Indications for cytostatic therapy in metastatic breast cancer.

Generalized breast cancer is always incurable. The heterogeneity of this disease is reflected by wide variation in treatment response and survival duration. No well-defined factors have been found which can distinguish the patients most likely to benefit from chemotherapy. No superior drug combination or schedule has been convincingly established, and basic facts on quality of life issues are still lacking. The most important treatment goal is to provide meaningful palliation for the individual patient. Indications for chemotherapy are life-threatening disease, distant metastases in receptor-negative disease, and clinically hormone resistant disease. In future trials the importance of potentially relevant biological factors for treatment should be evaluated, and such analyses should, at least partly, replace the presently conducted phase II and phase III studies.     

乳腺癌骨转移疼痛的综合治疗

目的　探讨缓解乳腺癌骨转移疼痛 ,恢复患者活动能力的方法。方法　 31例乳腺癌骨转移患者采用以CMFP或CAFP方案化疗为主 ,辅以放射性同位素或双磷酸盐类药物综合治疗 ,观察治疗后疼痛缓解、活动能力恢复及骨外转移灶的变化情况。结果　全组骨痛缓解率为 87.1 % (2 7/ 31 ) ,功能活动恢复 85 .7% (6/ 7) ,骨外转移灶的有效率为 67.9% (1 9/ 2 8)。结论　以化疗为主的综合治疗 ,不仅能较好地控制骨外转移灶的发展 ,而且能显著地缓解骨痛 ,恢复患者的活动能力     

Capecitabine maintenance therapy for XT chemotherapy-sensitive patients with metastatic triple-negative breast cancer

Objective： To investigate the efficacy and safety of capecitabine maintenance therapy（MT） after initial capecitabine plus docetaxel（XT） chemotherapy in patients with metastatic triple-negative breast cancer（m TNBC）.
Methods： Fifty-five m TNBC patients treated with XT chemotherapy between May 2007 and June 2013 were retrospectively analyzed. When initial disease control was achieved by the combination chemotherapy, capecitabine was continued for 32 patients（MT）, while 23 patients remained without any treatment（nonMT）. We compared progression-free survival（PFS） and safety of both groups.
Results： The median PFS of 55 patients was 8.1 months, overall median PFS time of 32 patients in the capecitabine MT group and 23 in the non-MT group was 10.1 vs. 6.7 months（P=0.032）, respectively. When compared PFS time of maintenance treatment, single-agent capecitabine prolonged PFS by 7.1 months, for non-MT patients, the PFS without any treatment was 3.1 months, and this between-group difference was statistically significant（P=0.003）. Adverse events, including of hematologic toxicity, gastrointestinal toxicities, hand-foot syndrome and abnormal liver function were not significantly different between two groups.
Conclusions： After initial disease control was achieved with the XT combination chemotherapy, capecitabine MT can significantly prolong PFS time with a favorable safety profile in m TNBC patients.     

Personalizing therapy for metastatic breast cancer

Treatments for metastatic breast cancer are increasingly tailored towards individual tumor biology. For tumors that overexpress HER2, progressing on trastuzumab and lapatinib, a range of active agents including pertuzumab, neratinib and trastuzumab-MCC-DM1, have demonstrated activity when combined with trastuzumab. In HER2-normal metastatic breast cancer, recent studies suggest that the addition of bevacizumab to first-line chemotherapy improves progression-free survival irrespective of choice of cytotoxic agent. Another interesting area of investigation is the inhibition of poly-ADP-ribose polymerase, an enzyme important for DNA repair. This strategy may be particularly effective in patients with inherited defects in DNA repair or by the co-administration of DNA damaging cytotoxic chemotherapy. This article covers key new areas of systemic therapy for MBC from the American Society of Clinical Oncology 2009 annual meeting.     

晚期转移性乳腺癌内分泌治疗进展

晚期转移性乳腺癌患者由于体质差,对二次手术和化疗一般不能耐受.内分泌治疗由于副作用小,缓解率高,为广大医患所接受,特别是雌激素受体(ER)或孕激素受体(PR)阳性的患者,其治疗效果甚至优于化疗.由于雌激素来源的不同,绝经前后内分泌治疗药物选择有所不同.现综述晚期转移性乳腺癌内分泌治疗的现状.     

