Everolimus-Related Pneumonitis in Patients with Metastatic Breast Cancer: Incidence,Radiographic Patterns,and Relevance to Clinical Outcome

BackgroundThis study investigated the incidence, radiographic patterns, and relevance to clinical outcome of everolimus‐related pneumonitis (ERP) in patients with metastatic breast cancer (MBC).Materials and MethodsData of patients with MBC treated with everolimus who had baseline and at least one follow‐up chest computed tomography (CT) were obtained from a medical electronic database system. An independent review of the CT scans of these patients was conducted by two radiologists ({"type":"clinical-trial","attrs":{"text":"NCT 03730428","term_id":"NCT03730428"}}NCT 03730428). Log‐rank and Cox proportional hazard regression analyses were used for time‐to‐event analyses.ResultsERP was radiographically detected in 45 of 86 patients (52.3%). In more than 80% of these patients, ERP occurred during the first 4 months of everolimus treatment. Only 14 of the 45 patients with ERP were symptomatic (31.1%). Symptoms included cough, fever, and shortness of breath. Bilateral and lower distribution of the pneumonitis was most common. In most of the cases, ground‐glass opacities and reticular opacities were noticed. Elderly patients were more likely to develop ERP. Patients with ERP had significantly longer progression‐free survival (PFS; 6.8 vs. 4.1 months, p = .024) and overall survival (OS; 42.8 vs. 21.3 months, p = .016). ERP was a predictor of OS improvement confirmed by multivariate Cox analysis (hazard ratio, 0.49; 95% confidence interval, 0.25–0.97; p = .040).ConclusionsERP was noted in half of the patients with MBC treated with everolimus. Our data suggested that ERP was associated with improved prognosis and may be used as a biomarker for the efficacy of everolimus in MBC. Close monitoring, prompt diagnosis, and proper treatment for ERP are essential to maintain the quality of life of patients and achieve maximum treatment benefits.Implications for PracticeEverolimus‐related pneumonitis (ERP) is one of the most worrying drug adverse events, especially in Asian patients. However, little has been known about the clinical and radiographic details of ERP in patients with metastatic breast cancers (MBCs) treated with everolimus. The present study investigated the clinical characteristics, radiographic patterns, and its correlation with treatment outcome in patients with MBC. ERP was identified in more than half of patients with MBC during everolimus therapy and was associated with improved outcome. Close monitoring and prompt diagnosis and appropriate treatment for ERP are critical for the preservation of patients'' quality of life and achievement of maximal treatment benefits.     

A Real-World Study on Oral Vinorelbine for the Treatment of Metastatic Breast Cancer

Background: Vinorelbine can be used to treat metastatic breast cancer as a single agent or in combination withother chemotherapy agents, although there is little real-world data for its use, particularly the oral form, in China.The current study aimed to explore the efficacy and safety of oral vinorelbine in patients with metastatic breastcancer in real-world clinical practice. Methods: A total of 194 patients with metastatic breast cancer received oralvinorelbine as a treatment between February 2017 and January 2021 at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciencesand Peking Union Medical College. The efficacy, in terms of progression-free survival and overall survival,and safety of oral vinorelbine were evaluated. Results: At a median follow-up period of 17.0 months, 152 patientsfinally exhibited disease progression, and 55 succumbed to the disease. During the follow-up, 53 patients demonstrated a partial response, and 106 achieved a stable disease, with an objective response rate of 27.3%. Additionally,118 patients demonstrated a partial response or stable disease for ≥24 weeks, with a clinical benefit rate of 60.8%.The median progression-free survival was 6.2 months (95% confidence interval, 5.0–7.4), and the median overallsurvival was not evaluated. No treatment-associated mortalities occurred. The most common adverse eventsincluded leukopenia (73.2%), neutropenia (72.7%), anemia (65.5%), and diarrhea (46.9%). Conclusions: Oral vinorelbine appears to be efficacious for metastatic breast cancer with acceptable toxicity for real-world use in China.     

Treatment‐Related Mortality With Everolimus in Cancer Patients

Introduction.

The overall incidence and odds of fatal adverse events (FAEs) after exposure to everolimus are not well defined. We performed a comprehensive meta-analysis of published randomized controlled trials (RCTs) to determine the role of everolimus in treatment-related mortality in patients with cancer.

Methods.

PubMed databases and abstracts from the proceedings of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium were searched for RCTs of everolimus either alone or in combination with another agent compared with the control arm without everolimus and that reported deaths from an adverse event from January 1966 to July 2013. The primary objective was to determine the difference of FAEs between everolimus-treated patients and control group patients.

