First-Line Therapy in Metastatic, RAS Wild-Type, Left-Sided Colorectal Cancer: Should Everyone Receive Anti-EGFR Therapy?

PURPOSE OF REVIEW: This narrative review explores the efficacy and applicability of anti-EGFR therapy as the first-line treatment for patients with RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC). It critically examines current guidelines, along with recent evidence in the literature, to assess whether it should be universally applied. RECENT FINDINGS: Recent evidences highlight the variability of the response to anti-EGFR therapies due to molecular diversity and several clinical factors, such as RAS mutational status and primary tumor location. Anti-EGFR plus chemotherapy is the standard first-line treatment for most patients with MSS, RAS-WT, left-sided mCRC. Whether this combination is the best treatment for these patients remains an open question. This review delves into the role of EGFR inhibition in mCRC, focusing on clinical factors and the knowledge of biology, molecular targets, and biomarkers. It underscores the crucial role of a personalized approach, empowering healthcare providers and equipping them with the confidence to make informed decisions.

Rachel score: a nomogram model for predicting the prognosis of lung neuroendocrine tumors.

BACKGROUND: Lung NET, classified in typical carcinoids (TC) and atypical carcinoids (AC), are highly heterogeneous in their biology and prognosis. The histological subtype and TNM stage are well-established prognostic factors for lung NET. In a previous work by our group, we demonstrated a significant impact of laterality on lung NET survival outcomes. MATERIALS AND METHODS: We developed a nomogram that integrates relevant prognostic factors to predict lung NET outcomes. By adding the scores for each of the variables included in the model, it was possible to obtain a prognostic score (Rachel score). Wilcoxon non-parametric statistical test was applied among parameters and Harrell's concordance index was used to measure the models' predictive power. To test the discriminatory power and the predictive accuracy of the model, we calculated Gonen and Heller concordance index. Time-dependent ROC curves and their area under the curve (AUC) were used to evaluate the models' predictive performance. RESULTS: By applying Rachel score, we were able to identify three prognostic groups (specifically, high, medium and low risk). These three groups were associate to well-defined ranges of points according to the obtained nomogram (I: 0-90, II: 91-130; III: > 130 points), providing a useful tool for prognostic stratification. The overall survival (OS) and progression free survival (PFS) Kaplan-Meier curves confirmed significant differences (p < 0.0001) among the three groups identified by Rachel score. CONCLUSIONS: A prognostic nomogram was developed, incorporating variables with significant impact on lung NET survival. The nomogram showed a satisfactory and stable ability to predict OS and PFS in this population, confirming the heterogeneity beyond the histopathological diagnosis of TC vs AC.

Chemotherapy-Induced Changes in Plasma Amino Acids and Lipid Oxidation of Resected Patients with Colorectal Cancer: A Background for Future Studies.

Previous studies have documented that FOLFOX and XELOX therapies negatively impact the metabolism of skeletal muscle and extra-muscle districts. This pilot study tested whether three-month FOLFOX or XELOX therapy produced changes in plasma amino acid levels (PAAL) (an estimation of whole-body amino acid metabolism) and in plasma levels of malondialdehyde (MDA), a marker of lipid hyper oxidation. Fourteen ambulatory, resected patients with colorectal cancer scheduled to receive FOLFOX (n = 9) or XELOX (n = 5) therapy, after overnight fasting, underwent peripheral venous blood sampling, to determine PAAL and MDA before, during, and at the end of three-month therapy. Fifteen healthy matched subjects (controls) only underwent measures of PAAL at baseline. The results showed changes in 87.5% of plasma essential amino acids (EAAs) and 38.4% of non-EAAs in patients treated with FOLFOX or XELOX. These changes in EAAs occurred in two opposite directions: EAAs decreased with FOLFOX and increased or did not decrease with XELOX (interactions: from p = 0.034 to p = 0.003). Baseline plasma MDA levels in both FOLFOX and XELOX patients were above the normal range of values, and increased, albeit not significantly, during therapy. In conclusion, three-month FOLFOX or XELOX therapy affected plasma EAAs differently but not the baseline MDA levels, which were already high.

Time-varying prognostic value of primary tumor sidedness in metastatic colorectal cancer: A population-based study and meta-analysis.

