Associations of tissue tumor mutational burden and mutational status with clinical outcomes in KEYNOTE-042: pembrolizumab versus chemotherapy for advanced PD-L1-positive NSCLC.

BACKGROUND: We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial. PATIENTS AND METHODS: This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome. RESULTS: Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status. CONCLUSION: tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status.

Clinical significance of p95HER2 overexpression, PTEN loss and PI3K expression in p185HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies.

Retraction to: British Journal of Cancer (2014) 110, 1968-1976; doi:10.1038/bjc.2014.72. It has been brought to our attention that, as a result of a miscommunication, the antibody used in this study in order to determine the expression of p95 HER2 in metastatic breast cancer patients is in fact directed against p95 NBS1, a component of the MRN complex, and is completely unrelated to p95 HER2. Therefore, a relationship between p95 HER2 overexpression and outcome cannot be established based on the results described and we wish to retract our paper. The authors, the editors of British Journal of Cancer, and the referees of this paper are grateful to colleagues in the field who have brought this problem to our attention and we apologise for any confusion that has, inadvertently, been caused.

Clinical significance of p95HER2 overexpression, PTEN loss and PI3K expression in p185HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies.

BACKGROUND: Overexpression of p185HER2 is an established poor prognostic factor in breast cancer, portending an aggressive course and potential for early metastasis. On the other hand, monoclonal antibody trastuzumab is widely used in the clinic to target this overexpressed oncogene. Unfortunately, ~30-40% of all patients overexpressing HER2 respond to trastuzumab, warranting further research regarding the structure and additional modulation of the receptor. In this study, we aimed to investigate the response to trastuzumab in terms of the potential roles of several oncogenic pathways (phosphatase and tensin homologue (PTEN) and phosphatidylinositol 3-kinase (PI3K)) and a truncated receptor protein, p95HER2, retrospectively. MATERIALS AND METHODS: Paraffin-embedded primary tumour tissues of 100 HER2-positive metastatic breast cancer patients who received trastuzumab with combination cytotoxic chemotherapy were analysed with immunohistochemical method for p95HER2, p85 (PI3K) and PTEN. Relationship between variables were tested via χ(2), Fischer's exact test and Mann-Whitney U tests, wherever appropriate. Progression-free survival (PFS) and overall survival (OS) periods were calculated with Kaplan-Meier method and survival curves of subgroups were compared with log-rank test. RESULTS: Percentage of patients was found to be 33%, 57% and 42% positive for p95 expression, PTEN and PI3K, respectively. p95-expressing tumours had statistically lower response rates for trastuzumab than tumours not expressing p95 (P=0.001). On the contrary, PTEN-expressing tumours had statistically higher response rates for trastuzumab than tumours not expressing PTEN (P=0.012). PI3K expression had no significant effect on trastuzumab response. Median PFS for p95-expressing and not expressing tumours were 8 months (95% CI, 2.5-13.4 months) and 22 months (95% CI, 9.9-34 months), respectively (P=0.0001). Median PFS for PTEN-expressing and not expressing tumours were 15.3 months (95% CI, 12.6-34 months) and 12.1 months (95% CI, 7.9-16.2 months), respectively (P=0.04). Median OS for p95-expressing and not expressing tumours were 24 months (95% CI, 8.3-40.4 months) and 29.1 months (95% CI, 8.6-43.2 months), respectively (P=0.045). Median OS for PTEN-expressing and not expressing tumours were 25.1 months (95% CI, 7.5-40.1 months) and 26.8 months (95% CI, 8.1-42 months), respectively, which was not statistically significant (P=0.5). Level of PI3K expression had no effect on PFS and OS in our patient population. Presence of visceral metastases HR=2.38 ((95% CI, 1.2-4.5), P=0.009), p95 expression HR=2.1 ((95% CI, 1.1-3.7), P=0.03) and response to trastuzumab HR=2.2 ((95% CI, 1.18-4.47), P=0.014) are identified as factors independently affecting PFS. Response to trastuzumab HR=1.7 ((95% CI, 1.14-3.47), P=0.013) was identified as the single parameter influencing survival by Cox regression analysis. CONCLUSIONS: Presence of p95 predicted a poorer response to trastuzumab treatment, shorter PFS and OS in our HER2-positive metastatic breast cancer cohort. In addition, loss of PTEN predicted a poorer response to trastuzumab treatment and shorter PFS but not OS. We could not find an effect of PI3K expression on the above-mentioned parameters.