Results.

In total, 2,997 patients with multiple solid tumors from nine RCTs were included. The overall incidence of FAEs in cancer patients treated with everolimus was 0.7% (95% CI 0.3%–1.1%) compared with 0.4% (95% CI 0.0%–0.7%) in cancer patients who did not receive everolimus. The odds ratio of FAEs was greater in everolimus-treated patients (Peto odds ratio = 3.80, 95% CI 1.59–9.07, p = .003). In subgroup analyses, no significant difference was found in the incidence or odds of FAEs by everolimus administration (alone or in combination) or tumor type (breast cancer vs. nonbreast cancer; p = .63).

Conclusion.

In patients with cancer, everolimus is associated with a small but significant increase in the odds of a treatment-related fatal events.     

长春瑞滨联合希罗达对蒽环类/紫杉类治疗后复发转移性乳腺癌的疗效观察

目的探讨长春瑞滨联合希罗达方案对蒽环类/紫杉类治疗后晚期复发转移乳腺癌的近期疗效和不良反应。方法40例应用蒽环类/紫杉类治疗后复发转移性乳腺癌患者,长春瑞滨25 mg/m²,静脉快速滴入,第1、8天;希罗达1 000 mg/m²,早晚两次餐后30 min口服,连用14天,21天为1周期,每例患者至少接受2周期的治疗。结果40例患者完全缓解（CR）3例,部分缓解（PR）16例,病情稳定(SD)14例,病情进展（PD）7例,总有效率47.5%,临床获益率为70%,中位疾病进展时间(TTP)为8.5月。常见不良反应为骨髓抑制、消化道反应、手足综合征、神经毒性,少数患者出现口腔炎、头晕、乏力和胸闷等。结论长春瑞滨联合希罗达方案对紫杉/蒽环类治疗后复发转移乳腺癌疗效确切。治疗过程中患者耐受性好,不良反应轻。     

Aggressive Subsets of Metastatic Triple Negative Breast Cancer

BackgroundRelative to other metastatic breast cancer subtypes, metastatic triple-negative breast cancer (mTNBC) has a shorter duration of response to therapy and worse overall survival. Among patients with mTNBC, it is hypothesized that inflammatory breast cancer (IBC) and young women have particularly aggressive phenotypes. We investigated clinical and cell-free DNA (cfDNA) characteristics of inflammatory-mTNBC and young-mTNBC.Patients and MethodsWe evaluated 158 patients with mTNBC who were stratified into 3 groups: (1) IBC; (2) patients aged 45 years or younger at primary diagnosis without IBC (non-IBC young); and (3) patients over age 45 at diagnosis without IBC. We evaluated clinicopathologic characteristics, sites of metastasis, survival outcomes, and the fraction of DNA in circulation derived from tumor (TFx).ResultsAnalysis of metastatic sites revealed that young patients without IBC had the most frequent lung metastases (P = .002). cfDNA analyses of first sample showed that TFx was highest in the non-IBC young group but not elevated in the IBC group (analysis of variance P = .056 for first TFx). Individually, median overall survival from metastatic diagnosis for the IBC group was 15.2 months; for the non-IBC young group, 21.2 months, and for the non-IBC over 45 group, 31.2 months. Patients with IBC and young patients without IBC had worse prognosis relative to patients over 45 without IBC (log-rank P = .023).ConclusionsAmong patients with mTNBC in this single-institution cohort, patients with IBC and young patients without IBC had significantly worse overall survival compared with patients over 45 without IBC. Young patients without IBC had significantly higher cfDNA TFx, whereas patients with IBC did not have elevated TFx despite a poor prognosis. These findings demonstrate that further analyses of mTNBC subsets are warranted.     

Effect of Surgery at Primary and Metastatic Sites in Patients With Stage IV Breast Cancer

