Endocrine treatment in breast cancer: Cure,resistance and beyond

Hormone receptor positive breast cancer (HR-positive BC) is the most frequent BC subtype (∼70%), with endocrine treatment constituting its therapeutic cornerstone; despite its efficacy, endocrine resistance can develop, clinically as a relapse or a progression of the early or advanced disease respectively, hence necessitating alternative treatments. Over the last two decades, improved understanding of the molecular mechanisms of endocrine resistance has been achieved, with numerous targeted agents undergoing clinical development. Despite the multifactorial genesis of endocrine resistance, fuelled not only by alternative oncogenic signaling pathways of tumor cells, but also by tumor microenvironment-mediated mechanisms, successful clinical development of new agents has been recently noted. However, predictive biomarkers for accurate ‘navigation’ across the different treatment options are urgently needed. In this article, we present a thorough overview of the different clinical scenarios of BC endocrine resistance, and the recent advances in endocrine treatment, we describe the basic molecular mediators of endocrine resistance and the respective targeted agents undergoing clinical development; finally, we provide our perspective on the future of BC endocrine treatment.     

Weekly paclitaxel infusion as salvage therapy in ovarian cancer

The majority of women diagnosed with epithelial ovarian cancer will have persistent or recurrent disease after initial treatment. We evaluated response and toxicity in women with advanced stage disease given salvage paclitaxel as a low-dose, weekly infusion. We performed a retrospective review of 22 women with advanced stage epithelial ovarian (19 women) or primary peritoneal carcinoma (3 women) who had received low-dose, weekly paclitaxel salvage therapy. All women had refractory, persistent, or recurrent disease following first-line treatment with paclitaxel and platin chemotherapy. Response and toxicity were assessed. Measurable disease present on physical or radiologic exam and serum carbohydrate antigen-125 levels were used to assess disease response. Overall response rate to low-dose, weekly paclitaxel salvage therapy was 50% (27% complete, 23% partial). Median progression-free interval (PFI) in responders was 27 weeks (range, 14-68 weeks). Stabilization of disease occurred in an additional 27% of patients with a median PFI of 22 weeks (range, 15-89 weeks). No difference in response was detected between the 7 women with platin-sensitive disease and the 15 women with platin-resistant disease (P=0.19). The median dose of paclitaxel was 80 mg/m² (range, 60-80 mg/m²). During a total of 325 weeks of paclitaxel treatment (median per patient, 12 weeks; range, 6-49 weeks), 13 treatment delays occurred (hematologic indication, 9; nonhematologic indication, 4). No cases of grade 4 hematologic toxicity, sepsis, or worsening neuropathy were documented. Weekly paclitaxel infusion given as salvage therapy results in significant clinical response, even in women previously treated with paclitaxel. The regimen is well tolerated with no cases of grade 4 neutropenia or worsening neuropathy in our population.     

Treatment of late sequelae after radiotherapy for head and neck cancer

Radiotherapy (RT) is used to treat approximately 80% of patients with cancer of the head and neck. Despite enormous advances in RT planning and delivery, a significant number of patients will experience radiation-associated toxicities, especially those treated with concurrent systemic agents. Many effective management options are available for acute RT-associated toxicities, but treatment options are much more limited and of variable benefit among patients who develop late sequelae after RT. The adverse impact of developing late tissue damage in irradiated patients may range from bothersome symptoms that negatively affect their quality of life to severe life-threatening complications. In the region of the head and neck, among the most problematic late effects are impaired function of the salivary glands and swallowing apparatus. Other tissues and structures in the region may be at risk, depending mainly on the location of the irradiated tumor relative to the mandible and hearing apparatus. Here, we review the available evidence on the use of different therapeutic strategies to alleviate common late sequelae of RT in head and neck cancer patients, with a focus on the critical assessment of the treatment options for xerostomia, dysphagia, mandibular osteoradionecrosis, trismus, and hearing loss.     

A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity

Background and purpose

This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2 years after radiotherapy.

Materials and methods

A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer.

Results

Quantile–quantile plots show more associations at the P < 5 × 10⁻⁷ level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients. However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts.

Conclusions

This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable.     

