Research ArticleExperimental Studies

PIK3CA Mutations as a Prognostic Factor in Patients With Residual Rectal Cancer After Neoadjuvant Chemoradiotherapy

JUNGSUP BYUN, NORA JEE-YOUNG PARK, GHILSUK YOON, MIN KYU KANG, HYE JIN KIM, SOO YEUN PARK, JUN SEOK PARK, GYU SEOG CHOI, JIN HO BAEK, JONG GWANG KIM and AN NA SEO
Anticancer Research April 2023, 43 (4) 1513-1520; DOI: https://doi.org/10.21873/anticanres.16300

Abstract

Background/Aim: PIK3CA mediates various cellular processes, such as transformation, tumor initiation and proliferation, and resistance to apoptosis. This study was conducted to identify the clinical significance and prognostic effect of PIK3CA mutations in patients with residual rectal cancer who underwent surgery after neoadjuvant chemoradiotherapy (NACRT). Patients and Methods: Formalin-fixed and paraffin-embedded surgical specimens were collected from 128 patients between January 2006 and December 2011 and analyzed using real-time polymerase chain reaction for hotspot mutations in exons 9 and 20 of the PIK3CA gene. Results: Of the 128 patients, 109 were analyzed and 19 were excluded because of poor DNA quality. Mutations in PIK3CA were identified in three patients (2.8%), all of which were detected in exon 20 of the PIK3CA gene. PIK3CA mutations significantly correlated with lymphatic invasion (p=0.016), lymph node metastasis (p=0.034), and higher pathological disease stage (p=0.040). By univariate analysis, patients with PIK3CA mutations were observed to have significantly shorter cancer-specific survival (CSS) (p=0.001) and disease-free survival (DFS) (p=0.006) than PIK3CA wild-type patients. However, PIK3CA mutations were not an independent prognostic factor for CSS (p=0.319) or DFS (p=0.219) in multivariate modeling. Conclusion: Our findings indicate that PIK3CA mutation plays a role in oncogenesis in rectal cancer and may be considered as a candidate therapeutic approach targeting the PIK3/Akt/mTOR pathway in patients with residual rectal cancer after NACRT.

Key Words:

Neoadjuvant chemoradiotherapy (NACRT) followed by total mesorectal excision (TME) has been established as the standard treatment for reducing large or locally advanced rectal cancers (1, 2). Patients with tumors who achieve a pathological complete response (ypCR) to NACRT have been shown to have higher disease-free survival rates than those with partial or no response (3, 4). However, pCR is generally achieved in only 8-30% of patients, and its predictive value depends partially on currently unknown molecular factors (4, 5). Similarly, following NACRT, most patients show partial or no response, and the tumor regression grade (TRG) is not an accurate prognostic factor for patient outcome. Therefore, the development of better predictive or prognostic markers is required for a more accurate stratification of patients with partial or no response to NACRT.

The phosphatidylinositol 3-kinase (PI3K) pathway is one of the most frequently activated and altered signaling pathways in human cancers, including breast, gastric, and colorectal cancers (CRC) (6-10). As this pathway plays essential roles in cellular activities, including cell growth and proliferation, metabolism, and survival, as well as in pathological processes, such as cancer progression, metastasis, and resistance to chemotherapy, the PI3K/AKT signaling pathway has been considered extremely important in the carcinogenesis process (10-12). This pathway involves the generation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) by PI3K (9, 10). The PI3K family consist of p110 catalytic subunits (p110α and p110β) and a p85 regulatory subunit, and, in particular, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which provides instructions for production of the p110α protein, which, in turn, encodes the catalytic subunit of PI3K (9, 10). Missense mutations of PIK3CA have been discovered in numerous human cancers, which have been implicated in the oncogenic role of PIK3CA (9, 10, 13, 14). Hot spots of PIK3CA mutations are usually found in exons 9 (residues E542 and E545 of the helical domain) and 20 (residue H1047 of the kinase domain) (13, 15). In clinical practice, several drugs targeting multiple levels of PI3K/AKT/mTOR have been developed, including ATP-competitive inhibitors of the ATP-binding pocket of p110, and p110α-specific inhibitors (9, 16). A recent meta-analysis of 12,747 patients with CRC demonstrated the neutral prognostic impacts of PIK3CA mutations on overall survival (OS) and progression-free survival (PFS) (14). That study also characterized the prognostic effects of PIK3CA mutations in exons 9 and 20 separately, and neither exon 9 nor 20 mutations were found to be significantly associated with patient survival (14). Another meta-analysis of 576 patients with metastatic CRC (mCRC) demonstrated that KRAS wild type mCRC with an exon 20 PIK3CA mutation may be less susceptible to treatment with anti-EGFR monoclonal antibodies (17).

Accumulating evidence suggests that rectal cancer is distinct from colon cancer, with different risk factors, etiologies, and possible molecular characteristics (4, 18). Therefore, the clinical influence of PIK3CA mutations should be investigated separately in patients with colon and rectal cancer, while only limited data on rectal cancer are currently available. Therefore, this study assessed the clinical significance and prognostic effect of PIK3CA mutations in patients with locally advanced mid- or low-rectal cancer treated by NACRT.