We studied the prognostic value of primary tumor sidedness in metastatic colorectal cancer over time and across treatment lines. Population data on synchronous metastatic colorectal cancer patients were extracted from the Netherlands Cancer Registry and SEER database. Pubmed, EMBASE and Cochrane library were searched for prospective studies on metastatic colorectal cancer to conduct a meta-analysis. Inclusion criteria consisted of metastatic disease, systemic treatment with palliative intent and specification of primary tumor location. Data were pooled using a random-effects model. For the population-based data, multivariable Cox models were constructed. The Grambsch-Therneau test was conducted to evaluate the potential time-varying nature of sidedness. Meta-regression incorporating treatment-line as variable was conducted to test the pre-specified hypothesis that the prognostic value of sidedness varies over time. Analysis of 12 885 and 16 160 synchronous metastatic colorectal cancer patients registered in the Netherlands Cancer Registry and SEER database, respectively, indicated a time-varying prognostic value of sidedness (P < .01). Thirty-one studies were selected for the meta-analysis (9558 patients for overall survival analysis). Pooled univariable hazard ratioleft-sided/right-sided for overall survival was 0.71 (95% CI: 0.65-0.76) in 1st-line, 0.76 (0.54-1.06) in 2nd-line and 1.01 (0.86-1.19) in 3rd-line studies. Hazard ratios were significantly influenced by treatment line (P = .035). The prognostic value of sidedness of the primary tumor in metastatic colorectal cancer patients treated with palliative systemic therapy decreases over time since diagnosis, suggesting that sidedness may not be a useful stratification factor in late-line trials. This decrease in prognostic value should be taken into account when providing prognostic information to patients.

A Belgian Population-Based Study Reveals Subgroups of Right-sided Colorectal Cancer with a Better Prognosis Compared to Left-sided Cancer.

BACKGROUND: Patients with left-sided colorectal cancer (L-CRC) are known to have a significantly better prognosis than those with right-sided CRC (R-CRC). It has been hypothesized that RAS, BRAF mutations, or deficient mismatch repair status (MMR) might be responsible for the prognostic effect of primary tumor location (PTL). This study aims to evaluate the prognostic effect of PTL in the Belgian population and to determine the role of biomarkers (MMR, BRAF, and RAS status) in this effect. PATIENTS AND METHODS: We performed a retrospective analysis of Belgian Cancer Registry data. First, we studied the prognostic effect of PTL on 5-year relative survival of 91,946 patients diagnosed with CRC (all stages) from 2004-2015. Second, we investigated the interaction between biomarkers and the prognostic effect of PTL in 1818 patients diagnosed with stage IV CRC in 2014-2015. RESULTS: L-CRC was associated with a significantly better 5-year relative survival compared to R-CRC in all stages and ages combined (68.4%, 95% CI, 67.7-69.1% vs 65.6%, 95% CI, 64.7-66.4%). Also, when stratified by age, sex, and stage, the prognosis of L-CRC was better compared to R-CRC in most subgroups. Only in stage II and certain subgroups of elderly patients, the opposite was observed. Furthermore, our data showed that none of the biomarkers had a significant interaction with the effect of PTL on survival. CONCLUSION: This population-based study confirms that L-CRC is associated with significantly better relative survival compared to R-CRC, in all stages and ages combined. Furthermore, in stage IV L-CRC is associated with a longer survival than R-CRC, regardless of MMR, RAS, and BRAF status.

The effects of chemotherapy, primary tumor location and histological subtype on the survival of stage III colon cancer patients.

OBJECTIVE: Colon cancer (CC) is one of the most common cancers worldwide and has a poor prognosis. Surgery followed by adjuvant chemotherapy is the standard treatment strategy for stage III CC patients. Primary tumor location (PTL) is an important factor for the long-term survival of CC. However, the difference in the prognosis between the histological subtypes of mucinous adenocarcinoma (MAC) and nonspecific adenocarcinoma (AC) in stage III CC patients is unclear. The correlation of chemotherapy, PTL and histological subtype with the overall survival (OS) of stage III CC patients has not yet been explored. METHODS: Patients diagnosed with stage III CC from 2010 to 2016 in the Surveillance, Epidemiology, and End Results (SEER) database were retrieved. The clinicopathological features and OS were analyzed according to the chemotherapy, PTL and histological subtype. RESULTS: A total of 28,765 eligible stage III CC patients were enrolled in this study. The results showed that chemotherapy, left-sided CC (LCC) and AC were favorable prognostic factors for OS. Right-sided CC (RCC) had worse OS than LCC regardless of chemotherapy. MAC had worse OS than AC in the patients with chemotherapy, but the survival benefits disappeared in the patients without chemotherapy. Additionally, in LCC, MAC had worse OS than AC regardless of chemotherapy. However, in RCC, MAC had worse OS than AC in patients with chemotherapy but had similar OS to AC in patients without chemotherapy. In the AC group, RCC had worse OS than LCC regardless of chemotherapy. In the MAC group, RCC had comparable OS to LCC regardless of chemotherapy. Four subgroups, i.e., RCC/MAC, RCC/AC, LCC/MAC and LCC/AC, all showed benefits from chemotherapy. Among them, LCC/AC had the best OS, and RCC/MAC had the worst OS compared with the other three subgroups. CONCLUSION: The prognosis of MAC is worse than that of AC in stage III CC. LCC/AC has the best OS, while RCC/MAC has the worst OS but still benefits from chemotherapy. The impact of chemotherapy on survival is greater than that of histological subtype, but the impact of histological subtype on survival is similar to that of PTL.

