Clinicopathologic features of hormone‐receptor‐positive breast cancer patients with late recurrence

The number of long‐term breast cancer survivors with a risk of late recurrence is increasing. Hormone‐receptor‐positive patients have greater risks of late recurrence. Although several studies demonstrated that extended adjuvant endocrine therapy reduces the incidence of late recurrence, it remains unclear which hormone‐receptor‐positive patients have greater risks of late recurrence. Hormone‐receptor‐positive breast cancer patients were retrospectively selected from the prospective database of primary breast cancer patients treated at Keio University Hospital from January 1989 to December 2003. Late recurrence was defined as initial recurrence after 5 years from the initial surgery. We evaluated the clinicopathologic features of breast cancer patients with late recurrence. At a median follow‐up of 10.9 years (range, 5.1‐23.8), 371 patients had no recurrence, 90 had early recurrence (within 5 years), and 83 had late recurrence. Multivariate analysis revealed that >4 involved lymph nodes were significant risk factors for late recurrence (P < .001), whereas 1‐3 positive nodes were not. Endocrine therapy significantly reduced the incidence of late recurrence (P < .001). After menopause, adjuvant therapy with aromatase inhibitors resulted in longer disease‐free survival than tamoxifen (10‐year disease‐free survival: 97.6% vs 89.7%, P = .0955). High nodal involvement was significantly correlated with late recurrence in hormone‐receptor‐positive breast cancer patients. Hormone‐receptor‐positive breast cancer patients who receive adjuvant endocrine therapy with tamoxifen alone might be candidates for extended endocrine therapy.     

Systematic literature review of clinical trials of endocrine therapies for premenopausal women with metastatic HR+ HER2− breast cancer

Several endocrine‐based therapies have recently been evaluated as treatments for premenopausal women with hormone‐receptor‐positive/human‐epidermal‐growth‐factor‐receptor 2 negative (HR+/HER2?) metastatic breast cancer (mBC). We conducted a systematic review and assessed the feasibility of an indirect treatment comparison (ITC) to characterize the comparative efficacy of endocrine‐based therapies in this setting. A systematic literature review (SLR) of Medline, EMBASE, Cochrane Library and key conferences was performed to identify randomized clinical trials (RCTs) satisfying the following criteria: (a) included pre/perimenopausal women with HR+/HER2? mBC, (b) included endocrine‐based therapies, (c) reported efficacy, safety, or quality of life outcomes, and (d) was published in 2007 or later (when HER2 testing was standardized). The clinical and methodological similarities across trials were assessed to evaluate the feasibility of an ITC. Four RCTs (PALOMA‐3, MONARCH‐2, KCSG BR10‐04 and MONALEESA‐7) and eight regimens (palbociclib + fulvestrant + goserelin, fulvestrant + goserelin, abemaciclib + fulvestrant + gonadotropin‐releasing hormone agonist [GnRHa], fulvestrant + GnRHa, anastrozole + goserelin, goserelin, ribociclib + NSAI/tamoxifen + goserelin and NSAI/tamoxifen + goserelin) were selected. MONALEESA‐7 was the only phase 3 trial investigating endocrine‐based therapies as first‐line in only pre/perimenopausal women with HR+/HER2? mBC; the other three trials focused on the ET‐failure setting and their pre/perimenopausal populations were relatively small. ITCs were methodologically unfeasible due to critical differences in treatment settings and lack of common comparators across trials. Therefore, we were not able to characterize the relative efficacy of the different endocrine‐based therapies available in the premenopausal HR+/HER2? mBC setting. This systematic review provides a comprehensive assessment of the available trial evidence on the efficacy and safety of endocrine‐based therapies for premenopausal women with HR+/HER2? mBC. Only four trials have reported relevant data in this setting, and MONALEESA‐7 is currently the only trial focused on premenopausal HR+ HER2? mBC in the first‐line setting.     

Gemcitabine and vinorelbine combination in patients with metastatic breast cancer

Both gemcitabine and vinorelbine as single agents have significant activity against metastatic breast cancer, with an overall response rate ranging from 14% to 40%. Because each drug has different mechanisms of action and toxicity profile, we have evaluated the activity and tolerability as a combined regimen in metastatic breast cancer patients. Thirty-two breast cancer patients with prior chemotherapy for metastatic disease received a combination of gemcitabine and vinorelbine at 1,200 and 30 mg/m ², respectively. The drugs were administered on days 1 and 8 of every 21-day cycle. The study was designed to evaluate the response rate, the duration of response, the time to progression, and overall survival. Toxicity and tolerability of this combination were also evaluated. Out of 32 patients analyzed, a complete response was achieved in 2 patients (6.3%) and a partial response in 12 patients (37.5%), with an overall response rate of 43.8%. After a median follow-up of 7 months, the median duration of response was 5.3 months, and the time to progression was 5.0 months. Overall survival was not reached because the majority of the patients were alive at the time of analysis. The gemcitabine and vinorelbine combination was tolerable, with hematologic toxicity being the most common side-effect. Three patients suffered from grade 4 neutropenia, and none suffered from grade 4 thrombocytopenia. Nonhematologic toxicity was minimal and transient, with nausea and phlebitis being the most common. The gemcitabine and vinorelbine combination at the previously specified doses shows significant activity in metastatic breast cancer patients. The treatment is well tolerated and has an acceptable toxicity profile. In patients previously treated with anthracyclines and taxanes, this combination regimen offers an alternative treatment with preservation of a good quality of life.     