Preoperative chemoradiotherapy improves local recurrence free survival in locally advanced rectal cancer.

PURPOSE: Preoperative chemoradiotherapy (pre-CRT) followed by total mesorectal excision (TME) is the recommended therapy for patients with locally advanced rectal cancer (LARC). The primary aim of this study was to compare the rates of local and distant recurrence and overall survival (OS) in LARC patients who received pre-CRT vs postoperative (post) CRT. METHODS: The medical records of 158 rectal cancer patients with clinical stage T3, T4 or N positive disease who received either pre-CRT or post-CRT between 2000-2009 were retrospectively analysed. Pre-CRT employed protracted 5-fluorouracil (5FU) infusion, whereas post-CRT included bolus 5FU and leucovorin concurrently with radiation therapy (RT). Radiation dose was 50.4 Gy in 82% and 45 Gy in 18% of the patients. RESULTS: 158 patients (65 females, 93 males) were analysed. Median age was 56.5 years (range 19-78). Fifty-three (34%) patients received pre-CRT and 105 (66%) post-CRT. Median follow-up was 43.3 months (range 8-182) and 47.6 months (range 9-194) in pre-CRT and post-CRT patients, respectively. After pre-CRT, significant downstaging was achieved. However, the type of surgical resection was not influenced by the administration of pre-CRT in tumors ≥5 cm distant from the anal verge (p=0.3). Pathologic complete response was achieved in 20% of the patients in the pre-CRT group. Local recurrence free survival (LRFS) at 5-years was 89.2% in the pre-CRT and 74.8% in the post-CRT group (p=0.04). Distant recurrence free survival (DRFS) at 5-years was 81.7% and 68.5 % in pre-CRT and post-CRT groups, respectively (p=0.1). OS was similar in the two groups (71.4 vs 64.4%, p=0.9). CONCLUSION: Treatment of LARC with pre-CRT followed by surgery improved LRFS as compared to surgery followed by post-CRT, but failed to improve DRFS or OS in our patient population.

Clinicopathologic and prognostic evaluation of invasive breast carcinoma molecular subtypes and GATA3 expression.

PURPOSE: recently, molecular subclassification of breast carcinomas has been proposed as a new prognostic parameter. METHODS: we classified 222 invasive breast carcinoma cases in 5 molecular subtypes by using tissue microarray (TMA) and immunohistochemistry methods. These subtypes were luminal A (estrogen receptor/ER and/or progesterone receptor/ PR positive), luminal B (ER and/or PR positive + HER2 positive), HER2-expressing type (ER and PR negative, HER2 positive), basal-like type (ER, PR and HER2 negative, positive with at least one of these myoepithelial markers: CK5/6, CK14, EGFR) and null type (ER, PR, HER2 and myoepithelial markers negative). We compared these subtypes according to their clinicopathological features and GATA3 expression. RESULTS: luminal A was the most frequent subtype. According to overall survival rates, HER2-expressing and basal- like types had the worst prognosis, while luminal A had the best. However, luminal B had the worst prognosis according to disease free survival. Most of the squamous differentiated metaplastic carcinomas were basal-like type. Tubular and mucinous carcinomas were luminal A. Most basal-like tumors were grade III. The majority of grade I tumors were luminal A. GATA3 positivity was associated with low grade tumors and luminal A subtype. CONCLUSION: molecular classification can be accepted as an independent prognostic factor for invasive breast carcinomas. GATA3 expression was associated with luminal A and low histological grade. However, it wasn't shown as an independent parameter.

Determining predominating histologic component in malignant mixed müllerian tumors: is it worth it?

