The dismal lethality of lung cancer is due to late stage at diagnosis and inherent therapeutic resistance. The incorporation of targeted therapies has modestly improved clinical outcomes, but the ...identification of new targets could further improve clinical outcomes by guiding stratification of poor-risk early stage patients and individualizing therapeutic choices. We hypothesized that a sequential, combined microarray approach would be valuable to identify and validate new targets in lung cancer. We profiled gene expression signatures during lung epithelial cell immortalization and transformation, and showed that genes involved in mitosis were progressively enhanced in carcinogenesis. 28 genes were validated by immunoblotting and 4 genes were further evaluated in non-small cell lung cancer tissue microarrays. Although CDK1 was highly expressed in tumor tissues, its loss from the cytoplasm unexpectedly predicted poor survival and conferred resistance to chemotherapy in multiple cell lines, especially microtubule-directed agents. An analysis of expression of CDK1 and CDK1-associated genes in the NCI60 cell line database confirmed the broad association of these genes with chemotherapeutic responsiveness. These results have implications for personalizing lung cancer therapy and highlight the potential of combined approaches for biomarker discovery.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We conducted a phase I study of a weekly nab‐paclitaxel and S‐1 combination therapy in patients with human epidermal growth factor receptor type 2‐negative metastatic breast cancer. The primary ...objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S‐1 dose (65 or 80 mg/m2) and nab‐paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose‐limiting toxicity was observed in one patient at Level 3 (100 mg/m2 nab‐paclitaxel on days 1, 8, and 15 with 80 mg/m2 S‐1 daily for 14 days, followed by 7 days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3–4 treatment‐related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression‐free survival was 13.2 and 21.0 months, respectively. The present results show the feasibility and potential for long‐term administration of this combination therapy.
Weekly nab‐paclitaxel plus S‐1 in patients with MBC.
Somatic mutations in the epidermal growth factor receptor gene are associated with a therapeutic response to epidermal growth factor receptor tyrosine kinase inhibitors such as gefitinib and ...erlotinib in patients with non-small cell lung cancer. Although the safety profile of these drugs is favorable, a small proportion of patients with EGFR mutation-positive non-small cell lung cancer must discontinue treatment because of adverse events such as interstitial lung disease and hepatotoxicity. Subsequent chemotherapy has not been optimized in such patients.
We performed a retrospective analysis of EGFR mutation-positive non-small cell lung cancer patients who received both gefitinib and erlotinib at our institution. Patients received the second epidermal growth factor receptor-tyrosine kinase inhibitor after experiencing an adverse event or progressive disease on the first epidermal growth factor receptor-tyrosine kinase inhibitor.
We identified 14 patients who received both gefitinib and erlotinib in the course of their treatment. Three patients initially treated with gefitinib and two with erlotinib discontinued epidermal growth factor receptor-tyrosine kinase inhibitor therapy because of severe non-hematologic toxicity (one because of gefitinib-induced interstitial lung disease, one because of erlotinib-induced lupus erythematosus-like eruption and three because of hepatotoxicity). All five of these patients were able successfully to continue therapy with the second epidermal growth factor receptor-tyrosine kinase inhibitor with no evidence of a recurrent adverse event. Progression-free survival was significantly longer in these five patients than in the nine patients who discontinued treatment with the first epidermal growth factor receptor-tyrosine kinase inhibitor because of disease progression.
EGFR mutation-positive non-small cell lung cancer patients who discontinue treatment with a first epidermal growth factor receptor-tyrosine kinase inhibitor because of an adverse event benefit substantially from switching to a second epidermal growth factor receptor-tyrosine kinase inhibitor before the development of drug resistance.