Clinical impact of primary tumor sidedness and sex on unresectable post-recurrence survival in resected pathological stage II-III colorectal cancers: a nationwide multicenter retrospective study.

BACKGROUND: Several studies have demonstrated that right-sided tumors have poorer prognosis than left-sided tumors in patients with unresectable colorectal cancer (CRC). The predictive ability of the tumor sidedness in CRC treated with chemotherapy in each sex is unclear. METHODS: Subjects were 964 unresectable recurrent patients treated with chemotherapy with stage II-III CRC after curative resection between 2004 and 2012. Post-recurrence cancer-specific survival (CSS) for each sex was examined. RESULTS: Patients were 603 males (222 right-side tumors (cecum to transverse colon) and 381 left-sided tumors (descending colon to rectum)), and 361 females (167 right-side tumors and 194 left-sided tumors). Right-sided tumors developed peritoneal recurrences in males and females. Left-sided tumors were associated with locoregional recurrences in males and with lung recurrences in females. Right-sided tumors were associated with shorter post-recurrence CSS in both sexes. In males, multivariate analyses showed that right-sided tumors were associated with shorter post-recurrence CSS (HR: 1.53, P < 0.0001) together with the presence of regional lymph node metastasis histopathological type of other than differentiated adenocarcinoma, the recurrence of liver only, the recurrence of peritoneal dissemination only, and relapse-free interval less than one-year. In females, multivariate analyses showed that right-sided tumors were associated with shorter post-recurrence CSS (HR: 1.50, P = 0.0019) together with advanced depth of invasion, the presence of regional lymph node metastasis, and recurrence of liver only. CONCLUSIONS: Primary tumor sidedness in both sexes in unresectable recurrent CRC patients treated with chemotherapy may have prognostic implications for post-recurrence CSS.

Prognostic value of the combination of primary tumor location and RAS mutational status on patients with colorectal liver metastasis undergoing hepatectomy.

OBJECTIVE: To assess prognostic influences of RAS mutational status and primary tumor site on cases with colorectal liver metastasis (CRLM) who underwent hepatectomy. METHODS: Clinicopathological data of 762 patients with CRLM who underwent hepatectomy between January 2000 and November 2018 were retrospectively analyzed. The left-sided tumors (LST) included tumors located in the splenic flexure, descending colon, sigmoid colon, and rectum; while right-sided tumors (RST) included those located in the cecum, ascending colon, and transverse colon. RAS mutational status was determined using Sanger sequencing or next-generation sequencing, including KRAS (Codons 12, 13, and 61) and NRAS (Codons 12, 13, and 61), which were defined as wild-type (RASwt) and mutant-type (RASmut), respectively. Survival curves were plotted using the Kaplan-Meier plotter and compared by the log rank test. The clinicopathological data were analyzed using univariate and multivariate analyses. RESULTS: The 5-year overall survival (OS) in the LST group was longer than that in the RST group (OS: 47.1% vs. 31.0%, p = 0.000, respectively), and the OS in the RASwt group was longer compared with that in the RASmut group (OS: 53.6% vs. 24.0%, p = 0.000). Besides, overall survival of the patients after hepatectomy was alternative, which was stratified by primary tumor site, with the 1-, 3-, and 5-year survival rates of 93.1%, 62.1%, and 47.1% for patients with LST, and 91.1%, 42.8%, and 31.0% for patients with RST, respectively. OS and disease-free survival (DFS) were significantly different stratified by RAS mutational status, with the 1-, 3-, and 5-year rates of 96.9%, 67.9%, and 53.6% for patients with RASwt tumors, and 85.7%, 41.5%, and 24.0% for patients with RASmut tumors, respectively. The 1-, 3-, and 5-year DFS rates were 51.9%, 30.0%, and 26.7% for patients with RASwt tumors, and 35.8%, 18.2%, and 14.9% for patients with RASmut tumors, respectively. The results of multivariate analysis showed that RAS mutational status and primary tumor site were both independent influencing factors of OS. CONCLUSION: RAS mutational status and primary tumor site affect OS independently in CRLM patients undergoing hepatectomy. The worse prognosis of RST cannot be simply attributed to the imbalance of RAS mutational status in different primary tumor sites.

