to benefit from adjuvant therapy.

Footnotes

Acknowledgments

This work was supported by Youth Fund of National Natural Science Foundation of China (Grant No. 81502042) and Natural Science Foundation for Young Scholars of Jiangsu Province, China (Grant No. BK20140171).

Conflict of interest

The authors declare that they have no competing interests.

References

Chen

Zheng

Baade

P.D.

Zhang

Zeng

Bray

et al., Cancer statistics in China, 2015, CA Cancer J Clin 66(2) (2016), 115–132.

Lombardi

Gebbia

Silvestris

Testa

Colucci

and Maiello

, Adjuvant therapy in colon cancer, Oncology 77(Suppl 1) (2009), 50–56.

André

de Gramont

Vernerey

Chibaudel

Bonnetain

Tijeras-Raballand

et al., Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: Updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study, J Clin Oncol 33(35) (2015), 4176–4187.

André

Boni

Mounedji-Boudiaf

Navarro

Tabernero

Hickish

et al., Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer, N Engl J Med 350(23) (2004), 2343–2351.

Benson

A.B.

Schrag

Somerfield

M.R.

Cohen

A.M.

Figueredo

A.T.

Flynn

P.J.

et al., American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer, J Clin Oncol 22(16) (2004), 3408–3419.

Bayraktar

U.D.

Chen

Bayraktar

Sands

L.R.

Marchetti

Montero

A.J.

et al., Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon adenocarcinoma? Cancer 117(11) (2011), 2364–2370.

Saltz

L.B.

, Adjuvant therapy for colon cancer, Surg Oncol Clin N Am 19(4) (2010), 819–827.

Schell

M.J.

Yang

Teer

J.K.

F.Y.

Madan

Coppola

et al., A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC, Nat Commun 7 (2016), 11743. doi: 10.1038/ncomms11743.

Dallol

Buhmeida

Al-Ahwal

M.S.

Al-Maghrabi

Bajouh

Al-Khayyat

et al., Clinical significance of frequent somatic mutations detected by high-throughput targeted sequencing in archived colorectal cancer samples, J Transl Med 14(1) (2016), 118.

10.

de Gramont

Chibaudel

Larsen

A.K.

Tournigand

and André

, GERCOR French Oncology Research Group, The evolution of adjuvant therapy in the treatment of early-stage colon cancer, Clin Colorectal Cancer 10(4) (2011), 218–226.

11.

No authors listed, Efficacy of adjuvant fluorouracil and folinic acid in colon cancer, International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators, Lancet 345(8955) (1995), 939–944.

12.

André

Boni

Navarro

Tabernero

Hickish

Topham

et al., Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial, J Clin Oncol 27(19) (2009), 3109–3116.

13.

Duffy

M.J.

Lamerz

Haglund

Nicolini

Kalousova

Holubec

et al., Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update, Int J Cancer 134(11) (2014), 2513–2522.

14.

Giessen

Nagel

Glas

Spelsberg

Lau-Werner

Modest

D.P.

et al., Evaluation of preoperative serum markers for individual patient prognosis in stage I-III rectal cancer, Tumour Biol 35(10) (2014), 10237–10248.

15.

Huo

Y.R.

Huang

Liauw

Zhao

and Morris

D.L.

, Prognostic value of carcinoembryonic antigen (CEA), AFP, CA19-9 and CA125 for patients with colorectal cancer with peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneal chemotherapy, Anticancer Res 36(3) (2016), 1041–1049.

16.

Bast, Jr.

R.C.

Klug

T.L.

St John

Jenison

Niloff

J.M.

Lazarus

et al., A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer, N Engl J Med 309(15) (1983), 883–887.

17.

Gadducci

Notarnicola

Menichetti

Lanfredini

Fanucchi

and Cosio

, Has serum CA 125 assay at the time of relapse a prognostic relevance for patients with recurrent ovarian carcinoma after primary cytoreduction and platinum- and paclitaxel-based chemotherapy? Eur J Gynaecol Oncol 37(2) (2016), 182–188.

18.

Liu

H.X.

Wang

W.Q.

C.T.

Xiang

J.F.