Patients and Methods

Patient selection. The medical records of 145 patients with rectal cancer with residual disease who underwent surgery after NACRT at Kyungpook National University Hospital and Kyungpook National University Chilgok Hospital between January 2006 and December 2011 were retrieved from the center’s database, and their clinical and pathological information was obtained (19, 20). Representative formalin fixed paraffin-embedded (FFPE) samples of 128 unselected residual rectal cancers were collected from the tumor bank of the Department of Pathology in our hospital. All patients had histologically proven adenocarcinoma and were excluded if they showed clinical evidence of distant metastases at the time of diagnosis and time of reported ypCR. Tumors were staged according to the 7th edition of the American Joint Committee on Cancer TNM classification system. This study has been reported according to the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) criteria (21).

Ethical statement. This study was approved by the Institutional Review Board of Kyungpook National University of Chilgok Hospital (IRB No. 2014-04-215) and was conducted in accordance with the amended Declaration of Helsinki. Informed consent was waived by the institutional review board due to the retrospective design of the study; however, all patient information was de-identified and anonymized before the study was conducted.

Preoperative treatment and surgery. All patients with clinical T3, T4, or node-positive disease received NACRT according to our standard institutional practice and underwent regular follow-up (19, 20, 22, 23). Long-course radiotherapy was administered to the whole pelvis at a total radiation dose of 45 or 50 Gy in 25 fractions (1.8 or 2 Gy per fraction, respectively) five times per week for 5 weeks (22, 23). The chemotherapy regimen was 5-fluorouracil, either as a bolus infusion (425 mg/m2/day) plus leucovorin (20 mg/m2/day) or as a continuous infusion, 5 days per week (250 mg/m2/day) during radiotherapy (22, 23). Curative surgical resection was planned within 6-8 weeks after the completion of NACRT. TME with autonomic nerve preservation was performed following the standard surgical procedure, which included low anterior, intersphincteric, and abdominoperineal resection (23). All patients were treated according to standard practice guidelines and were regularly monitored after surgery.

Histological evaluation. All available hematoxylin & eosin (H&E)-stained slides were reviewed by a single expert gastrointestinal pathologist (ANS). To evaluate primary tumor response to NACRT, we used the 5-point TRG grade as initially described by Rodel et al. (3) as follows: (1) Grade 0=no regression; (2) Grade 1=regression of <25% of tumor mass; (3) Grade 2=regression of 25-50% of tumor mass; (4) Grade 3=regression of >50% of tumor mass; (5) Grade 4=complete regression or ypCR. In cases with no tumor cells within acellular mucin pools in the whole section, immunohistochemistry for cytokeratin was performed, and ypCR was reconfirmed. As mentioned above, all cases with ypCR were excluded from this study.

Prior to fixation, all surgical specimens were inked to the periphery of the mesorectum and sliced into transverse sections (22, 24, 25). The circumferential resection margin (CRM) was measured as the distance from the outermost part of the tumor cells to the inked fascia recti using a microscope graticule (22, 24, 25). CRM positivity was considered ≤1 mm (24). When cases with CRMs of 1-2 mm were detected, additional multiple-level serial and deep sections were performed to identify CRM positivity by hidden tumor cells (24).

Detection of PIK3CA mutations. Genomic DNA was extracted from FFPE tissue sections of surgically resected residual rectal cancers after NACRT using the Maxwell® 16FFPE Tissue LEV DNA Purification kit (Promega, Seoul, Republic of Korea), according to the manufacturer’s protocol. Briefly, residual tumor areas were marked on H&E-stained slides by a pathologist (ANS), and three to five serial sections (5 μm-thick) were cut and manually dissected using blades.

PIK3CA mutations were evaluated for the presence of exons 9 (codon 542, codon 545, and codon 546) and 20 (codon 1047) using the PNAClamp™PIK3CA mutation detection kit (Panagene, Daejeon, Republic of Korea) in a peptide nucleic acid (PNA)-mediated real-time polymerase chain reaction (PCR) according to the manufacturer’s instructions. The cycle threshold (Ct) values for the control and mutation assays were automatically calculated using SYBR Green amplification plots, followed by calculation of delta-Ct values. A high delta-Ct value indicated that the mutant was efficiently amplified. The cutoff value of delta-Ct was regarded as 2 for PIK3CA mutations.

Detection of KRAS and BRAF mutations. KRAS exon 2 (codons 12 and 13) and BRAF V600E mutation status were confirmed by PNA-mediated real-time PCR using PNAClamp™ KRAS and PNAClamp™ BRAF Mutation Detection kits (Panagene), as described above. KRAS and BRAF mutation status was used as our data analyzed previously (19, 20, 22, 26).

Statistical analyses. All results were analyzed using SPSS version 18.0 for Windows (SPSS Inc., Chicago, IL, USA). The correlation between clinicopathological parameters and PIK3CA mutation was assessed using the Chi-square or Fisher’s exact test, as appropriate. The Pearson correlation (R) test was used to evaluate the correlation between PIK3CA mutations and other molecular results, such as KRAS and BRAF mutations, and HER2 amplification. Disease-free survival (DFS) and cancer-specific survival (CSS) were calculated using the time-to-event method to account for censoring. DFS was defined as the time from surgery to disease recurrence or death, and CSS was calculated as the time from surgery to death caused by rectal cancer, as applicable. Survival curves for DFS and CSS were constructed using the Kaplan–Meier method, and significance was estimated using the log-rank test. Variables with p<0.05 in univariate analysis were included in the Multivariate Cox proportional hazards regression. Hazard ratios with 95% confidence intervals were calculated for each factor. All tests of significance were two-tailed, and statistical significance was considered at p<0.05.