BackgroundThere is no clear evidence of a survival benefit of resection of the primary tumor, or distant site resection (metastasectomy) in patients with stage IV breast cancer.Patients and MethodsThis retrospective analysis of stage IV breast cancer using the National Cancer Database. To evaluate variables associated with surgery at the primary site, we used univariate analyses followed by multivariate logistic regression. Consequently, we evaluated the impact of lumpectomy, mastectomy or metastasectomy on survival by conducting multivariate Cox regression survival analyses on the following groups: all stage IV patients; a subset of those with only one metastatic site; and another subset with metastasis to multiple distant sites.ResultsA total of 54,871 stage IV breast cancer patients were included in this analysis. Variables associated with the use of surgery at the primary were: age, race, Charlson/Deyo score, insurance and facility type, involved breast quadrant, receptor status, N stage, extent of metastasis, and year of diagnosis. Survival analysis showed that both lumpectomy (median overall survival [OS], 45 months) and mastectomy (median OS, 44 months) were associated with better OS compared to no surgery (median OS, 22 months). The statistical effect was larger in the subgroup with metastasis to one site, but still significant in the subgroup with multiple metastatic sites. Distant site resection also yielded a survival benefit.ConclusionIn patients with metastasis to only one site, metastasectomy was associated with better OS when that site was the liver, lung, or brain.     

Economic Analysis of Psychosocial Group Therapy in Women with Metastatic Breast Cancer

Purpose

Metastatic breast cancer is associated with psychological distress in one-third of patients. We examined the impact of group psychosocial support on health care costs in metastatic breast cancer. Psychosocial interventions have been shown to reduce psychological distress in these patients. In other diseases, depression and anxiety have been associated with higher health care system resource utilization.

Methods

Data on health care system resources utilization were collected as part of a Canadian multicenter randomized controlled trial of a supportive-expressive group support in metastatic breast cancer. Costs were obtained from one tertiary care hospital in Toronto. A cost minimization analysis was conducted since there was no survival difference; the primary endpoint of the study. Cost-effectiveness analyses were conducted for mood and pain.

Results

Total health care utilization costs (including costs of the group therapy intervention) for the intervention and control groups were $31,715 and $28,189, respectively per patient. The difference in total costs between groups ($3,526) was not statistically significant (P = 0.53). The cost-effectiveness analysis for mood showed the intervention group to have an increased cost of $5,550 per patient for an effect size of 0.5 on the POMS scale. The corresponding cost for pain was $4,309. An exploratory analysis on patients who were more distressed at baseline showed a non-significant decrease in cost in favor of the intervention arm (difference of $3,911 P = 0.66).

Conclusion

Psychosocial intervention, in the form of supportive-expressive group support for metastatic breast cancer, does not lower health care system resource utilization.     

Impact of Her-2 Overexpression on Survival of Patients with Metastatic Breast Cancer

Introduction: Breast cancer is a complex and heterogeneous disease which is increasingly important as a public health problem. In Brazil, 57,960 new cases have been estimated to be the burden in 2016 and 2017. Despite advances in early diagnosis and therapy, approximately 20-30% of patients, even with early stage lesions, will develop distant metastatic disease. Tumors with similar clinical and pathological presentations may have differing behavior, so it is important to understand specific biological characteristics. Objective: To investigate tumor markers of primary tumors featuring pleural metastasis to identify organ-specific characteristics of metastatic breast cancer. Methods: In a historical cohort study, immunohistochemistry was performed on cell blocks of neoplastic pleural effusions and results were compared with clinicopathological data. Results: The median survival time with Her-2 overexpression in malignant pleural effusions was 2.2 months, whereas cases without overexpression survived, on average, for seven months (p = 0.02). Conclusions: We emphasize that metastases may behave independently of primary tumors, but the present results indicate that therapeutic agents targeting Her-2 overexpression could increase survival in metastatic breast cancer cases.     

miRNA-29在正常乳腺、原发性乳腺癌及转移性乳腺癌组织中的表达意义

目的 探讨微小RNA-29 (miRNA-29)在正常乳腺、原发性乳腺癌以及转移性乳腺癌组织中的表达,并分析miRNA-29、基质金属蛋白酶-2(MMP-2)在疾病发生与进展中的作用.方法 选取286例乳腺癌患者,其中原发性乳腺癌205例,转移性乳腺癌81例,同期选取150例无乳腺疾病的健康妇女为对照组.采用RT-PCR检测miRNA-29与MMP-2表达水平.结果 三组乳腺标本中miRNA-29与MMP-2水平比较差异均具有统计学意义(P＜0.05),其miRNA-29与MMP-2表达呈负相关性,而肿瘤大小、病理分期、HER-2及ki-67均与miRNA-29表达具有密切相关性(P＜0.05).结论 miRNA-29与乳腺癌的发生、发展与转移等过程均具相关性,明确其表达水平有助于病情评估及临床治疗.     

Eribulin Monotherapy in Patients Aged 70 Years and Older With Metastatic Breast Cancer

Purpose.