肾癌靶向治疗的常见不良反应及其治疗策略

 随着对肾癌(RCC)分子机制研究的深入,针对血管内皮生长因子（VEGF）及其受体等为靶点的肾癌靶向治疗药物取得重大进展,极大改善了进展期或转移性肾癌患者的预后。但临床试验表明,靶向治疗药物会导致高血压、骨髓抑制、肺炎等药物相关性不良反应,临床中及时发现并采取有效干预措施,对改善患者生活质量和提高靶向治疗效果尤为重要。     

厄洛替尼相关性皮疹及其临床诊治

厄洛替尼是一种高效、高特异性、可逆的表皮生长因子受体酪氨酸激酶抑制剂(EGFRTKI),通过抑制EGFR(HER1)的自身磷酸化,从而抑制下游信号传导与细胞增殖.临床研究表明,厄洛替尼对多种实体肿瘤具有较好的治疗疗效.厄洛替尼相关性皮疹是常见的不良反应,直接干扰了患者的正常治疗,严重影响生活质量甚至可导致治疗中断.有效的评估和治疗患者皮疹反应具有积极的意义.     

Mortality and cancer incidence following radiotherapy for seminoma of the testis

From the records of the Thames Cancer Registry, 859 patients were identified, who were treated with radiotherapy for seminoma of the testis between 1961 and 1985. Second cancer incidence and mortality and also causes of non-cancer deaths in the study population were examined. Fifty-one (6%) patients died of testicular cancer, 42 within 5 years of diagnosis. There were 42 second cancers (other than second testicular cancers), and 20 deaths from second cancer (expected, 22.1 — non-significant). The only subtype of cancer with a notable excess was leukaemia (4 incident cases observed; 0.64 expected; relative risk 6.2, 95%) C.I., 2.7–14.8, 95% C.I., 2.7–14.7). The overall death rate from causes other than testicular cancer was not elevated (82 observed, 82.06 expected). There was some suggestion of an increase in the risk of mortality with time; for 10 or more years after treatment the relative risk was 1.31 (95% C.I., 0.95–1.81). There was no evidence of excess non-cancer deaths (62 observed, 60 expected). We conclude that there is no definite evidence from this investigation of increased risk of mortality secondary to radiotherapy; however, the excess incidence of leukaemia may be treatment-related and the cohort will be followed further.     

Differences in cancer drug assessment between Spain and the United Kingdom

ObjectivesThere is no Spanish Government agency resembling the National Institute for Health and Care Excellence (NICE) in the United Kingdom (UK) that carries out a centralised evaluation and makes decisions about funding. Therefore, we aim to assess the differences between NICE and the Spanish bodies in terms of their respective processes. We compare the decisions concerning cancer drugs in the assessments made by NICE/Single Technology Appraisal with assessments made by MADRE methodology.MethodsWe included all cancer drugs assessed by NICE and all MADRE reports made using a shared reports process (GENESIS) and reports from Catalonia (CAMDHA) and Andalucía (GFTHA). We compared the number of drugs assessed, the decisions taken by NICE and Spanish organizations and timelines.ResultsBetween January 2011 and December 2013 NICE appraised 24 cancer drugs. In Spain, 44 reports were produced using MADRE methodology. For the 14 drugs assessed by both NICE and Spanish bodies, NICE rejected a high proportion of the drugs (50% versus 26%). GENESIS, with a median of 8 months, made decisions more quickly than NICE (13.5 months) and GFTHA (17 months). The slowest organisation was CAMDHA (24.5 months).ConclusionsMore drugs are assessed in Spain than by NICE because there are more organisations in Spain doing this work and their processes are simpler. NICE rejects more drugs as it uses cost-effectiveness thresholds that lead to a ‘not-recommended’ decision, and Spanish bodies recommend cancer drugs for subgroups of patients where better results can be obtained. Timelines are better for Spanish Committees, probably because of the greater number of steps in the appraisal process by NICE.     