Chemo-hormonal therapy for metastatic breast cancer patients: Treatment strategy

In spite of major advances in screening, surgery, radiation therapy, endocrine and chemotherapy (CT) for patients with early-stage breast cancer (BC), there has been only a modest progress in improving survival for women with metastases. Almost all MBC patients are ultimately candidates for systemic therapy, either hormonal or CT. The choice of therapy depends on the disease free interval from the end of adjuvant therapy, whether or not the patient is symptomatic and, if so, the severity these symptoms; and whether the tumour is hormone receptor positive or negative. Standard first-line chemotherapy consists of anthracyclines plus or minus a taxane depending on the end point of treatment. A recently published individual patient’s data metanalysis confirms this concept. Taxane-based combinations were significantly better than A-based combinations in terms of response rate (RR) and progression free survival, but not in terms of survival. Polichemotherapy remain indicated if the end point is citoreduction of high tumour burden. Single agent taxane and single agent A are equivalent in term of RR and overall survival (OS) and are prescribed if the end point is the control of disease and prolongation of survival. First line aromatase inhibitors (steroidal or non-steroidal) and subsequent fulvestrant or an AI of the opposite class is an appropriate sequence for the treatment of advanced endocrine responsive disease. The benefit of an angiogenetic therapy with the scope of blocking certain critical pathways for tumoural cells (for example angiogenesis), has recently been confirmed in at least 2 phase III trials comparing CT with or without bevacizumab. The near future will tell us if a new scenario will become standard in clinical practice.     

Potential predictive factors for response to weekly paclitaxel treatment in patients with metastatic breast cancer

The authors compare results obtained from weekly paclitaxel treatment in advanced breast cancer patients with biological and clinical prognostic factors. Expression of c-erbB-2, Ki-67, p53 and hormone receptors (HR) was examined by immunohistochemistry in samples of breast tissue from 30 patients. Univariate analysis showed that Ki-67 positivity and low performance status (PS) were associated with poor outcome (P <0.05). We observed that expression of p53 and c-erbB-2 did not have any negative effect on response to chemotherapy and survival. HR-negative patients had better response and slightly statistically significant overall survival (OS) rates compared to HR-positive patients (P >0.05). In a multivariate analysis low PS was the only significant predictor of shorter survival (P <0.05). In conclusion, while the expression of p53 and c-erbB-2 did not have any effect on treatment results, negative Ki-67 expression and negative HR status were associated with better OS in this patient population. PS was the only significant predictor for OS.     

ESR1 mutations: Moving towards guiding treatment decision-making in metastatic breast cancer patients

Mutations in the gene coding for the estrogen receptor (ER), ESR1, have been associated with acquired endocrine resistance in patients with ER-positive metastatic breast cancer (MBC). Functional studies revealed that these ESR1 mutations lead to constitutive activity of the ER, meaning that the receptor is active in absence of its ligand estrogen, conferring resistance against several endocrine agents. While recent clinical studies reported that the occurrence of ESR1 mutations is rare in primary breast cancer tumors, these mutations are more frequently observed in metastatic tissue and circulating cell-free DNA of MBC patients pretreated with endocrine therapy. Given the assumed impact that the presence of ESR1 mutations has on outcome to endocrine therapy, assessing ESR1 mutations in MBC patients is likely to be of significant interest to further individualize treatment for MBC patients. Here, ESR1 mutation detection methods and the most relevant pre-clinical and clinical studies on ESR1 mutations regarding endocrine resistance are reviewed, with particular interest in the ultimate goal of guiding treatment decision-making based on ESR1 mutations.     

A group cognitive behaviour therapy programme with metastatic breast cancer patients

One‐hundred and twenty‐four patients with metastatic breast cancer were randomised to either a group Cognitive Behaviour Therapy (CBT) intervention, or to a no‐therapy control group condition. Both groups received standard oncological care; however, therapy recipients also attended eight weekly sessions of group CBT, followed by a family night, and three further monthly sessions. Patients completed the ‘Profile of Mood States’ (POMS) and the Coopersmith Self‐esteem Inventory (CSI) before and after therapy, and at 3 and 6 month follow‐up periods. Outcome data in the period following therapy showed reduced depression and total mood disturbance, as well as improved self‐esteem amongst therapy participants, relative to a no‐therapy control group. These improvements were no longer evident at the 3 or 6 month follow‐up assessments. We also report on the difficulties associated with conducting a group intervention with this patient cohort. Copyright © 1999 John Wiley & Sons, Ltd.     