Results

Patient characteristics. PIK3CA mutations results were obtained in 109 (85.2%) of the 128 FFPE residual rectal cancer specimens after NACRT due to poor DNA quality in 19 samples. In the end, data from 109 patients were included in the analysis. Of those with PIK3CA mutations results available, three patients (2.8%) had PIK3CA mutations, and all of these were detected in exon 20 of the PIK3CA gene. Of the 109 included patients, 77 (70.6%) patients were men and 32 (29.4%) were women, with a median age of 61 (range=29-85). For pathological stage, according to the 7th AJCC TNM classification system, 21 tumors (19.3%) were ypstage I, 52 (47.7%) were ypstage II, and 36 (33.0%) were ypstage III. When compared according to clinical staging, 70 (64.2%) patients experienced tumor down-staging after NACRT. Four patients (3.7%) were scored as TRG 0, 18 (16.5%) as TRG 1, 44 (40.4%) as TRG 2, and 43 (39.4%) as TRG 3.

Association with clinicopathological parameters. As summarized in Table I, PIK3CA-mutated patients were significantly more likely to have higher lymphovascular invasion (p=0.016), metastatic lymph nodes (p=0.034), higher pathological stages (p=0.040), and a lack of tumor down-staging after NACRT (p=0.044), compared to PIK3CA wild-type patients.

View this table:
Table I.

The association between clinicopathological parameters and PIK3CA mutations.

Differences in patient outcomes. At the time of our final analyses (December 2017), the median follow-up time was 75.6 months (range=3.1-141.7 months), during which 48 patients (44.0%) experienced recurrence and 34 (31.2%) died of rectal cancer. As shown in Figure 1, patients with PIK3CA mutations had shorter CSS (p=0.001) and DFS (p=0.006) than PIK3CA wild-type patients. In a Cox proportional hazard model adjusted for ypT category, ypN category, TRG, venous invasion, lymphatic invasion, perineural invasion, and CRM, no significant difference in survival was observed with respect to PIK3CA mutations (CSS p=0.319, HR=1.961, 95% CI=0.521-7.378; DFS p=0.219, HR=2.340, 95% CI=0.604-9.066) (Table II). N category, venous invasion, and CRM were found to be independent prognostic factors for CSS and/or DFS.

Figure 1.
Figure 1.

Kaplan–Meier curves for (A) cancer-specific survival (CSS) and (B) disease-free survival (DFS) by PIK3CA mutations status. Patients with PIK3CA mutations (green line) had reduced CSS and DFS as compared to patients with wild-type (blue line), using the log-rank test.

View this table:
Table II.

Multivariate analyses for cancer-specific survival and disease-free survival.

Discussion

In this study, we investigated the prevalence of PIK3CA mutations and their associations with clinicopathological parameters, as well as the relationship between PIK3CA mutations and clinical outcomes in patients with residual rectal cancer after NACRT. We detected an overall somatic mutation rate of 2.8% (3/109 patients), all of which were detected in exon 20 of the PIK3CA gene when the common hotspots C775 (H1047R, H1047Y, and H1047L), C760 (E542K, E542G, and E542V), C763 (E545K, E545G, and E545D), and C764 (Q546E, Q546K, Q546P, and Q546R) were tested. Among these 13 hotspots, H1047R in exon 20, and E545K and E542K in exon 9 represent 87% of all currently known mutations in the PIK3CA gene (27). Our low prevalence is in contrast to that of other previously published meta-analyses on PIK3CA mutations in CRC patients that reported PIK3CA mutations in 10-18% of patients with CRC (14, 17). However, as previously mentioned, rectal cancer can be distinguished from colon cancer based on its possible molecular characteristics. Furthermore, because our cases were specimens that had undergone NACRT, the results may have differed from those whose samples were taken before NACRT (28, 29). Sclafani et al. reported that PIK3CA mutations were found in 9% of patients with locally advanced rectal cancer in one multicenter study (30). They evaluated PIK3CA mutations in paired biopsy and resection specimens and found a mutation rate of 11% in pre-NACRT biopsy samples and 3% in resection specimens after NACRT. The mutation rate of their post-resection specimens was similar to our result of 2.8% (30). Sclafani et al. also showed that the concordance rate between the two was 96% for PIK3CA mutations (30). In their study, despite a high concordance, a definite difference in PIK3CA mutations rates between biopsy and resection specimens suggested that PIK3CA mutations may be associated with a response to NACRT. In our results, PIK3CA mutations were correlated with the absence of tumor down-staging following NACRT, although there was no association with TRG. Consistent with our hypothesis, Chang et al. found 12 gene mutations that were more frequently observed in patients with CR than in those with a poor response before NACRT. These genes included ATM, BRAF, CDKN2A, EGFR, FLT3, GNA11, KDR, KIT, PIK3CA, PTEN, PTPN11, SMAD4 and TP53 (31). Therefore, in future studies, it would be beneficial to compare biopsy specimens before NACRT and surgical specimens after NACRT in terms of changes in molecular and/or microenvironments.