The effectiveness of radiotherapy in preventing disease recurrence after breast cancer surgery

Background and objectivesThe locoregional management of breast cancer has a critical impact on prognosis. This study aimed to analyze the effectiveness of radiotherapy against the deleterious effect of positive surgical margins on disease outcomes.MethodsRetrospective, single-center study enrolled 721 breast cancer patients with a median follow-up of approximately 64.50 months (3.67–247.40). Analyses were performed considering the end of adjuvant therapy, except endocrine therapy. Kaplan-Meier and Cox regression were performed to obtain the predictive value of treatments.ResultsThe minimally adequate radiotherapy (≥45 cGy) was associated with improved outcomes in breast cancer patients compared to inadequate radiotherapy (<45 cGy/no) by controlling locoregional relapses and distant metastasis. In patients with positive surgical margins (n = 53), radiotherapy was associated with an approximate decrease of 90% in locoregional relapse risk [adjusted HR: 0.108 (0.012–0.932), p = 0.043]. Radiotherapy did not alter the adverse effect of positive surgical margins, especially in patients with a higher risk of poorly differentiated tumors (n = 146), presence of lymphovascular invasion (n = 163), and triple-negative subtype (n = 113). Notwithstanding, radiotherapy was associated with respective decreases of distant metastasis risk of 75.2% [adjusted HR: 0.248 (0.081–0.762), p = 0.015] and 67.8% [adjusted HR: 0.322 (0.101–1.029), p = 0.056] in patients with triple-negative tumors or with lymphovascular invasion.ConclusionAdequate radiotherapy is associated with better outcomes in breast cancer. Despite improving locoregional relapse-free survival, radiotherapy does not ablate positive surgical margins, a factor of poorer prognosis that prevails mainly in patients with factors of higher relapse risk.     

放疗同期IP方案化疗治疗局部晚期食管癌临床研究

目的探讨放疗同期IP方案化疗治疗局部晚期食管癌的临床疗效及毒性反应。方法 68例局部晚期食管癌患者随机分为IP方案同期放疗组(研究组)35例和单纯放疗组(对照组)33例, 两组放疗均采用常规分割放射治疗, 总剂量60Gy, 化疗采用放疗第一天开始伊立替康(国产艾力):65mg/m² ivgtt第1、8天;DDP:30mg/m² ivgtt第1、8天, 每21天为一周期, 共四周期。结果 研究组治疗晚期食管癌缓解率(91.4%)明显优于单放组(66.7%), 两年总生存率及一、二年的无疾病进展生存率前者也明显高于后者, 具统计学意义(P＜0.05);IP方案组恶心呕吐、骨髓抑制(白细胞减少)和腹泻的发生率高于单放组。结论 IP方案化疗同期放疗治疗局部晚期食管癌疗效肯定, 能提高生存率, 但毒副反应增加, 患者可耐受, 值得临床推广应用。     

紫杉类药物在乳腺癌治疗中的耐药机制

目前研究提示紫杉类耐药可能与多药耐药相关蛋白(MRP)表达增高、Ⅲβ-微管过表达、微管相关蛋白tau的过表达有关,而与HER2的表达成负相关.针对这些耐药靶点可逆转或者延缓紫杉类药物耐药的发生,为临床上更好地使用紫杉类药物提供一定参考.     

晚期非小细胞肺癌厄洛替尼耐药研究进展

酪氨酸激酶抑制剂(TKI)厄洛替尼作为晚期非小细胞肺癌(NSCLC)靶向治疗药物,延长了患者的生存时间,但其耐药性的发生成为其进一步应用的瓶颈.现已证实T790M突变、KRAS突变、c-met癌基因扩增在耐药机制中起重要作用.针对不同耐药机制,第2代TKI的应用、再次应用化疗或厄洛替尼以及针对失败模式进行后续治疗等多项临床试验不断开展.     

Changes in biologic markers of oxidative stress and plasma endotoxin levels in gynecologic cancer patients treated with pelvic radiotherapy: a pilot study

Objective

We conducted a pilot study to evaluate the effects of pelvic radiotherapy on biologic markers of oxidative stress and plasma endotoxin levels, and to assess the relationship between the changes of such factors and radiotherapy-related complications.

Methods

Twelve gynecologic cancer patients who were treated via pelvic radiotherapy with or without concurrent chemotherapy were enrolled in this study. Biologic markers of oxidative stress, such as glutathione (GSH) and oxidized glutathione (GSSG), as well as endotoxin levels, were measured weekly during treatment. Subjective symptoms were assessed using the Korean version of the EORTC QLQ-C30 at the baseline and on the 5th week of radiotherapy.