含卡培他滨联合化疗方案序贯卡培他滨维持治疗转移性乳腺癌患者的疗效观察

目的探讨含卡培他滨联合化疗方案治疗晚期转移性乳腺癌(MBC)后继续予卡培他滨单药维持治疗的疗效和安全性。方法选取2012年6月至2016年6月间湖南省肿瘤医院收治的158例MBC患者,分别接受3种不同的含卡培他滨联合化疗方案治疗后,将疗效评价为缓解或稳定的139例患者分为维持治疗组(73例)和未维持组(66例)。维持治疗组患者予以口服卡培他滨单药维持治疗,未维持组患者予以定期随访观察。评价所有患者的疗效和不良反应。结果维持治疗组患者中位无进展生存时间(PFS)明显长于未维持组患者,差异有统计学意义(P<0.05)。158例患者联合治疗近期客观有效率(ORR)为48.1%,疾病控制率(DCR)为88.0%。年龄>45岁的患者有较高的ORR(P<0.05)。维持治疗组患者维持阶段ORR为16.4%,DCR为68.5%。在亚组分析中,联合化疗采用GX方案的患者中位PFS较TX或NX联合化疗有延长的趋势,转移灶≥3处患者的中位PFS较转移灶数目为1~2处有缩短的趋势,转移后2线及以上治疗患者的中位PFS较转移后1线治疗的患者也有缩短的趋势,但差异均无统计学意义(均P>0.05)。主要不良反应为血液学不良反应、手足综合征和胃肠道不良反应,患者均可以耐受。结论卡培他滨是MBC维持治疗的有效药物,能够延缓患者的疾病进展,且具有较轻的不良反应。     

Carboplatin in combination therapy for metastatic breast cancer

BACKGROUND: Anthracycline-based regimens have a limited role in patients with metastatic breast cancer due to cumulative cardiotoxicity and their common use in adjuvant chemotherapy. New nonanthracycline regimens are, therefore, needed for metastatic disease. Single-agent carboplatin is active in patients with previously untreated metastatic breast cancer, producing response rates of 20%-35%. Preclinical studies have demonstrated synergistic antitumor efficacy of carboplatin and trastuzumab in HER2(+) models. METHODS: Phase II and III clinical trial data of combination therapy with carboplatin (Paraplatin; Bristol-Myers Squibb; Princeton, NJ), a taxane, and/or trastuzumab (Herceptin; Genentech, Inc.; South San Francisco, CA) in metastatic breast cancer were identified from multiple sources, including: A) clinical trial data published in peer-reviewed journals within the last 5 years; B) preliminary clinical trial data from abstracts recently presented at national meetings; and C) phase III protocols currently evaluating carboplatin-based combination regimens. RESULTS: In several phase II studies, combination carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb) therapy was active and reasonably well tolerated in the first-line treatment of metastatic breast cancer, producing objective response rates of 53%-62%-substantially higher rates than those seen in other phase II trials of either drug alone. Similar phase II data for carboplatin with docetaxel (Taxotere; Aventis; Bridgewater, NJ) have been reported, and recent phase III data suggest that adding carboplatin to a paclitaxel/trastuzumab regimen produces superior efficacy than paclitaxel/trastuzumab alone for patients with HER2(+) metastatic disease. Drug scheduling plays an important role in the therapeutic ratio of this combination treatment. CONCLUSIONS: Incorporation of carboplatin as a standard agent in first-line treatment of metastatic breast cancer has support from several recent studies. Preliminary results of combination carboplatin/taxane therapy with trastuzumab in metastatic disease are encouraging, and other carboplatin combinations are also being investigated in other phase II and III trials in patients selected based on the HER2 status of their cancer. Results are eagerly awaited.     

Updates in endocrine therapy for metastatic breast cancer

Endocrine therapy (ET) remains the mainstay of treatment for steroid hormone receptor-positive, human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC). Tumor resistance to hormone therapy has led to the development of novel endocrine drug combinations, transforming the landscape of MBC management. The options for ET are expanding, with promising agents in the pipeline. Although MBC remains incurable, many patients can enjoy years of survival with good quality of life by cycling through the many available agents. With the plethora of available agents and rapid approvals, clinicians look to evidence-based guidelines to assist in treatment selection to maximize patient well-being. In this review, we provide a contemporary review of the advances in ET and a suggested algorithm to guide clinicians in daily management of patients with hormone receptor-positive, HER2-negative MBC. We will discuss landmark trials and highlight their impact in reshaping treatment approaches. Finally, we will provide a glimpse into advances on the horizon and the promise they bring to improve outcomes in patients with advanced breast cancer.     