We also found that PIK3CA mutations were detected in residual rectal cancers with poor characteristics (presence of lymphatic invasion and lymph node metastasis, high pathological stage, and absence of tumor down-staging after NACRT). Zhu et al. reported that the presence of PIK3CA mutations is an independent predictor of distant metastasis in CRC (32). In addition to this, our results showed that PIK3CA mutations were closely correlated with poor CSS and DFS, although their prognostic independence was not demonstrated. In CRC, the association between PIK3CA mutations and prognosis presents conflicting results (14, 33-37). Previously published meta-analyses have suggested that PIK3CA mutations have neutral prognostic effects on OS and PFS (14). Interestingly, Manceau et al. reported that PIK3CA mutations are associated with good prognoses in patients with microsatellite stable stage I-III colon cancer in their multicenter study (34). In contrast, other studies have shown that PIK3CA mutations are associated with poor survival, which is consistent with our findings (35-37). However, most previous retrospective studies have reported mixed sets of patients with colon and rectal cancers. Among these studies, He et al., who evaluated rectal cancer only, showed that PIK3CA mutation is an independent predictor for the development of local recurrences, along with TNM stage in stages I-III rectal cancer without NACRT (37). However, Sclafani et al. reported no association between PIK3CA mutations and their baseline prognostic factors (30). Unfortunately, unlike their study, our study evaluated a homogenous cohort of patients with locally advanced stage II/III rectal cancer treated with NACRT at a single institution. To the best of our knowledge, this is the first report of PIK3CA mutation and its aggressive behavior in East Asian patients with residual rectal cancers after NACRT.

PIK3CA regulates the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway, and its mutations have been found in a variety of cancers (38, 39). Clinical trials evaluating the efficacy of PI3K/AKT/mTOR axis inhibitors in patients with advanced cancers and PIK3CA mutations are currently underway (38, 40). Recently, alpelisib, a PI3K inhibitor, was approved by the Food and Drug Administration of the United States and by the European Medicines Agency, for patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced or metastatic breast cancer (41-43). In contrast, everolimus (an mTOR inhibitor) plus paclitaxel did not lead to improved outcomes in patients with previously treated metastatic gastric/gastroesophageal junction cancers (RADPAC trial; NCT01248403) (44). Taken together, although it is not known whether PIK3CA can be a therapeutic target in patients with locally advanced rectal cancer, our data may help to advance basic knowledge and further develop PIK3CA-targeted therapies.

One of the main limitations of this study is its small sample size and retrospective nature of data collection from a single institution. As a result, an inherent selection bias may have influenced our results. In addition, there may not be enough statistical power in this dataset to make a conclusive statement regarding the clinical significance of our findings. As mentioned above, the unavailability of a comparison between PIK3CA mutations and biopsy specimens before NACRT is another key limitation. However, these findings can serve as a basis for further studies on the subject with large patient numbers and multiple institutions.

Conclusion

In conclusion, we showed that PIK3CA mutations are associated with lymphatic invasion, lymph node metastasis, and poor outcomes, despite their rarity (2.8%) in patients with residual rectal cancer after NACRT. Our data suggest that PIK3CA mutations may increase tumor aggressiveness, and thus might be a potential therapeutic target in rectal cancer, although future confirmatory investigations in this vein are warranted. Furthermore, a large-scale study of the clinical effect of PIK3CA mutations on the response to NACRT by comparing pre-NACRT biopsies and post-NACRT resection specimens is required.

Acknowledgements

These cases were presented as posters at the USCAP 108th Annual Meeting in 2019. In addition, this research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning (grant number: NRF-2015R1C1A1A02037597).

Footnotes

  • Authors’ Contributions

    A.N. Seo made substantial contributions to the conception and design of this study. J. Byun and A. N. Seo wrote and revised the first draft and reviewed the final article. J. Byun and A. N. Seo conducted experiments. A.N. Seo performed statistical analyses. J. Y. Park, G. Yoon, M. K. Kang, H. J. Kim, S. Y. Park, J. S. Park, G. S. Choi, J. H. Baek and J. G. Kim collected and interpreted clinical data and specimens. All Authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work.

  • Conflicts of Interest

    The Authors declare no conflicts of interest.

  • Received January 24, 2023.
  • Revision received February 13, 2023.
  • Accepted February 14, 2023.