Results

No changes were noted in the level of GSH in whole blood, but the GSH/GSSG ratio was reduced dramatically after the initiation of radiotherapy. The mean plasma endotoxin for all patients tended to increase and persisted during radiotherapy, and the number of patients who evidenced clinically significant endotoxin levels (defined as >0.005 EU/mL) also increased. Nausea/vomiting and diarrhea were significantly changed (p=0.019 and p<0.001, respectively). A significant relationship was noted to exist between the changes in the endotoxin level and nausea/vomiting (p=0.001). However, such symptoms did not correlate with the changes of oxidative stress markers.

Conclusion

Pelvic radiotherapy oxidized the GSH redox system and increased plasma endotoxin. Further investigations containing interventional and longitudinal studies will be required to assess the effects of the changes in oxidative stress markers and endotoxin on radiotherapy-related adverse events.     

Radiotherapy for rectal cancer is associated with reduced serum testosterone and increased FSH and LH

PURPOSE: It is known that scattered radiation to the testes during pelvic radiotherapy can affect fertility, but there is little knowledge on its effects on male sex hormones. The aim of this study was to determine whether radiotherapy for rectal cancer affects testosterone production. METHODS AND MATERIALS: All male patients who had received adjuvant radiotherapy for rectal cancer from 1993 to 2003 were identified from the Norwegian Rectal Cancer Registry. Patients treated with surgery alone were randomly selected from the same registry as control subjects. Serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and sex hormone binding globulin (SHBG) were analyzed, and free testosterone was calculated (N = 290). Information about the radiotherapy treatment was collected from the patient hospital charts. RESULTS: Serum FSH was 3 times higher in the radiotherapy group than in the control group (median, 18.8 vs. 6.3 IU/L, p <0.001), and serum LH was 1.7 times higher (median, 7.5 vs. 4.5 IU/l, p <0.001). In the radiotherapy group, 27% of patients had testosterone levels below the reference range (8-35 nmol/L), compared with 10% of the nonirradiated patients (p <0.001). Irradiated patients had lower serum testosterone (mean, 11.1 vs. 13.4 nmol/L, p <0.001) and lower calculated free testosterone (mean, 214 vs. 235 pmol/L, p <0.05) than control subjects. Total testosterone, calculated free testosterone, and gonadotropins were related to the distance from the bony pelvic structures to the caudal field edge. CONCLUSIONS: Increased serum levels of gonadotropins and subnormal serum levels of testosterone indicate that curative radiotherapy for rectal cancer can result in permanent testicular dysfunction.     

Skeletal sequelae of cancer and cancer treatment

Introduction  Survivors of cancer may experience lingering adverse skeletal effects such as osteoporosis and osteomalacia. Skeletal disorders are often associated with advancing age, but these effects can be exacerbated by exposure to cancer and its treatment. This review will explore the cancer and cancer treatment-related causes of skeletal disorders. Methods  We performed a comprehensive search, using various Internet-based medical search engines such as PubMed, Medline Plus, Scopus, and Google Scholar, for published articles on the skeletal effects of cancer and cancer therapies. Results  One-hundred-forty-two publications, including journal articles, books, and book chapters, met the inclusion criteria. They included case reports, literature reviews, systematic analyses, and cohort reports. Skeletal effects resulting from cancer and cancer therapies, including hypogonadism, androgen deprivation therapy, estrogen suppression, glucocorticoids/corticosteroids, methotrexate, megestrol acetate, platinum compounds, cyclophosphamide, doxorubicin, interferon-alpha, valproic acid, cyclosporine, vitamin A, NSAIDS, estramustine, ifosfamide, radiotherapy, and combined chemotherapeutic regimens, were identified and described. Skeletal effects of hyperparathyroidism, vitamin D deficiency, gastrectomy, hypophosphatemia, and hyperprolactinemia resulting from cancer therapies were also described. Discussion/Conclusions  The publications researched during this review both highlight and emphasize the association between cancer therapies, including chemotherapy and radiotherapy, and skeletal dysfunction. Implications for cancer survivors  These studies confirm that cancer survivors experience a more rapid acceleration of bone loss than their age-matched peers who were never diagnosed with cancer. Further studies are needed to better address the skeletal needs of cancer survivors.