Impact of Primary Tumor Location on Survival After Curative Resection in Patients with Colon Cancer: A Meta-Analysis of Propensity Score-Matching Studies.

BACKGROUND: Recent retrospective subgroup analyses of patients with unresectable colon cancer (CC) receiving systemic chemotherapy have demonstrated that there is a significant difference in treatment outcome between patients with right-sided CC (RSCC) and those with left-sided CC (LSCC). However, it is impossible to divide patients with CC randomly into RSCC and LSCC groups before surgery. Therefore, the aim of this study is to explore the impact of primary tumor location (PTL) on survival after curative surgery for patients with CC using propensity score-matching (PSM) studies instead of randomization. MATERIALS AND METHODS: We performed a comprehensive electronic search of the literature up to January 2019 to identify studies that had used databases allowing comparison of postoperative survival between patients with RSCC and those with LSCC. To integrate the impact of PTL on 5-year overall survival (OS) after curative surgery, a meta-analysis was performed using random-effects models to calculate the risk ratio (RR) and 95% confidence interval (CI) for the selected PSM studies. RESULTS: Five studies involving a total of 398,687 patients with CC were included in this meta-analysis. Among 205,641 patients with RSCC, 69,091 (33.6%) died during the observation period, whereas among 193,046 patients with LSCC, 63,380 (32.8%) died during the same period. These results revealed that patients with RSCC and those with LSCC had almost the same 5-year OS (RR, 0.98; 95% CI, 0.89-1.07; p = .64; I2 = 97%). CONCLUSION: This meta-analysis has demonstrated that there was no significant difference in 5-year OS between patients with RSCC and those with LSCC after curative resection. IMPLICATIONS FOR PRACTICE: To integrate the impact of primary tumor location (PTL) on 5-year overall survival (OS) after curative surgery, five propensity score-matching (PSM) studies involving a total of 398,687 patients with colon cancer (CC) were included in this meta-analysis. Among 205,641 patients with right-sided CC (RSCC), 69,091 (33.6%) died during the observation period, whereas among 193,046 patients with left-sided CC (LSCC), 63,380 (32.8%) died during the same period. These results revealed that patients with RSCC and those with LSCC had almost the same 5-year OS (risk ratio, 0.98; 95% confidence interval, 0.89-1.07; p = .64; I2 = 97%).

Impact of biomarkers and primary tumor location on the metastatic colorectal cancer first-line treatment landscape in five European countries.

Background: Advances in therapies for patients with metastatic colorectal cancer (mCRC) and improved understanding of prognostic and predictive factors have impacted treatment decisions. Materials & methods: This study used a large oncology database to investigate patterns of monoclonal antibody (mAb) plus chemotherapy treatment in France, Germany, Italy, Spain and the UK in mCRC patients treated in first line in 2018. Results: Anti-EGFR mAbs were most often administered to patients with RAS wild-type mCRC and those with left-sided tumors, while anti-VEGF mAbs were preferred in RAS mutant and right-sided tumors. Adopted treatment strategies differed between countries, largely due to reimbursement. Conclusion: Biomarker status and primary tumor location steered treatment decisions in first line. Adopted treatment strategies differed between participating countries.

Lay abstract Each patient's cancer is unique. For example, colon cancer on the left side is different from colon cancer on the right side. Colon cancer is different from cancer of the rectum. Cancers also have changes in their genes, which means some treatments should work, while others may not. Doctors can select among different medicines to find the drug that works best for each patient. We looked at patients with cancer of the colon or rectum that has spread to other organs. We tried to find out how doctors in Europe select drugs for their patients after performing tests called RAS or BRAF. We found that doctors make different choices in different countries.

Prognostic impact of tumor location in resected gallbladder cancer: A national cohort analysis.