References

  1. ↵
    1. Sauer R,
    2. Becker H,
    3. Hohenberger W,
    4. Rödel C,
    5. Wittekind C,
    6. Fietkau R,
    7. Martus P,
    8. Tschmelitsch J,
    9. Hager E,
    10. Hess CF,
    11. Karstens JH,
    12. Liersch T,
    13. Schmidberger H,
    14. Raab R and German Rectal Cancer Study Group
    : Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351(17): 1731-1740, 2004. PMID: 15496622. DOI: 10.1056/NEJMoa040694
    OpenUrlCrossRefPubMed
  2. ↵
    1. Sauer R,
    2. Liersch T,
    3. Merkel S,
    4. Fietkau R,
    5. Hohenberger W,
    6. Hess C,
    7. Becker H,
    8. Raab HR,
    9. Villanueva MT,
    10. Witzigmann H,
    11. Wittekind C,
    12. Beissbarth T and
    13. Rödel C
    : Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 30(16): 1926-1933, 2012. PMID: 22529255. DOI: 10.1200/JCO.2011.40.1836
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Rödel C,
    2. Martus P,
    3. Papadoupolos T,
    4. Füzesi L,
    5. Klimpfinger M,
    6. Fietkau R,
    7. Liersch T,
    8. Hohenberger W,
    9. Raab R,
    10. Sauer R and
    11. Wittekind C
    : Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 23(34): 8688-8696, 2005. PMID: 16246976. DOI: 10.1200/JCO.2005.02.1329
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Glynne-Jones R,
    2. Wyrwicz L,
    3. Tiret E,
    4. Brown G,
    5. Rödel C,
    6. Cervantes A,
    7. Arnold D and ESMO Guidelines Committee
    : Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 29(Suppl 4): iv263, 2018. PMID: 29741565. DOI: 10.1093/annonc/mdy161
    OpenUrlCrossRefPubMed
  5. ↵
    1. Valentini V,
    2. Barba MC and
    3. Gambacorta MA
    : The role of multimodality treatment in M0 rectal cancer: evidence and research. Eur Rev Med Pharmacol Sci 14(4): 334-341, 2010. PMID: 20496544.
    OpenUrlPubMed
  6. ↵
    1. Vivanco I and
    2. Sawyers CL
    : The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2(7): 489-501, 2002. PMID: 12094235. DOI: 10.1038/nrc839
    OpenUrlCrossRefPubMed
    1. Velho S,
    2. Oliveira C,
    3. Ferreira A,
    4. Ferreira AC,
    5. Suriano G,
    6. Schwartz S Jr.,
    7. Duval A,
    8. Carneiro F,
    9. Machado JC,
    10. Hamelin R and
    11. Seruca R
    : The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer 41(11): 1649-1654, 2005. PMID: 15994075. DOI: 10.1016/j.ejca.2005.04.022
    OpenUrlCrossRefPubMed
    1. Kang S,
    2. Bader AG and
    3. Vogt PK
    : Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 102(3): 802-807, 2005. PMID: 15647370. DOI: 10.1073/pnas.0408864102
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Miller TW,
    2. Rexer BN,
    3. Garrett JT and
    4. Arteaga CL
    : Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res 13(6): 224, 2011. PMID: 22114931. DOI: 10.1186/bcr3039
    OpenUrlCrossRefPubMed
  10. ↵
    1. Li H,
    2. Chen S,
    3. Li H,
    4. Cui J,
    5. Gao Y,
    6. Wu D,
    7. Luan S,
    8. Qin Y,
    9. Zhai T,
    10. Liu D and
    11. Huo Z
    : Association between PIK3CA alteration and prognosis of gastric cancer patients: a meta-analysis. Oncotarget 9(7): 7651-7659, 2018. PMID: 29484141. DOI: 10.18632/oncotarget.23871
    OpenUrlCrossRefPubMed
    1. Willems L,
    2. Tamburini J,
    3. Chapuis N,
    4. Lacombe C,
    5. Mayeux P and
    6. Bouscary D
    : PI3K and mTOR signaling pathways in cancer: new data on targeted therapies. Curr Oncol Rep 14(2): 129-138, 2012. PMID: 22350330. DOI: 10.1007/s11912-012-0227-y
    OpenUrlCrossRefPubMed
  12. ↵
    1. Matsuoka T and
    2. Yashiro M
    : The role of PI3K/Akt/mTOR signaling in gastric carcinoma. Cancers (Basel) 6(3): 1441-1463, 2014. PMID: 25003395. DOI: 10.3390/cancers6031441
    OpenUrlCrossRefPubMed
  13. ↵
    1. Catasus L,
    2. Gallardo A,
    3. Cuatrecasas M and
    4. Prat J
    : PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters. Mod Pathol 21(2): 131-139, 2008. PMID: 18084252. DOI: 10.1038/modpathol.3800992
    OpenUrlCrossRefPubMed
  14. ↵
    1. Mei ZB,
    2. Duan CY,
    3. Li CB,
    4. Cui L and
    5. Ogino S
    : Prognostic role of tumor PIK3CA mutation in colorectal cancer: a systematic review and meta-analysis. Ann Oncol 27(10): 1836-1848, 2016. PMID: 27436848. DOI: 10.1093/annonc/mdw264
    OpenUrlCrossRefPubMed
  15. ↵
    1. Samuels Y,
    2. Wang Z,
    3. Bardelli A,
    4. Silliman N,
    5. Ptak J,
    6. Szabo S,
    7. Yan H,
    8. Gazdar A,
    9. Powell SM,
    10. Riggins GJ,
    11. Willson JK,