Liu

et al., Serum CA125 is a novel predictive marker for pancreatic cancer metastasis and correlates with the metastasis-associated burden, Oncotarget 7(5) (2016), 5943–5956.

19.

Suenaga

Matsusaka

Ueno

Yamamoto

Shinozaki

Mizunuma

et al., Predictors of the efficacy of FOLFIRI plus bevacizumab as second-line treatment in metastatic colorectal cancer patients, Surg Today 41(8) (2011), 1067–1074.

20.

Sugiura

Uesaka

Kanemoto

Mizuno

Sasaki

Furukawa

et al., Serum CA19-9 is a significant predictor among preoperative parameters for early recurrence after resection of pancreatic adenocarcinoma, J Gastrointest Surg 16(5) (2012), 977–985.

21.

Nozawa

Ishihara

Kawai

Hata

Kiyomatsu

Tanaka

et al., A high preoperative carbohydrate antigen 19-9 level is a risk factor for recurrence in stage II colorectal cancer, Acta Oncol 56(5) (2017), 634–638.

22.

Ozawa

Ishihara

Kawai

Nozawa

Yamaguchi

Kitayama

et al., Prognostic significance of preoperative serum carbohydrate antigen 19-9 in patients with stage IV colorectal cancer, Clin Colorectal Cancer 15(4) (2016), e157–e163.

23.

Yothers

O’Connell

M.J.

Lee

Lopatin

Clark-Langone

K.M.

Millward

et al., Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin, J Clin Oncol 31(36) (2013), 4512–4519.

24.

Fang

S.H.

Efron

J.E.

Berho

M.E.

and Wexner

S.D.

, Dilemma of stage II colon cancer and decision making for adjuvant chemotherapy, J Am Coll Surg 219(5) (2014), 1056–1069.

25.

O’Connell

M.J.

Lavery

Yothers

Paik

Clark-Langone

K.M.

Lopatin

et al., Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin, J Clin Oncol 28(25) (2010), 3937–3944.

26.

Mettu

N.B.

Hurwitz

and Hsu

D.S.

, Use of molecular biomarkers to inform adjuvant therapy for colon cancer, Oncology (Williston Park) 27(8) (2013), 746–754.

27.

Sinicrope

F.A.

Mahoney

M.R.

Smyrk

T.C.

Thibodeau

S.N.

Warren

R.S.

Bertagnolli

M.M.

et al., Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy, J Clin Oncol 31(29) (2013), 3664–3672.

28.

Yoon

H.H.

Tougeron

Shi

Alberts

S.R.

Mahoney

M.R.

Nelson

G.D.

et al., KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 alliance), Clin Cancer Res 20(11) (2014), 3033–3043.

29.

Zhu

X.L.

Cai

Zhang

Yang

Sheng

W.Q.

Y.M.

et al., KRAS and BRAF gene mutations in correlation with clinicopathologic features of colorectal carcinoma in Chinese, Zhonghua Bing Li Xue Za Zhi 41(9) (2012), 584–589.

30.

Gonsalves

W.I.

Mahoney

M.R.

Sargent

D.J.

Nelson

G.D.

Alberts

S.R.

Sinicrope

F.A.

et al., Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147, J Natl Cancer Inst 106(7) (2014). doi: 10.1093/jnci/dju106.

Lower serum CA125 level,negative vascular invasion,and wild BRAF were strongly associated with better 2-year disease-free survival in patients with stage III colorectal cancer who received adjuvant chemotherapy

Abstract

BACKGROUND:

OBJECTIVE:

Methods:

RESULTS:

CONCLUSION:

Keywords

1. Background

Table 1 2-year DFS estimates according to clinical and pathological characteristics for patients with stage III colorectal cancer after adjuvant chemotherapy (univariable analysis)

3.1 Clinical characteristics

3.2 Two-year DFS among patients with or without adjuvant chemotherapy

3.3 The effect of clinical and pathological characteristics on adjuvant chemotherapy outcomes

3.5 The effect of gene mutation status on adjuvant chemotherapy response

4. Discussion

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
2-year DFS estimates according to clinical and pathological characteristics for patients with stage III colorectal cancer after adjuvant chemotherapy (univariable analysis)