BACKGROUND AND OBJECTIVES: Tumor location (peritoneal vs hepatic) has been incorporated in the 8th edition of the American Joint Committee on Cancer Staging system for gallbladder cancer. However, larger studies are needed to confirm the prognostic impact of tumor location. METHODS: Patients with pathologically-confirmed gallbladder cancer with information on primary tumor location were included from the National Cancer Database (2009-2012). We compared patients with hepatic-side tumors to those on the peritoneal side. Survival data were plotted using the Kaplan-Meier method. Prognostic factors were modeled with a multivariate Cox Proportional Hazards Model. Primary outcome was overall survival (OS). RESULTS: A total of 1251 patients were included. In comparison to patients with peritoneal-sided tumors, patients with hepatic-sided tumors were more likely to: be of higher pT stage (pT3: 49% vs 24%; P < .001); node positive (31% vs 24%; P = .016); undergo liver resection (53% vs 25%; P < .001); or have positive margins (29% vs 16%; P < .001). However, on multivariate analysis, there was no difference in OS between the groups (HR, 0.97; 95% CI, 0.79-1.18; P = .753). Liver resection was associated with improved survival regardless of tumor location in pT2 tumors (peritoneal: HR, 0.57; P = .034; hepatic: HR, 0.67; P < .001). CONCLUSIONS: This study failed to demonstrate the independent prognostic value of primary tumor location in patients with gallbladder cancer.

Incidence and prognosis of pulmonary metastasis in colorectal cancer: a population-based study.

PURPOSE: It is unclear how primary tumor location affects the pulmonary metastasis in colorectal cancer patients with different primary tumor locations. We aim to explore the relationship between primary tumor location and the incidence and prognosis of colorectal cancer patients with pulmonary metastasis at diagnosis. METHODS: From Surveillance, Epidemiology, and End Results (SEER) database, 9920 out of 192,969 CRC patients were identified with pulmonary metastasis at diagnosis between 2010 and 2015. Patients were classified into three subsets according to primary tumor location. The incidence of pulmonary metastasis and median survival were calculated. Multivariable logistic and Cox regression were performed to identify the risk factors of pulmonary metastasis and prognosis. RESULTS: The incidence of pulmonary metastasis was 5.14% in the entire colorectal cancer cohort and 25.66% in metastatic colorectal cancer patients. The median survival of those patients was 10 months. Rectal cancer patients exhibited the highest incidence of pulmonary metastasis, while they had the longest median survival (15 months). The right-sided colon cancer patients had the lowest incidence of pulmonary metastasis, but the shortest median survival (8 months). 61 to 80 years old, over 80, black, two or three extrapulmonary metastatic sites and CEA-positive had a negative influence both on the incidence and prognosis. CONCLUSIONS: The importance of primary tumor location in affecting the incidence of pulmonary metastasis and prognosis of colorectal cancer patients was highlighted in this study. Primary tumor location should be considered in clinical interference and personalized treatment for colorectal cancer patients with pulmonary metastasis.

Pattern and risk factors of local recurrence after nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: This study aims to identify predictive local recurrence risk factors and site-specific local recurrence pattern of upper tract urothelial carcinoma (UTUC) with different primary tumor locations. METHODS: Three hundred and eighty-nine UTUC patients with radical nephroureterectomy were included in this study. Univariate and multivariate Cox proportional hazards regressions were performed to measure the risk of local recurrence. We also mapped the position of local recurrence sites stratified by primary tumor locations. RESULTS: A total of 73 patients (18.7%) developed local recurrence within a median follow-up of 41 months (range, 3-80 months). For patients with local recurrence, the median interval of local recurrence was 9 months. Ureter tumor, multifocality, T stage, G grade, lymph node metastasis (LNM), lymph node dissection (LND), and lymph vascular invasion (LVI) were all significantly associated with increased local recurrence by univariable analyses (P < 0.05). Only multifocality, T3-4, G3, and LNM remained independent predictors of increased local recurrence by multivariable analyses. Adjuvant radiotherapy could reduce the local recurrence (HR = 0.177; 95% CI 0.064-0.493, P = 0.001). Patients with local recurrence had poorer cancer-specific survival (4-year cancer-specific survival rate 36 ± 7.5% vs 88.4 ± 2.2%, P = 0.000). We evaluated local recurrence pattern stratified by tumor locations. Para-aortic lymph node region was the most common recurrence area for all the patients. Left-sided UTUC had more than 70% recurrent lymph nodes in the left para-aortic region (LPA). For right-sided UTUC patients, recurrent para-aortic lymph nodes distributed in the LPA (33.3%), aortocaval (AC) (41.5%), and right paracaval (RPC) (25.2%) regions. Recurrence in the internal and external iliac regions was only found in the distal ureter group (P < 0.05). Renal pelvic fossa recurrence was only found in renal pelvic tumor (22.2%, P = 0.007). The ureter tumor bed recurrence rate was higher for ureter patients (P = 0.001). CONCLUSIONS: Multifocality, T3-4, G3, and LNM are predictors of higher local recurrence rate of UTUC. Adjuvant radiotherapy can reduce local recurrence rate. Local recurrence patterns are different according to primary tumor locations.