    12. Markowitz S,
    13. Kinzler KW,
    14. Vogelstein B and
    15. Velculescu VE
    : High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670): 554, 2004. PMID: 15016963. DOI: 10.1126/science.1096502
    OpenUrlFREE Full Text
  16. ↵
    1. Folkes AJ,
    2. Ahmadi K,
    3. Alderton WK,
    4. Alix S,
    5. Baker SJ,
    6. Box G,
    7. Chuckowree IS,
    8. Clarke PA,
    9. Depledge P,
    10. Eccles SA,
    11. Friedman LS,
    12. Hayes A,
    13. Hancox TC,
    14. Kugendradas A,
    15. Lensun L,
    16. Moore P,
    17. Olivero AG,
    18. Pang J,
    19. Patel S,
    20. Pergl-Wilson GH,
    21. Raynaud FI,
    22. Robson A,
    23. Saghir N,
    24. Salphati L,
    25. Sohal S,
    26. Ultsch MH,
    27. Valenti M,
    28. Wallweber HJ,
    29. Wan NC,
    30. Wiesmann C,
    31. Workman P,
    32. Zhyvoloup A,
    33. Zvelebil MJ and
    34. Shuttleworth SJ
    : The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem 51(18): 5522-5532, 2008. PMID: 18754654. DOI: 10.1021/jm800295d
    OpenUrlCrossRefPubMed
  17. ↵
    1. Mao C,
    2. Yang ZY,
    3. Hu XF,
    4. Chen Q and
    5. Tang JL
    : PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Ann Oncol 23(6): 1518-1525, 2012. PMID: 22039088. DOI: 10.1093/annonc/mdr464
    OpenUrlCrossRefPubMed
  18. ↵
    1. Wei EK,
    2. Giovannucci E,
    3. Wu K,
    4. Rosner B,
    5. Fuchs CS,
    6. Willett WC and
    7. Colditz GA
    : Comparison of risk factors for colon and rectal cancer. Int J Cancer 108(3): 433-442, 2004. PMID: 14648711. DOI: 10.1002/ijc.11540
    OpenUrlCrossRefPubMed
  19. ↵
    1. Yoon G,
    2. Kim SM,
    3. Kim HJ and
    4. Seo AN
    : Clinical influence of cancer stem cells on residual disease after preoperative chemoradiotherapy for rectal cancer. Tumour Biol 37(3): 3571-3580, 2016. PMID: 26456957. DOI: 10.1007/s13277-015-4201-9
    OpenUrlCrossRefPubMed
  20. ↵
    1. Yoon G,
    2. Lee H,
    3. Kim JH,
    4. Hur K and
    5. Seo AN
    : Clinical significance of fibroblast growth factor receptor 2 expression in patients with residual rectal cancer after preoperative chemoradiotherapy: relationship with KRAS or BRAF mutations and MSI status. Tumour Biol 37(8): 10209-10218, 2016. PMID: 26831663. DOI: 10.1007/s13277-016-4899-z
    OpenUrlCrossRefPubMed
  21. ↵
    1. McShane LM,
    2. Altman DG,
    3. Sauerbrei W,
    4. Taube SE,
    5. Gion M,
    6. Clark GM and Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics
    : REporting recommendations for tumor MARKer prognostic studies (REMARK). Nat Clin Pract Oncol 2(8): 416-422, 2005. PMID: 16130938.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Yoon G,
    2. Park JY,
    3. Kim HJ,
    4. Choi GS,
    5. Kim JG,
    6. Kang BW,
    7. Kang MK and
    8. Seo AN
    : ARID3A positivity correlated with favorable prognosis in patients with residual rectal cancer after neoadjuvant chemoradiotherapy. Anticancer Res 39(6): 2845-2853, 2019. PMID: 31177122. DOI: 10.21873/anticanres.13413
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Kim HJ,
    2. Choi GS,
    3. Park JS,
    4. Park S,
    5. Kawai K and
    6. Watanabe T
    : Clinical significance of thrombocytosis before preoperative chemoradiotherapy in rectal cancer: predicting pathologic tumor response and oncologic outcome. Ann Surg Oncol 22(2): 513-519, 2015. PMID: 25145505. DOI: 10.1245/s10434-014-3988-8
    OpenUrlCrossRefPubMed
  24. ↵
    1. Kim SM,
    2. Yoon G and
    3. Seo AN
    : What are the most important prognostic factors in patients with residual rectal cancer after preoperative chemoradiotherapy? Yeungnam Univ J Med 36(2): 124-135, 2019. PMID: 31620624. DOI: 10.12701/yujm.2019.00157
    OpenUrlCrossRefPubMed
  25. ↵
    1. Rullier A,
    2. Gourgou-Bourgade S,
    3. Jarlier M,
    4. Bibeau F,
    5. Chassagne-Clément C,
    6. Hennequin C,
    7. Tisseau L,
    8. Leroux A,
    9. Ettore F,
    10. Peoc’h M,
    11. Diebold MA,
    12. Robin YM,
    13. Kleinclaus I,
    14. Mineur L,
    15. Petitjean C,
    16. Mosnier JF,
    17. Soubeyran I,
    18. Padilla N,
    19. Lemaistre AI,
    20. Bérille J,
    21. Denis B,
    22. Conroy T and
    23. Gérard JP
    : Predictive factors of positive circumferential resection margin after radiochemotherapy for rectal cancer: the French randomised trial ACCORD12/0405 PRODIGE 2. Eur J Cancer 49(1): 82-89, 2013. PMID: 22909998. DOI: 10.1016/j.ejca.2012.06.028
    OpenUrlCrossRefPubMed
  26. ↵
    1. Park JS,
    2. Yoon G,