Summary
Extramammary Paget’s disease is a malignant intraepithelial carcinoma, which constitutes less than 1 % of all vulvar malignancies. Surgical resection is the first treatment of choice and ...standard chemotherapy has not been established for advanced or recurrent disease. Experimental and clinical studies have identified human epidermal growth receptor 2 as a potential therapeutic target. A 63-year-old male was referred for recurrent extramammary Paget’s disease after surgery. Human epidermal growth receptor 2 was shown to be overexpressed and amplified by immunohistochemical analysis and fluorescence in situ hybridization analysis, respectively. After two cycles of trastuzumab monotherapy, all lymph node metastases decreased in size. However, he experienced recurrence in the lymph nodes during the seven courses of trastuzumab. As a subsequent treatment, trastuzumab was administered in combination with docetaxel and pertuzumab; clinical response was sustained for 12 months without significant adverse events.
Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases, and almost half of newly diagnosed patients have metastatic disease. Pemetrexed is a widely used drug for NSCLC and ...inhibits several folate-dependent enzymes including thymidylate synthase (TS). Increased expression of TS confers resistance to pemetrexed in vitro and predicts poor response to pemetrexed. Rapamycin is an mTOR inhibitor and suppresses cap-dependent synthesis of specific mRNA species. Here, we show that the combination of rapamycin and pemetrexed synergistically inhibits proliferation of NSCLC cells. Although pemetrexed as a single agent induced TS, pretreatment with rapamycin suppressed pemetrexed-induced TS expression. In vivo, the combination of rapamycin and pemetrexed inhibited growth of NSCLC xenografts, which correlated with decreased mTOR activity and suppression of pemetrexed-induced TS expression. The ability of rapamycin to enhance the efficacy of pemetrexed and prevent TS expression has implications for the design of Phase I and/or Phase II NSCLC clinical trials with mTOR inhibitors in combination with pemetrexed.
Purpose: Human and murine preneoplastic lung lesions induced by tobacco exposure are characterized by increased activation of the
Akt/mammalian target of rapamycin (mTOR) pathway, suggesting a role ...for this pathway in lung cancer development. To test this,
we did studies with rapamycin, an inhibitor of mTOR, in A/J mice that had been exposed to the tobacco-specific carcinogen
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).
Experimental Design: Tumorigenesis was induced by i.p. injection of NNK, and rapamycin was administered 1 or 26 weeks after NNK administration.
Biomarkers associated with mTOR inhibition were assessed in lung and/or surrogate tissues using immunohistochemistry and immunoblotting.
Rapamycin levels were measured using mass spectroscopy.
Results: Rapamycin was administered on a daily (5 of 7 days) regimen beginning 26 weeks after NNK decreased tumor size, proliferative
rate, and mTOR activity. Multiplicity was not affected. Comparing this regimen with an every-other-day (qod) regimen revealed
that rapamycin levels were better maintained with qod administration, reaching a nadir of 16.4 ng/mL, a level relevant in
humans. When begun 1 week after NNK, this regimen was well tolerated and decreased tumor multiplicity by 90%. Tumors that
did develop showed decreased phenotypic progression and a 74% decrease in size that correlated with decreased proliferation
and inhibition of mTOR.
Conclusions: Tobacco carcinogen–induced lung tumors in A/J mice are dependent upon mTOR activity because rapamycin markedly reduced the
development and growth of tumors. Combined with the Food and Drug Administration approval of rapamycin and broad clinical
experience, these studies provide a rationale to assess rapamycin in trials with smokers at high risk to develop lung cancer.
