The treatment paradigm for colorectal cancer (CRC) has changed significantly over the past decade with targeted therapeutics. Human epidermal growth factor receptor 2 ( HER2) amplification is seen among 3%-4% of patients with metastatic CRC (mCRC). The biological discovery of HER2 amplification in cancer cells has led to practice-changing drug development for several solid tumors, including breast, gastric, and esophageal cancers. HER2 amplification is now highly actionable in CRC with distinct therapeutic combinations, including the combination of monoclonal antibodies and HER2 receptor–specific tyrosine kinase inhibitors, as well as antibody-drug conjugates, that delivers targeted cytotoxic agents. However, it is essential to define the therapeutic role and sequence of these different combinations, some of which are already part of standard clinical practice. In this review article, we discuss recent clinical studies demonstrating the clinical benefits of each distinct therapeutic approach and their impacts on the current management of HER2-amplified mCRC. We also review ongoing clinical trials targeting the HER2 pathway in mCRC and elaborate on novel therapeutic opportunities in this space that may further define the changing paradigm of HER2-targeted therapy for CRC.

Background: First-line treatments for metastatic pancreatic cancer are chemotherapy regimens consisting of 5-fluorouracil or gemcitabine; however, there are no biomarkers to help determine which patients might benefit from which treatment regimens. We aimed to show that microRNAs let-7c and 7d can be used as independent predictive biomarkers for metastatic pancreatic cancer. Methods: A total of 55 patients who had first-line chemotherapy with FOLFIRINOX or gemcitabine + capecitabine were included. Patients were divided into groups based on let-7c and let-7d levels and chemotherapy treatment as let-7c-7d high FOLFIRINOX, let-7c-7d high gemcitabine + capecitabine, let-7c-7d low FOLFIRINOX, and let-7c-7d low gemcitabine + capecitabine. Blood samples were taken from patients before chemotherapy for microRNA let-7c and 7d analysis. MicroRNA isolation was performed using a miRNeasy Serum/Plasma Kit and identified using spectrophotometric measurements. After isolation, microRNA was converted to cDNA using a microRNA cDNA Synthesis Kit with poly (A) polymerase tailing. The expression of microRNA was examined using quantitative real-time polymerase chain reaction. Results: The overall survival of patients who received FOLFIRINOX treatment with a high let-7c-7d level was statistically significantly longer than those who received gemcitabine + capecitabine with a high let-7c-7d level. In addition, patients with low let-7c expression receiving FOLFIRINOX progressed significantly 2.104 times earlier than patients with high let-7c expression receiving FOLFIRINOX. Conclusion: The serum MicroRNA let-7c level was found to be an independent predictive biomarker in the FOLFIRINOX treatment group.

239 Background: The benefit of immunotherapy for patients with mCRC with high tumor mutational burden (TMB-H) has been widely debated. In 2020, the FDA approved the use of pembrolizumab for the treatment of patients with TMB-H unresectable or metastatic solid tumors, with TMB-H defined as ≥10 mutations/Mb on a commercial tissue-based assay, based on KEYNOTE 158 results. However, the clinical value of applying this universal cut off to mCRC needs further investigation. Methods: We queried Moffitt Cancer Center (MCC) databases for patients with MSS mCRC, harboring TMB-H (tested with tissue and/or liquid biopsies) who received immunotherapy between January 2018 and December 2021. Patients with incomplete records were excluded. Clinical data were extracted by trained staff from electronic medical records. Objective response rate was measured by using clinical assessment from chart review. Results: We identified 40 patients with TMB-H MSS mCRC 13 of whom received immune checkpoint inhibitor therapy. Female patients represented 31% (n=4) of the 13 treated patients. Median age for the patients was 60 years (range 34-71. Thirty-eight percent (n=5) of the primary tumors originated in the right side. Thirty-one percent (n=4) presented with stage 4 CRC at diagnosis. Histopathology was adenocarcinoma in 92% (n=12) and one had neuroendocrine differentiation. Tumors were well-differentiated 8% (n=1), moderately differentiated 46% (n=6), or poorly differentiated 23% (n=3). Four patients (31%) had POLE/ POLD-1 mutations. The objective response rate (ORR) was 31% (4/13) with responses limited to tumors only with POLE/ POLD-1 mutations (100%, 4/4). The median progression free survival (mPFS) was 3.8 months for the overall cohort and 28.5 months for patients with POLE/POLD-1 mutated tumors. Agent specific analysis showed mPFS for patients treated with pembrolizumab was 3.5 months (mean 5.2; range 0.6-15.7), and 3.4 months (mean 12.1; range 0.5-12.1) for patients treated with nivolumab. Five patients received immunotherapy in combination with regorafenib. The mPFS for these patients was 3.4 months (mean 3.8; range 0.5-8.0). Of five patients with TMB>30 (38%), 4 (80%) had POLE/POLD-1 mutated tumors. One case without POLE/POLD-1 mutations, but with a TMB>30 did not experience any response. Conclusions: Although TMB-H demonstrated therapeutic significance in the KEYNOTE 158 study, the utility of 10 mutations/MB as a universal cutoff warrants additional evaluation. Here we report that a TMB-H cutoff value of ≥ 10 for patients with MSS CRC was not associated with clinically meaningful response to immunotherapy, but patients with MSS CRC with POLE/ POLD-1 mutations may be more likely to benefit from immunotherapy.