    3. Kim HJ,
    4. Park SY,
    5. Choi GS,
    6. Kang MK,
    7. Kim JG,
    8. Jang JS and
    9. Seo AN
    : HER2 status in patients with residual rectal cancer after preoperative chemoradiotherapy: the relationship with molecular results and clinicopathologic features. Virchows Arch 473(4): 413-423, 2018. PMID: 30056472. DOI: 10.1007/s00428-018-2409-y
    OpenUrlCrossRefPubMed
  27. ↵
    1. Martínez-Sáez O,
    2. Chic N,
    3. Pascual T,
    4. Adamo B,
    5. Vidal M,
    6. González-Farré B,
    7. Sanfeliu E,
    8. Schettini F,
    9. Conte B,
    10. Brasó-Maristany F,
    11. Rodríguez A,
    12. Martínez D,
    13. Galván P,
    14. Rodríguez AB,
    15. Martinez A,
    16. Muñoz M and
    17. Prat A
    : Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res 22(1): 45, 2020. PMID: 32404150. DOI: 10.1186/s13058-020-01284-9
    OpenUrlCrossRefPubMed
  28. ↵
    1. Liu C,
    2. Wang P,
    3. Sun Y,
    4. Dou X,
    5. Hu X,
    6. Zou W,
    7. Sun Y,
    8. Hu Q and
    9. Yue J
    : Neoadjuvant chemoradiotherapy changes the landscape of soluble immune checkpoint molecules in patients with locally advanced rectal cancer. Front Oncol 12: 756811, 2022. PMID: 35530332. DOI: 10.3389/fonc.2022.756811
    OpenUrlCrossRefPubMed
  29. ↵
    1. Trumpi K,
    2. Ubink I,
    3. Trinh A,
    4. Djafarihamedani M,
    5. Jongen JM,
    6. Govaert KM,
    7. Elias SG,
    8. van Hooff SR,
    9. Medema JP,
    10. Lacle MM,
    11. Vermeulen L,
    12. Borel Rinkes IHM and
    13. Kranenburg O
    : Neoadjuvant chemotherapy affects molecular classification of colorectal tumors. Oncogenesis 6(7): e357, 2017. PMID: 28692036. DOI: 10.1038/oncsis.2017.48
    OpenUrlCrossRefPubMed
  30. ↵
    1. Sclafani F,
    2. Wilson SH,
    3. Cunningham D,
    4. Gonzalez De Castro D,
    5. Kalaitzaki E,
    6. Begum R,
    7. Wotherspoon A,
    8. Capdevila J,
    9. Glimelius B,
    10. Roselló S,
    11. Thomas J,
    12. Tait D,
    13. Brown G,
    14. Oates J and
    15. Chau I
    : Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients. Int J Cancer 146(1): 94-102, 2020. PMID: 31199501. DOI: 10.1002/ijc.32507
    OpenUrlCrossRefPubMed
  31. ↵
    1. Chang YK,
    2. Tseng HH,
    3. Leung CM,
    4. Lu KC and
    5. Tsai KW
    : Targeted next-generation sequencing-based multiple gene mutation profiling of patients with rectal adenocarcinoma receiving or not receiving neoadjuvant chemoradiotherapy. Int J Mol Sci 23(18): 10353, 2022. PMID: 36142267. DOI: 10.3390/ijms231810353
    OpenUrlCrossRefPubMed
  32. ↵
    1. Zhu K,
    2. Yan H,
    3. Wang R,
    4. Zhu H,
    5. Meng X,
    6. Xu X,
    7. Dou X and
    8. Chen D
    : Mutations of KRAS and PIK3CA as independent predictors of distant metastases in colorectal cancer. Med Oncol 31(7): 16, 2014. PMID: 24861917. DOI: 10.1007/s12032-014-0016-6
    OpenUrlCrossRefPubMed
  33. ↵
    1. Sato T,
    2. Osumi H,
    3. Shinozaki E,
    4. Ooki A,
    5. Shimozaki K,
    6. Kamiimabeppu D,
    7. Nakayama I,
    8. Wakatsuki T,
    9. Ogura M,
    10. Takahari D,
    11. Chin K and
    12. Yamaguchi K
    : Clinical impact of primary tumor location and RAS, BRAF V600E, and PIK3CA mutations on epidermal growth factor receptor inhibitor efficacy as third-line chemotherapy for metastatic colorectal cancer. Anticancer Res 41(8): 3905-3915, 2021. PMID: 34281853. DOI: 10.21873/anticanres.15186
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Manceau G,
    2. Marisa L,
    3. Boige V,
    4. Duval A,
    5. Gaub MP,
    6. Milano G,
    7. Selves J,
    8. Olschwang S,
    9. Jooste V,
    10. le Legrain M,
    11. Lecorre D,
    12. Guenot D,
    13. Etienne-Grimaldi MC,
    14. Kirzin S,
    15. Martin L,
    16. Lepage C,
    17. Bouvier AM and
    18. Laurent-Puig P
    : PIK3CA mutations predict recurrence in localized microsatellite stable colon cancer. Cancer Med 4(3): 371-382, 2015. PMID: 25641861. DOI: 10.1002/cam4.370
    OpenUrlCrossRefPubMed
  35. ↵
    1. Iida S,
    2. Kato S,
    3. Ishiguro M,
    4. Matsuyama T,
    5. Ishikawa T,
    6. Kobayashi H,
    7. Higuchi T,
    8. Uetake H,
    9. Enomoto M and
    10. Sugihara K
    : PIK3CA mutation and methylation influences the outcome of colorectal cancer. Oncol Lett 3(3): 565-570, 2012. PMID: 22740953. DOI: 10.3892/ol.2011.544
    OpenUrlCrossRefPubMed
    1. Rosty C,
    2. Young JP,
    3. Walsh MD,
    4. Clendenning M,
    5. Sanderson K,
    6. Walters RJ,
    7. Parry S,
    8. Jenkins MA,