Malignant mixed müllerian tumors (MMMT) are highly aggressive tumors, usually diagnosed in advanced stage. Cases of MMMT derive from either ovary or uterus. In our study, we investigated the role of carcinomatous and sarcomatous component on response to chemotherapy and disease outcome. We retrospectively analyzed 25 patients with MMMT who were treated in our outpatient clinic from 1998 to 2003. All the paraffin specimens were reevaluated according to the histopathologic features (primary site and percentages of carcinomatous and sarcomatous component) and the effect of predominant histologic type on response to treatment. Primary tumor sites were ovary and endometrium in 36% and 64% of patients, respectively. Ten of 25 patients (40%) were treated with a combination chemotherapy regimen of cisplatin-ifosfamide (PI) and 7 patients (28%) were treated with paclitaxel-carboplatin (PC) protocol. Despite chemotherapy, 17.6% of patients had progressive disease. The remaining 13 patients (54.2%) responded to chemotherapy. Response rates of patients treated with PC (100%) were remarkably higher than the response rates of patients treated with PI (66.6%). Moreover, patients with predominating carcinomatous component had a higher response rate (87.5%) than patients with predominating sarcomatous component (66.6%). MMMT are highly chemoresponsive tumors, irrespective of primary site. One of the best predictors to response is the histologic pattern. Predominating histopathologic feature (carcinoma or sarcoma) should be taken into consideration in predicting the response and planning the chemotherapy regimen.

Metastatic primitive neuroectodermal tumor of the ovary in pregnancy.

Primitive neuroectodermal tumor (PNET) is a small round tumor belonging to the PNET/Ewing's sarcoma family. We hereby report a case of PNET of the ovary, which was detected at the second trimester of pregnancy. Chemotherapy was administered and a healthy baby was delivered by cesarean section. After the pregnancy, the mother was found to have metastatic disease. Chemotherapy was continued, but she died due to progressive disease 13 months after the initial diagnosis. In this case report, we discuss chemotherapy options during pregnancy and the importance of multidisciplinary approach to unusual presentations of rare tumors.

Safety and efficacy of transdermal fentanyl in patients with cancer pain: phase IV, Turkish oncology group trial.

We have performed a prospective evaluation of the efficacy, safety and convenience of the transdermal therapeutic system - fentanyl (TTS-F) in Turkish cancer patients when it was newly available in Turkey. Ninety-nine patients with historically confirmed malignancy and pain entered the study; the mean age was 55.1 (16-58) years. The study duration was 28 days. Transdermal therapeutic system - fentanyl was used in opioid-naïve or pre-treated patients. Most patients reported a decrease in pain severity. Use of rescue medication decreased from day 4 to day 28. The majority of patients rated patch convenience of use as excellent. A total of 22.2% of patients experienced adverse events that were either probably related or very likely to be related to the study drug. The majority of the adverse events mentioned were related to the digestive system. Eighteen serious adverse events were reported by 13 patients. Six events were doubtfully related, and 12 events were not related to the study drug. Four patients died during the trial. None of these deaths was attributed to the study drug. In conclusion, the trial showed that TTS-F is easily managed, effective and will help to enable the appropriate opioid administration to patients who are suffering from cancer pain in Turkey.

Devastating effects of chemotherapy: deafness and acute renal failure in a patient with epithelial ovarian cancer.

Paclitaxel and platinum combination is the standard chemotherapy regimen for patients with advanced epithelial ovarian cancer. The dose-limiting toxicity effects of this combination are myelosuppression and neuropathy. Herein, we report a case of a 71-year-old female with advanced epithelial ovarian cancer who developed bilateral total loss of hearing and acute renal failure related with paclitaxel- and carboplatin-based chemotherapy. Acute renal failure accompanied by complete loss of hearing in patients treated with carboplatin and paclitaxel combination has not been previously reported. This uncommon adverse effect of carboplatin and paclitaxel combination was discussed, and all the literature in English related with the toxicity of paclitaxel and carboplatin were reviewed.

Should mammographic screening be done in primary ovarian cancer?: A case control study in Turkish women.