Aminoglutethimide in patients with metastatic breast cancer

Aminoglutethimide (AG) was administered as palliative therapy in 112 patients with metastatic breast cancer. In 36 patients, the dose level was 1000 mg/day; 76 patients received a dose level of 500 mg/day. Patients with brain or liver metastasis were excluded, as were patients with tumors determined to be negative for estrogen receptors. Objective regression was observed in 35 (31%) patients, with the duration of response ranging from 4 to 36 + months (mean, 12 months; median, 10 months). Response was observed in 11 of 31 (35%) patients with soft tissue metastasis; 16/59 (27%) patients with osseous metastasis; and 8 of 22 (36%) having visceral metastasis. In 93 patients with positive estrogen receptor (ER), 33 responded (35%), whereas in 19 patients with unknown ER status, two responded (11%). Response to previous treatment with tamoxifen (TAM) had occurred in 31 patients; of these, response to AG was noted in 11 (35%). Of 24 patients failing to respond to prior treatment with tamoxifen, four (17%) responded to subsequent therapy with AG. Thirteen patients had previously received combination chemotherapy, and response to AG was noted in two (15%). The side effects observed in this study included skin rash in ten patients, fever in eight, somnolence in three, weakness and dizziness in one, headache in one, insomnia in one, dyspnea in one, and ataxia in one. Treatment had to be discontinued in eight patients, due to the severity of the side effects. As expected, patients receiving AG at the lower dose level of 500 mg/day experienced fewer and less severe side effects than those treated with the higher dose. The response rate in the 1000 mg/day group was 10/36 (28%) and in the 500 mg/day group, it was 25/76 (33%). The lower dosage was better tolerated without apparent compromise in therapeutic efficacy.     

Potential biomarkers for anti-EGFR therapy in metastatic colorectal cancer

Anti-epidermal growth factor receptor (EGFR) therapy has established efficacy in metastatic colorectal cancer, but a significant number of patients do not respond to such treatment. Recently, various biomarkers were reported to be useful in predicting resistance to anti-EGFR. All the potential biomarkers predicting resistance to anti-EGFR are reviewed herein from five aspects. First, upstream molecules, including epiregulin (EREG) and amphiregulin (AREG), might play different roles according to their abnormal levels in tumor tissue and serum. Second, the EGFR amplification and distinct polymorphisms may have roles in identifying patients for initial anti-EGFR mAbs therapy, while rare EGFR mutations have limited predictive values. Third, among the downstream molecularly related factors, rat sarcoma viral oncogene (Ras) has been identified as a successful predictor, while B-Raf proto-oncogene (BRAF) is considered as a prognostic factor rather than a predictor. Fourth, among the molecular bypass pathway components, phosphatidylinositol 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) may be potential biomarkers in the future, while activation of hepatocyte growth factor (HGF)/c-Met signaling confers resistance to anti-EGFR therapy. Fifth, many microRNAs and additional molecular biomarkers are promising in predicting the efficacy of anti-EGFR therapy. Applications of multiple biomarkers are more effective than the use of a single biomarker in selecting patients who might benefit from cetuximab- or panitumumab-based treatments. Comprehensive molecular analyses of the EGFR signaling pathways should be considered in the future. Subsequent prospective trials will be required to further confirm the clinical utility of these biomarkers.     

Weekly paclitaxel therapy for metastatic breast cancer

We treated 12 patients with metastatic breast cancer with weekly paclitaxel therapy. Paclitaxel was administrated by 1 hour infusion at a dose of 80 mg/m2 after short premedication every week on an outpatient basis. Administration was continued for 3 weeks followed by 1 week rest. All patients had received prior metastatic chemotherapy, and prior anthracycline therapy was done in 66.7% of the patients. Partial responses were observed in 66.7% of the patients and progressive disease in 33.3%. The response rate was 66.7%. Responses were observed in 62.5% of the patients with prior anthracycline therapy. Grade 3/4 leukopenia and neutropenia occurred in 25% of the patients, respectively, and no grade 3/4 peripheral neuropathy was observed. Dyspnea occurred in 25% of the patients and was grade 3 in 16.7%. Dyspnea is thought to be one of the adverse events requiring caution with weekly paclitaxel administration. Weekly paclitaxel therapy is effective and well tolerated in patients with metastatic breast cancer.     

Risk factors for brain relapse in patients with metastatic breast cancer.

BACKGROUND: The occurrence of brain metastases is an emerging problem in patients with metastatic breast cancer. In the present study, we looked at risk factors for brain metastasis among patients with metastatic breast cancer. PATIENTS AND METHODS: The risk factors for brain metastasis were first determined in a series of 215 patients with metastatic breast cancer. Risk factors identified in the multivariate analysis were re-evaluated in a confirmatory series of 199 patients with metastatic breast cancer. All the patients had been included in prospective randomized trials that evaluated chemotherapy or endocrine therapy in an adjuvant setting. RESULTS: In the first series, the presence of lung metastases (hazard ratio = 4.3, 95% CI: 1.9-9.3, P=0.0003) and negative hormone receptor status (hazard ratio = 4.2, 95% CI: 1.7-11, P=0.002) were the only predictive factors associated with the occurrence of brain metastases in the multivariate analysis. The second series confirmed that the presence of lung metastases and negative hormone receptor status were associated with the occurrence of brain metastases. CONCLUSION: The presence of lung metastases as the first site of relapse and a negative hormone receptor status are predictive for the occurrence of brain metastases in patients with metastatic breast cancer. A prophylactic treatment should be evaluated in these subsets of patients.