    9. Win AK,
    10. Southey MC,
    11. Hopper JL,
    12. Giles GG,
    13. Williamson EJ,
    14. English DR and
    15. Buchanan DD
    : PIK3CA activating mutation in colorectal carcinoma: associations with molecular features and survival. PLoS One 8(6): e65479, 2013. PMID: 23785428. DOI: 10.1371/journal.pone.0065479
    OpenUrlCrossRefPubMed
  37. ↵
    1. He Y,
    2. Van’t Veer LJ,
    3. Mikolajewska-Hanclich I,
    4. van Velthuysen ML,
    5. Zeestraten EC,
    6. Nagtegaal ID,
    7. van de Velde CJ and
    8. Marijnen CA
    : PIK3CA mutations predict local recurrences in rectal cancer patients. Clin Cancer Res 15(22): 6956-6962, 2009. PMID: 19903786. DOI: 10.1158/1078-0432.CCR-09-1165
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Kim M and
    2. Seo AN
    : Molecular pathology of gastric cancer. J Gastric Cancer 22(4): 273-305, 2022. PMID: 36316106. DOI: 10.5230/jgc.2022.22.e35
    OpenUrlCrossRefPubMed
  39. ↵
    1. Fruman DA,
    2. Chiu H,
    3. Hopkins BD,
    4. Bagrodia S,
    5. Cantley LC and
    6. Abraham RT
    : The PI3K pathway in human disease. Cell 170(4): 605-635, 2017. PMID: 28802037. DOI: 10.1016/j.cell.2017.07.029
    OpenUrlCrossRefPubMed
  40. ↵
    1. Janku F,
    2. Tsimberidou AM,
    3. Garrido-Laguna I,
    4. Wang X,
    5. Luthra R,
    6. Hong DS,
    7. Naing A,
    8. Falchook GS,
    9. Moroney JW,
    10. Piha-Paul SA,
    11. Wheler JJ,
    12. Moulder SL,
    13. Fu S and
    14. Kurzrock R
    : PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. Mol Cancer Ther 10(3): 558-565, 2011. PMID: 21216929. DOI: 10.1158/1535-7163.MCT-10-0994
    OpenUrlAbstract/FREE Full Text
  41. ↵
    1. Juric D,
    2. Janku F,
    3. Rodón J,
    4. Burris HA,
    5. Mayer IA,
    6. Schuler M,
    7. Seggewiss-Bernhardt R,
    8. Gil-Martin M,
    9. Middleton MR,
    10. Baselga J,
    11. Bootle D,
    12. Demanse D,
    13. Blumenstein L,
    14. Schumacher K,
    15. Huang A,
    16. Quadt C and
    17. Rugo HS
    : Alpelisib plus fulvestrant in PIK3CA-altered and PIK3CA-wild-type estrogen receptor-positive advanced breast cancer: a phase 1b clinical trial. JAMA Oncol 5(2): e184475, 2019. PMID: 30543347. DOI: 10.1001/jamaoncol.2018.4475
    OpenUrlCrossRefPubMed
    1. André F,
    2. Ciruelos E,
    3. Rubovszky G,
    4. Campone M,
    5. Loibl S,
    6. Rugo HS,
    7. Iwata H,
    8. Conte P,
    9. Mayer IA,
    10. Kaufman B,
    11. Yamashita T,
    12. Lu YS,
    13. Inoue K,
    14. Takahashi M,
    15. Pápai Z,
    16. Longin AS,
    17. Mills D,
    18. Wilke C,
    19. Hirawat S,
    20. Juric D and SOLAR-1 Study Group
    : Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 380(20): 1929-1940, 2019. PMID: 31091374. DOI: 10.1056/NEJMoa1813904
    OpenUrlCrossRefPubMed
  43. ↵
    1. André F,
    2. Ciruelos EM,
    3. Juric D,
    4. Loibl S,
    5. Campone M,
    6. Mayer IA,
    7. Rubovszky G,
    8. Yamashita T,
    9. Kaufman B,
    10. Lu YS,
    11. Inoue K,
    12. Pápai Z,
    13. Takahashi M,
    14. Ghaznawi F,
    15. Mills D,
    16. Kaper M,
    17. Miller M,
    18. Conte PF,
    19. Iwata H and
    20. Rugo HS
    : Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol 32(2): 208-217, 2021. PMID: 33246021. DOI: 10.1016/j.annonc.2020.11.011
    OpenUrlCrossRefPubMed
  44. ↵
    1. Lorenzen S,
    2. Knorrenschild JR,
    3. Pauligk C,
    4. Hegewisch-Becker S,
    5. Seraphin J,
    6. Thuss-Patience P,
    7. Kopp HG,
    8. Dechow T,
    9. Vogel A,
    10. Luley KB,
    11. Pink D,
    12. Stahl M,
    13. Kullmann F,
    14. Hebart H,
    15. Siveke J,
    16. Egger M,
    17. Homann N,
    18. Probst S,
    19. Goetze TO and
    20. Al-Batran SE
    : Phase III randomized, double-blind study of paclitaxel with and without everolimus in patients with advanced gastric or esophagogastric junction carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen (RADPAC). Int J Cancer 147(9): 2493-2502, 2020. PMID: 32339253. DOI: 10.1002/ijc.33025
    OpenUrlCrossRefPubMed
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PIK3CA Mutations as a Prognostic Factor in Patients With Residual Rectal Cancer After Neoadjuvant Chemoradiotherapy
JUNGSUP BYUN, NORA JEE-YOUNG PARK, GHILSUK YOON, MIN KYU KANG, HYE JIN KIM, SOO YEUN PARK, JUN SEOK PARK, GYU SEOG CHOI, JIN HO BAEK, JONG GWANG KIM, AN NA SEO
Anticancer Research Apr 2023, 43 (4) 1513-1520; DOI: 10.21873/anticanres.16300
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