Following the demonstrated efficacy and safety of eribulin mesylate in heavily pretreated patients with metastatic breast cancer, an exploratory analysis was performed to investigate the effect of age in these patients.

Methods.

Data were pooled from two single-arm phase II studies and one open-label randomized phase III study in which patients received eribulin mesylate at 1.4 mg/m² as 2- to 5-minute intravenous infusions on days 1 and 8 of a 21-day cycle. The effect of age on median overall survival (OS), progression-free survival (PFS), overall response rate (ORR), clinical benefit rate (CBR), and incidence of adverse events (AEs) was calculated for four age groups (<50 years, 50–59 years, 60–69 years, ≥70 years).

Results.

Overall, 827 patients were included in the analysis (<50 years, n = 253; 50–59 years, n = 289; 60–69 years, n = 206; ≥70 years, n = 79). Age had no significant impact on OS (11.8 months, 12.3 months, 11.7 months, and 12.5 months, respectively; p = .82), PFS (3.5 months, 2.9 months, 3.8 months, and 4.0 months, respectively; p = .42), ORR (12.7%, 12.5%, 6.3%, and 10.1%, respectively), or CBR (20.2%, 20.8%, 20.4%, and 21.5%, respectively). Although some AEs had higher incidence in either the youngest or the oldest subgroup, there was no overall effect of age on the incidence of AEs (including neuropathy, neutropenia, and leukopenia).

Conclusion.

Eribulin monotherapy in these selected older patients with good baseline performance status led to OS, PFS, ORR, CBR, and tolerability similar to those of younger patients with metastatic breast cancer. The benefits and risks of eribulin appear to be similar across age groups.     

nab-Paclitaxel for the Treatment of Aggressive Metastatic Breast Cancer

Despite advances in early diagnosis, prevention, and treatment, breast cancer remains the second-leading cause of cancer-related deaths in women. The 5-year survival rate for patients with metastatic breast cancer (MBC) is just 24%. However, some forms of MBC appear to be more aggressive than others. Triple-negative breast cancer (TNBC; lacking overexpression of human epidermal growth factor receptor 2 [HER2] and expression of estrogen and progesterone receptors) and breast cancers that overexpress HER2 are the 2 biologically defined subtypes with the worst prognoses. Although a number of effective options have been developed for the treatment of HER2-overexpressing disease, TNBC remains a difficult-to-treat subtype. In addition to hormone receptor and HER2 status, multiple other factors are predictive of relatively poorer clinical outcomes, including visceral metastasis, short disease-free interval between the end of treatment for early-stage disease and diagnosis of MBC, and higher number of metastatic sites. There is an urgent need to improve therapy for patients with aggressive forms of breast cancer. Taxanes are considered among the most active classes of compounds against breast cancer. This review specifically examines the clinical trials in which nab-paclitaxel was used to treat patients with MBC and factors associated with poor prognosis.     

去甲长春花碱联合顺铂治疗转移性乳腺癌

目的：观察去甲长春花碱（vinorelbine,NVB)联合顺铂（cisplatin,DDP)治疗转移性乳腺癌的疗效及不良反应,方法：采用NVB25mfg/m^2d1.8DDP30mg/m^2d1-3,每3周重复一次,共用2－4周期。结果：40例患者中有效率45％（18／40）,CR2．5％（1／40）,PR42．5％（17／40）,主要剂量限制不良反应是白细胞减少（Ⅲ、Ⅳ度27．5％）,结论：NVB联合DDP治疗转移性乳腺癌有较好的疗效,且阿霉素和／或泰素治疗失败的患者亦有较好的疗效,不良反应中耐受。     

Patterns and Predictors of First-Line Taxane Use in Patients with Metastatic Triple-Negative Breast Cancer in US Clinical Practice

We investigated first-line (1L) treatment patterns and predictors of taxane use to better understand the evolving metastatic triple-negative breast cancer (mTNBC) treatment landscape. This retrospective analysis of the Truven Health MarketScan^® (Somers, NY, USA) Database included women with mTNBC who received 1L therapy within six months of diagnosis (January 2005–June 2015). Multivariate logistic regression models identified predictors of taxane use, adjusting for prognostic factors. A total of 2271 women with newly diagnosed mTNBC received 1L treatment during the study period. Half received a 1L taxane (53%), more often in combination than as monotherapy (58% versus 42%), though this varied by specific taxane. Nab-Paclitaxel monotherapy increased substantially after 2010. More recent treatment year (odds ratio, 2.16 (95% CI 1.69–2.76]) and number of metastases (≥3 versus 1: 1.73 (1.25–2.40)) predicted taxane monotherapy versus combination. Having a health maintenance organization versus a preferred provider organization plan predicted less nab-paclitaxel versus paclitaxel (0.32 (0.13–0.80)) or docetaxel (0.30 (0.10–0.89)) use. More recent index year (2011–2015 vs. 2005–2010) was the only predictor favoring nab-paclitaxel versus paclitaxel (2.01 (1.26–3.21)) or docetaxel (3.63 (2.11–6.26)). Taxane-containing regimens remained the most common 1L mTNBC treatments. Paclitaxel and nab-paclitaxel use changed substantially over time, with nab-paclitaxel use associated with insurance coverage.     