Contact with renal sinus is associated with poor prognosis in surgically treated pT1 clear cell renal cell carcinoma.

OBJECTIVE: To investigate the prognostic significance of contact with the renal sinus in patients with clear cell renal cell carcinoma. METHODS: A total of 787 pT1N0M0 clear cell renal cell carcinoma patients who had undergone radical or partial nephrectomy were reviewed retrospectively. A tumor in contact with the renal sinus was defined as a tumor radiologically attached to the renal sinus. Metastatic-free survival rates were analyzed in the total and propensity score-matched cohorts. A risk score model for metastasis after surgery was developed. RESULTS: Of the 787 patients, 411 (52.2%) had tumors in contact with renal sinus. The contact with renal sinus group showed poorer metastatic-free survival in both total and matched cohorts. In multivariate analysis, contact with renal sinus was an independent prognostic factor of metastasis, as well as Fuhrman grade, microvascular invasion and age. The scoring model likewise consisted of Fuhrman grade, microvascular invasion, age and contact with renal sinus. Metastasis-free survival curves were clearly stratified according to risk, with 5-year metastasis-free survival rates of 95.7% and 65.2% in the low- and high-risk groups, respectively (P < 0.001). CONCLUSIONS: Contact with the renal sinus is a significant risk factor for metastasis in T1 clear cell renal cell carcinoma after surgery. More intensive follow up should be recommended for patients with renal cell carcinoma that is in contact with the renal sinus.

Non-V600E BRAF mutations and EGFR signaling pathway in colorectal cancer.

The Raf murine sarcoma viral oncogene homolog B (BRAFV600E ) mutation (MT) in metastatic colorectal cancer (CRC) is a well-known prognostic indicator and a negative predictive biomarker for antiepidermal growth factor receptor (EGFR) treatment. However, the clinical characteristics and significance of BRAFnon-V600E MTs remain unclear. Here, we evaluated the clinical characteristics of BRAFnon-V600E MTs vs. those of other MTs in the EGFR signaling pathway, including BRAFV600E . Consecutive CRC patients in our institute from June 2012 to November 2013 were enrolled in our study. Multiplex genotyping of the EGFR pathway was performed with archival samples using a Luminex Assay for BRAFV600E /BRAFnon-V600E , KRAS/NRAS exons 2-4, and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA). We analyzed correlations among the MT profiles, clinical data and primary tumor locations in CRC. All statistical analyses were performed using R software. CRC samples (824) from 374 (45.4%) male and 450 (54.6%) female patients were analyzed, of which 154 (18.7%), 202 (24.5%), 270 (32.8%) or 198 (24.0%) had Stages I, II, III or IV or recurrent CRC, respectively. The frequencies of BRAFV600E /BRAFnon-V600E , KRAS (including exons 2-4), NRAS and PIK3CA MTs were 5.3/1.7, 41.4, 3.3 and 9.6%, respectively. The characteristics of patients with the BRAFV600E MT were an age of ≥65 years old, a right-sided primary tumor location, poorly differentiated histology and an advanced disease stage. In contrast, the characteristics of patients with BRAFnon-V600E MTs were a left-sided primary tumor location and well-differentiated histology. BRAFnon-V600E MTs were relatively rare and showed different characteristics compared to the BRAFV600E MT. These results may contribute to future precision medicine.

[Effect of the primary tumor location on the prognosis of breast invasive ductal carcinoma patients treated with radical mastectomy].