Makale bilim dalı: OnkolojiMakale başlığı: Over kanserinde nötrofil/lenfosit, trombosit/lenfosit, crp/albümin oranları ile klinikopatolojik özellikler ve sağkalım arasındaki ilişki. Kısa başlık: Over kanserinde nötrofil/lenfosit, trombosit/lenfosit, crp/albümin oranları Öz Amaç: Over kanseri jinekolojik kanserler arasında en yüksek ölüm oranına sahip olan kanserdir. Birçok kanserde inflamasyon temelli skorlar olan nötrofil lenfosit oranının (NLR), trombosit lenfosit oranının (PLR), CRP albumin oranının (CRP/Alb) prognoz üzerine etkisi gösterilmiştir. Biz de bu çalışmada NLR, PLR, CRP/Alb oranlarının over kanserinin prognozu üzerine olan etkisini değerlendirmeyi amaçladık. Yöntem: Çalışmamıza Eylül 2014-Aralık 2020 tarihleri arasında Pamukkale Üniversitesi Tıp Fakültesi Tıbbi Onkoloji Bilim dalı polikliniğine başvuran over karsinom tanılı evreleri 1 ile 4 arasında değişen toplam 124 hasta hasta çalışmaya dahil edildi. NLR, PLR, CRP/Alb kesme noktaları ROC analizi ile yapıldı. Bulgular: Hastalarımızın medyan yaşı 56 (sınırlar 24-84) idi. NLR oranı 63 hastada(%50), PLR oranı 56 hastada (%45), CRP/Alb oranı 61 hastada (%49) kesme değerine göre yüksek saptandı. PLR değeri ile progresyon sağkalım arasında istatistiksel olarak anlamlı ilişki yokken, genel sağkalımla istatistiksel olarak anlamlı ilişki bulunmaktaydı (p=0,01). PLR değeri yüksek olanlarda medyan genel sağkalım 23 ay iken PLR değeri düşük olanlarda 45 aydır olarak saptandı. CRP/Alb oranının ise hem progresyonsuz sağkalım hem de genel sağkalım ile istatistiksel olarak anlamlı ilişkisi mevcuttu (p=0,011; p=0,008). CRP/Alb değeri düşük olanlarda daha uzun progresyonsuz sağkalım ve genel sağkalım olduğu saptandı. Sonuç: Diğer kanser tiplerinde olduğu gibi over kanserinde de inflamasyon belirteçlerinin kanser progresyonu üzerine dolayısıyla prognoza olan etkisi dikkat çekmektedir. PLR oranının genel sağkalımla, CRP/Alb oranının ise hem genel sağkalım hemde progresyonsuz sağkalımla istatistiksel olarak anlamlı bir ilişkisi olduğunu gösterdik. Bu oranların gelecekte farklı tedavi gruplarını oluştururken hastaların seçiminde yardımcı olabileceği kanısındayız.

Aim The current standard treatment of locally advanced rectal carcinoma is total mesorectal excision and postoperative adjuvant chemotherapy after neoadjuvant concurrent chemoradiotherapy (NCRT). Many studies have shown that pathological complete response (pCR) is an important prognostic factor for patients receiving NCRT. Many studies have therefore been conducted to increase pCR rates by changing the perioperative treatment strategies. Prolonging the chemotherapy time may be a reasonable way to increase the effectiveness of NCRT, pCR, and survival rates. We investigated whether neoadjuvant consolidation chemotherapy had an effect on tumor response and survival. Methods The data of 163 patients diagnosed with locally advanced rectal carcinoma were evaluated. The data of 107 patients (Group 1) who were radiologically T3–T4 and/or N+ and received chemotherapy after NCRT until their operations were compared with the data of 56 patients (Group 2) who were operated after NCRT. Results Group 1 patients had tumor and node downstaging. Their pCR was found significantly higher than in Group 2 ( p = 0.005). In Group 1 patients with T3, pCR was significantly higher than for those with T4. The elapsed time between NCRT and surgery was significantly longer in patients with pCR (respectively, p = 0.012 and p = 0.008). Conclusion Neoadjuvant consolidation chemotherapy after NCRT is a safe approach that can lead to higher pathological complete response rates. The time until surgery with neoadjuvant consolidation chemotherapy may provide the chance to follow the patient without surgery in addition to increasing pCR.