Phase II Study of Paclitaxel and Dasatinib in Metastatic Breast Cancer

Background

Overexpression and activation of tyrosine kinase Src has been linked to breast carcinogenesis and bone metastases. We showed the feasibility of combining the SRC inhibitor dasatinib with weekly paclitaxel in patients with metastatic breast cancer (MBC) and herein report the subsequent phase II trial.

中等剂量卡培他滨单药治疗转移性乳腺癌的疗效及安全性

目的观察中等剂量［2 000 mg/(m²·d)］卡培他滨治疗转移性乳腺癌的疗效和不良反应。方法卡培他滨单药治疗43例转移性乳腺癌,2000 mg/(m²·d),d1～14,每3周为1周期。结果43例患者平均行8周期卡培他滨治疗,客观缓解率（CR+PR）为18.6%,临床获益率（CR+PR+SD）为86.0%。整体的中位无进展生存期（PFS）为7.1月（95%CI：5.8～8.4）,在一线治疗、二线治疗和三线及以上治疗亚组中差异无统计学意义,分别为7.1月、6.1月和8.1月（P=0.390）。在蒽环类药物与紫杉类药物治疗均失败的患者中,PFS明显缩短（6.1月 vs.7.1月,P=0.038）。大于65岁的患者PFS显著延长（8.1月 vs.6.1月,P=0.045）。主要不良反应为手足综合征19例（44.2%）。结论中等剂量［2 000 mg/(m²·d)］卡培他滨单药治疗转移性乳腺癌安全、有效。     

Variation in the Attitudes of Medical Oncologists Toward Research Biopsies in Patients With Metastatic Breast Cancer

Background.

Tissue from research biopsies provides access to insights into tumor biology. We aimed to determine medical oncologists’ (MOs’) attitudes toward research biopsies in patients with metastatic breast cancer (MBC).

Materials and Methods.

A total of 309 breast MOs from National Cancer Institute (NCI)-designated cancer centers were invited to complete a self-administered survey about their attitudes toward approaching patients for research purpose-only biopsies (RPOBs), performed as a standalone procedure, or additional biopsies, performed with a clinically indicated biopsy. The MOs were asked to predict what proportion of their MBC patients would consider undergoing research biopsies.

Results.

Of the 309 MOs, 221 (72%) responded. Of these 221 MOs, 30 were ineligible, leaving 191 eligible responders. Nearly all the MOs reported they were comfortable approaching patients regarding research biopsies of blood or skin. One fifth of MOs were uncomfortable approaching patients for RPOBs of the breast. One half of MOs were uncomfortable approaching patients for RPOBs of the liver. A significant variation was found in the perceptions by MOs of their patients’ willingness to undergo research biopsies. The factors associated with increased comfort in approaching patients for research biopsies included fewer years in practice, caring for patients who had undergone recent research biopsies, and the predicted willingness of patients to consent to biopsies. The risk of a biopsy and biopsy-related pain were the most common reasons for reluctance to refer patients for research biopsies.

Conclusion.

Significant variation exists, even at NCI centers, in the comfort level of MOs in approaching MBC patients for research biopsies. MOs’ attitudes toward research biopsies might be a modifiable factor in increasing tissue collection for research.

Implications for Practice:

Tissue-based research is critical in advancing our understanding of cancer biology, and obtaining tissue from a research biopsy provides an essential resource. This study demonstrates the variability of oncologists’ attitudes toward research biopsies and elicits factors associated with increased comfort levels with approaching patients for research biopsies. Biopsy risk and biopsy-related pain were commonly cited reasons not to refer patients for research biopsies. If the risk of a research biopsy is deemed sufficiently low enough to be acceptable, oncologists’ attitudes might be a potential target for education and change, which may assist in increasing the availability of tissue for cancer research.