Objective: To analyze the clinicopathological features and prognosis of breast invasive ductal carcinoma patients receiving radical mastectomy according to the primary tumor location. Methods: From January 2008 to December 2008, 993 patients with breast invasive ductal carcinoma received radical mastectomy in Tianjin Medical University Cancer Institute and Hospital. Patients were grouped according to the primary tumor location when breast cancer was diagnosed. The clinicopathological characteristics and follow-up information of them was collected and analyzed retrospectively. Results: Of the 993 patients, primary tumor located in the upper-outer quadrant (UOQ) in 556 patients (56.0%), the lower-outer quadrant (LOQ) in 97 (9.8%), the central portion in 99 (10.0%), the upper-inner quadrant (UIQ) in 186 (18.7%), and the lower-inner quadrant (LIQ) in 55 (5.5%). Patients in the central portion tended to have larger tumors, and more patients in the upper-inner quadrant received endocrine therapy. The estimated 5-year disease-free survival (DFS) rates of patients with primary lesion in the UOQ, LOQ, central portion, UIQ and LIQ were 90.3%, 88.7%, 79.8%, 86.0% and 72.7%, respectively, with significant differences (P<0.001). The 5-year overall survival (OS) rates were 97.5%, 96.9%, 90.9%, 94.1% and 87.3%, respectively, with significant differences (P<0.001). Multivariate analysis showed that 5-year recurrence and metastasis risks were significantly increased in patients with primary lesion in the central portion, UIQ and LIQ compared to other groups (P<0.001), and 5-year mortality risks were increased in these three groups (P=0.002). Conclusion: Primary lesion located in central portion and inner quadrant is an independent adverse prognostic factor for patients with breast invasive ductal carcinoma patients receiving radical mastectomy.

Should anti-EGFR mAbs be discontinued for conversion surgery in untreated right-sided metastatic colorectal cancer? A systematic review and meta-analysis.

BACKGROUND: Previous studies have demonstrated that left-sided tumors have better prognoses than right-sided tumors in RAS wild-type mCRC (metastatic colorectal cancer) patients, while anti-EGFR mAbs appear to have no advantage compared with bevacizumab for right-sided tumors in these patients. Nevertheless, it remains unclear whether primary tumor location affects patients' options for potentially curative resection. METHODS: PubMed, the Cochrane Library, Embase, ASCO, and ESMO conference abstracts were searched. The inclusion criteria were RCT (randomized controlled trials) studies that evaluated the efficacy of anti-EGFR mAbs based on primary tumor location. The outcomes included ORR, ETS, and DpR. ORs for ORR were calculated with 95% confidence intervals by Comprehensive Meta-Analysis, version 2.0. RESULT: Nine studies including nine RCTs were analyzed. Regardless of left- or right-sided tumors, the ORRs for anti-EGFR mAb (left-sided: 80.2%, 95% CI, 47-95%; I2 = 76.9%; right-sided: 46.1%, 95% CI, 39.4-53.0%; I2 = 18.9%) were both higher than the control arm including chemotherapy with or without bevacizumab. The ORs for anti-EGFR mAbs have a significant benefit compared with chemotherapy with or without bevacizumab in left-sided tumors (OR = 2.19, 95% CI, 1.41-3.38; P < 0.001). For right-sided tumors, anti-EGFR mAbs still significantly improved the ORR compared with chemotherapy alone (OR = 1.75, 95% CI, 1.05-2.90; P = 0.03), and the OR numerically favored the anti-EGFR mAbs compared with bevacizumab (OR = 1.281, 95% CI, 0.77-2.12; P = 0.335). The data of ETS and DpR from three RCTs also favored the EGFR antibody irrespective of tumor location. Resection data on differentiating tumor locations is inconclusive. For right-sided tumors, it should be noted that median PFS and OS were comparable for patients who achieved ETS in both treatment arms. CONCLUSIONS: Anti-EGFR mAbs have advantages in the tumor shrinkage regardless of left- or right-sided tumors, which is important for conversion therapy. For right-sided tumors, anti-EGFR mAbs should remain the first choice for potentially curative resection in RAS wild-type mCRC patients. ETS may represent a subgroup of patients with right-sided tumors who might benefit from the anti-EGFR mAb.

Primary tumor location predicts poor clinical outcome with cetuximab in RAS wild-type metastatic colorectal cancer.