Breast cancer is a significant global health problem. It is the most common malignancy in women. Mammographic screening is recommended for women older than 40 yr for early detection of breast cancer. The aim of this study is to evaluate the role of screening mammography in ovarian cancer independent of age. Eighty-four patients with ovarian cancer were evaluated with bilateral mammography. Two hundred asymptomatic healthy controls with a similar age distribution were also imaged with screening mammography. Mammography results were classified according to the American College of Radiology criteria in five groups. The median age of the study group was 51.4 (range, 27-77) and 49.3 (range, 30-75) in the control group. Screening mammography detected four cases of malignancy (4.8%) in patients with ovarian cancer; two were the primary breast carcinomas(2.5%) and two were metastatic cancers from the ovary. Five subjects (2.5%) among healthy controls were also found to have breast cancer. Although the incidence of primary breast carcinoma was found to be similar in the two groups (2.5%), mammographic imaging detected metastatic disease to the breast from the ovaries. Mammography should therefore be considered in patients with ovarian cancer independent of age.

Reactivation of hepatitis B virus infection with cytotoxic therapy in non-Hodgkin's lymphoma.

In patients with non-Hodgkin's lymphoma (NHL), there are some well-known tumor-related adverse prognostic factors that may increase the mortality rate. However, secondary factors such as viral hepatitis carriers that may decrease the cure rates are usually ignored. Reactivation of hepatitis B virus (HBV) infection in patients undergoing cytotoxic treatment for NHL is a well-known complication. Charts of 112 patients with NHL were retrospectively analyzed regarding their hepatitis serology, the indirect effects of seropositivity on disease outcome, and the precautions undertaken in these seropositive patients with NHL. Twelve patients (11%) with HBsAg positivity and two patients (1.7%) with antibody to hepatitis C virus positivity were detected. Eight out of 12 patients (67%) with HBsAg positivity and two patients (50%) with anti-HCV positivity showed reactivation of hepatitis during treatment of NHL. No reactivation was detected in four patients seropositive for HBV, who were given lamivudine prophylaxis before the initiation of chemotherapy schedules. Among patients with hepatitis reactivation, two were treated with lamivudine resulting in dramatic improvement and clinical remission of the disease. The remaining six patients with reactivation were left untreated, resulting in four deaths (67%) due to liver failure secondary to HBV and two deaths secondary to delayed treatment of NHL. One patient seropositive for anti-HCV also developed chronic hepatitis C. Determination of hepatitis serology in all patients with NHL before any chemotherapy administration is crucial, but insufficient, if not taken into consideration. In seropositive patients, HBV DNA should be determined and antiviral prophylaxis with lamivudine should be initiated before any treatment.

Do we really benefit from checking tumor markers in detecting recurrence in gastrointestinal cancer?

PURPOSE: To evaluate the role of tumor markers carcinoembryonic antigen (CEA) and CA 19.9 in the early detection of local or systemic recurrence in gastrointestinal malignancies. PATIENTS AND METHODS: Twenty-six patients with operable gastrointestinal cancer, who had elevated levels of either CEA or CA 19.9 or both during the postoperative follow-up period were evaluated. Serum estimation of tumor markers were carried out at 3-month intervals and the imaging and endoscopic procedures were performed at 6-month intervals or when a patient had an elevated tumor marker during follow-up. RESULTS: The difference of mean serum levels of CA 19.9 but not of CEA was found to be statistically significant between the two groups of patients with or without radiographically / endoscopically evident recurrent disease (p < 0.05). CONCLUSION: CA 19.9 was found to be a better, though not specific, indicator of recurrence. The relative small number of patients precludes reaching a firm conclusion. Further studies are needed to establish the role of these markers in determining early recurrence and their impact in overall survival.

Usefulness of the epithelial tumor marker CA-125 in non-Hodgkin's lymphoma.

CA-125, a commonly used tumor marker for epithelial ovarian cancer, is a glycoprotein found in normal tissues derived from coelomic epithelia. Increased serum levels of CA-125 have also been found in nongynecologic tumors and nonmalignant diseases involving the peritoneum. A few recent studies and sporadic case reports have reported increased CA-125 levels in patients with non-Hodgkin's lymphoma (NHL). In our study, we aimed to evaluate the serum levels of CA-125 in patients with NHL and determine its potential role to show disease activity in NHL. Serum levels of CA-125 were measured in 61 patients with NHL and were found to be correlated with clinical stage, site of involvement, and disease activity.