Abstract Objective For patients with HER2-positive breast cancer, the prognostic impact of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) is unclear when stratified by ...hormonal receptor (HR) status; however, the impact of pCR on survival when stratified by hormonal receptor (HR) status is uncertain. Patients and methods This multicenter retrospective study investigated the predictors of pCR and its prognostic value in Japanese patients 366 HER2-positive breast cancer who received NAC. pCR was defined as no invasive residual tumor in the breast or axilla. Results Median follow-up was 55 months. Multivariate analysis revealed that HR status (OR, 0.37; p < 0.001) was one of the independent predictors of pCR. Five-year recurrence-free survival was higher in HR-negative patients with pCR (93%) than in those without pCR (68%), and pCR was independently prognostic (hazard ratio, 0.32; p = 0.005). However, 5-year recurrence-free survival was not different between HR-positive patients with pCR (94%) and those without pCR (84%), and pCR was not significantly prognostic (hazard ratio, 0.53; p = 0.39). In addition, 5-year overall survivals were high and similar (97% in pCR, 94% in non-pCR). Among 204 patients treated with neoadjuvant trastuzumab, pCR was not significantly prognostic in the HR-positive group (hazard ratio, 0.63; p = 0.56). Conclusion Our study suggested that the HER2-positive HR-positive patients had a good prognosis despite the lower achievement rate of pCR, whose prognostic impact was smaller than that in the HER2-positive HR-negative patients. The treatment strategy for HER2-positive breast cancer can be stratified by HR status.
Bone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and ...irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients.
We retrospectively collected data on b-MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis.
The medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30–87) years. Eighty-seven patients were aged ≥60 years and 89 patients were aged < 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647–9.481; p = 0.002).
Bone-only MBC patients are more likely to experience an SSE even after treatment with ZA.
Anti‐HER2 therapies are beneficial for patients with HER2‐positive breast or gastric cancer. T‐DM1 is a HER2‐targeting antibody–drug conjugate (ADC) comprising the antibody trastuzumab, a linker, and ...the tubulin inhibitor DM1. Although effective in treating advanced breast cancer, all patients eventually develop T‐DM1 resistance. DS‐8201a is a new ADC incorporating an anti‐HER2 antibody, a newly developed, enzymatically cleavable peptide linker, and a novel, potent, exatecan‐derivative topoisomerase I inhibitor (DXd). DS‐8201a has a drug‐to‐antibody‐ratio (DAR) of 8, which is higher than that of T‐DM1 (3.5). Owing to these unique characteristics and unlike T‐DM1, DS‐8201a is effective against cancers with low‐HER2 expression. In the present work, T‐DM1‐resistant cells (N87‐TDMR), established using the HER2‐positive gastric cancer line NCI‐N87 and continuous T‐DM1 exposure, were shown to be susceptible to DS‐8201a. The ATP‐binding cassette (ABC) transporters ABCC2 and ABCG2 were upregulated in N87‐TDMR cells, but HER2 overexpression was retained. Furthermore, inhibition of ABCC2 and ABCG2 by MK571 restored T‐DM1 sensitivity. Therefore, resistance to T‐DM1 is caused by efflux of its payload DM1, due to aberrant expression of ABC transporters. In contrast to DM1, DXd payload of DS‐8201a inhibited the growth of N87‐TDMR cells in vitro. This suggests that either DXd may be a poor substrate of ABCC2 and ABCG2 in comparison to DM1, or the high DAR of DS‐8201a relative to T‐DM1 compensates for increased efflux. Notably, N87‐TDMR xenograft tumor growth was prevented by DS‐8201a. In conclusion, the efficacy of DS‐8201a as a treatment for patients with T‐DM1‐resistant breast or gastric cancer merits investigation.
What's new?
In certain cancers, amplification and dysregulation of the human epidermal growth factor receptor HER2 is associated with more aggressive disease and worse prognosis, making it an appealing therapeutic target. Of special clinical interest in this regard is the antibody–drug conjugate (ADC) DS‐8201a, which consists of an anti‐HER2 antibody, a peptide linker, and an exatecan‐derivative topoisomerase I inhibitor (DXd). In the current preclinical study with gastric cancer cells, DS‐8201a was found to overcome resistance to T‐DM1, an established HER2‐targeting ADC, by upregulating the ATP‐binding cassette transporters ABCC2 and ABCG2. Moreover, the DS‐8201a Dxd payload successfully inhibited the growth of T‐DMI‐resistant cells.
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