BACKGROUND: In metastatic colorectal cancer, the location of the primary tumor has been suggested to have biological significance. In this study, we investigated whether primary tumor location affects cetuximab efficacy in patients with RAS wild-type metastatic colorectal cancer. METHODS: Genotyping by the SequenomMassARRAY technology platform (OncoMap) targeting KRAS, NRAS, PIK3CA, and BRAF was performed in tumors from 307 patients who had been given cetuximab as salvage treatment. Tumors with mutated RAS (KRAS or NRAS; n = 127) and those with multiple primary location (n = 10) were excluded. Right colon cancer was defined as a tumor located in the proximal part to splenic flexure. RESULTS: A total of 170 patients were included in the study (right versus left, 23 and 147, respectively). Patients with right colon cancer showed more mutated BRAF (39.1% vs. 5.4%), mutated PIK3CA (13% vs. 1.4%), poorly differentiated tumor (17.4% vs. 3.4%), and peritoneal involvement (26.1% vs. 8.8%) than those with left colon and rectal cancer. Right colon cancer showed poorer progression-free survival (2.0 vs.5.0 months, P = 0.002) and overall survival (4.1 months and 13.0 months, P < 0.001) than the left colon and rectal cancer. By multivariable analysis, BRAF mutation, right colon primary, poorly differentiated histology, and peritoneal involvement were associated with risk of death. CONCLUSIONS: In RAS wild-type colon cancer treated with cetuximab as salvage treatment, right colon primary was associated with poorer survival outcomes than left colon and rectal cancer.

Phase II trial of capecitabine plus erlotinib versus capecitabine alone in patients with advanced colorectal cancer.

Aim & methods: Capecitabine monotherapy as palliation for advanced colorectal cancer (CRC) is generally well tolerated. Adding erlotinib, an EGFR-tyrosine kinase inhibitor, might improve efficacy versus capecitabine alone. 82 patients received capecitabine alone (Arm 1) or capecitabine with erlotinib (Arm 2). RESULTS: Median time-to-progression (TTP) in Arm 1 was 7.9 months versus 9.2 in Arm 2. In KRAS-wild type (WT) patients TTP was 8.4 and 11.7 months in Arms 1 and 2, respectively. In KRAS-mutated patients TTP was 7.4 and 1.9 months in Arms 1 and 2, respectively (p = 0.023). Arm 2 KRAS-WT patients, left-sided primaries, had an overall survival of 16.0 versus 12.1 months in right-sided primaries. CONCLUSION: Adding erlotinib to capecitabine increased TTP by 3.2 months in KRAS-WT patients. This study suggests that erlotinib harms patients with KRAS-mutated advanced CRC while it may provide benefit to those with KRAS-WT CRC. Further study of EGFR-tyrosine kinase inhibitors in patients with left-sided KRAS-WT CRC is warranted.

PTEN mRNA expression is less pronounced in left- than right-sided colon cancer: a retrospective observational study.

BACKGROUND: Several recent studies have reported that patients with metastatic colorectal cancer (CRC) whose primary tumor is located in left side of the colon have more favorable responses to anti-epidermal growth factor receptor (EGFR) antibody therapy than those with right-sided tumors. However, the mechanism for this phenomenon is unknown. METHODS: Fifty-two cases of primary CRC with liver metastases were analyzed in this retrospective study. The mRNA levels of 19 signal transduction genes in both primary tumor and liver metastases were measured by real-time reverse transcription polymerase chain reaction. The purposes of this study were (1) to determine the correspondence between signal transduction gene expressions in primary tumors and corresponding liver metastases, and (2) to determine whether expression levels of these genes differ by primary tumor location. RESULTS: mRNA expression levels of 14 of 19 signal transduction genes, including PTEN, ERBB2, MET, HGF, AREG, and EREG, showed significant correlations between the primary tumor and corresponding liver metastases. When the mRNA levels of the primary tumors were compared by tumor location, only PTEN mRNA expression differed significantly between left and right-sided CRC (median PTEN expression: left 1.00 vs. right 1.68; p = 0.017). When rectal cancers were separated from left-sided colon cancers, PTEN mRNA levels increased progressively from rectum to right-sided colon (median; rectum 0.84, left colon 1.23, right colon 1.68, p = 0.013). PTEN mRNA expression in liver metastases also differed significantly according to primary tumor location (median; left 0.92 vs. right 1.27, p = 0.048). There was no difference in overall survival between patients with high versus low levels of PTEN mRNA (p = 0.59). CONCLUSIONS: Our data suggest that the PIK3/AKT/mTOR pathway is more active in left- than right-sided CRC, which provides a possible explanation for the fact that efficacy of anti-EGFR therapy differs by location of primary tumor.