Personalized treatment in metastatic triple‐negative breast cancer: The outlook in 2020

Compared with other breast cancer subtypes, patients with triple‐negative breast cancer (TNBC), and irrespective to their disease stage, were always recognized to have the worst overall survival data. Although this does not seem different at the present time, yet the last few years have witnessed many breakthrough genomic and molecular findings, that could dramatically improve our understanding of the biological complexity of TNBC. Based on genomic analyses, it was consistently evident that TNBC comprises a heterogeneous group of cancers, which have numerous diverse molecular aberrations. This—in return—has provided a platform for a new generation of clinical trials using many innovative therapies, directed against such novel targets. At the present time, two PARP inhibitors and one anti‐PD‐L1 monoclonal antibody (in combination with chemotherapy) have been approved in certain subpopulations of metastatic TNBC (mTNBC) patients, which have finally brought this disease into the era of personalized medicine. In the current review, we will explore the genomic landscape of TNBC, through which many actionable targets were graduated. We will also discuss the results of the key—practice changing—clinical studies, and some upcoming personalized treatment options for patients with mTNBC, that may be clinically adopted in the near future.     

Oral metronomic cyclophosphamide and methotrexate plus fulvestrant in advanced breast cancer patients: a mono-institutional case-cohort report

Abstract: Fulvestrant is effective in postmenopausal women with estrogen receptor‐positive advanced breast cancer (ABC). So far, no published data exist on fulvestrant combined with chemotherapy. We retrospectively assessed the role of combining oral metronomic cyclophosphamide and methotrexate (CM) to fulvestrant in two cohorts (A and B) of heavily pre‐treated estrogen receptor‐positive advanced ABC patients. From October 2006 to September 2009, 33 postmenopausal patients received fulvestrant 250 mg via i.m. injection q28 days. In A, 20 patients added metronomic cyclophosphamide (50 mg p.o. daily) and methotrexate (2.5 mg p.o. twice daily on day 1 and day 4 weekly) after disease progression, continuing fulvestrant at the same dose. In B, 13 patients started fulvestrant plus metronomic CM upfront. Thirty‐two patients were evaluable for response. Clinical benefit (partial response + stable disease >24 months) for A + B was 56% (95% CI 38–74%). The addition of metronomic CM did not determine relevant toxicities. Treatment with fulvestrant plus metronomic CM was effective in advanced ABC and was minimally toxic providing long‐term disease control in a high proportion of patients. The prolonged clinical benefit, often desirable in such patients, supports this regimen as an additional and useful therapeutic tool.     

Hidden estrogen production from ovarian remnants leading to progression of disease in metastatic breast cancer

In premenopausal women with hormone dependent breast cancers, ovarian suppression is an important part of treatment, and is often achieved with a bilateral salpingo‐oophorectomy (BSO). However, this procedure can lead to ovarian remnant syndrome (ORS), a rare condition where the adnexal tissue is not completely removed and can produce estrogen. We describe a case of ORS in a patient with estrogen receptor positive (ER+) breast cancer who had progression of disease after undergoing a BSO, despite optimal therapy. ORS therefore poses a significant treatment challenge in premenopausal ER+ breast cancer patients thought to be rendered menopausal with a BSO.     

Surviving metastatic breast cancer for 18 years: a case report and review of the literature

We report a case of a 93-year-old woman who was diagnosed with estrogen receptor (ER)-positive, progesterone receptor-positive, T2N0M0 (stage I) breast cancer (BC) at the age of 45. Twenty-two years later, she was diagnosed with metastatic lesions to the lungs consistent with the breast primary. Her disease was stable on tamoxifen, anastrozole, and exemestane for 14 years. Subsequently, she was found to have metastatic lesions to thoracic spine as well as progressively increasing bilateral pleural effusions. At that time, she was deemed not to be a good candidate for chemotherapy and therapy was changed to fulvestrant. Two years later (38 years after initial diagnosis of BC), she was diagnosed with new metastatic liver lesions; although her pulmonary and bone metastases remained stable. Therefore, she was started on palliative chemotherapy with single-agent capecitabine. The treatment was discontinued after the second cycle upon the patient's request owing to grade 2 hand and foot syndrome. She expired 2 years later after fighting BC for four decades. She survived for 18 years after the diagnosis of metastatic breast cancer (MBC) while maintaining a good quality of life. To the authors' knowledge, this is the first reported case in the literature with the longest overall survival in a patient with MBC. We provide a detailed clinical analysis in conjunction with a brief literature review.     

Outcome and feasibility of palliative chemotherapy in very elderly patients with metastatic breast cancer

In the Netherlands, approximately 1300 women aged ≥75 years die every year of metastatic breast cancer (MBC). Data on palliative chemotherapy (CT) in very elderly patients are rare, and prospective studies appeared cumbersome. Therefore, we retrospectively analyzed the outcome and feasibility of chemotherapy in elderly MBC patients. Records of all patients with MBC aged ≥75 years who received first‐line palliative chemotherapy between January 2000 and December 2014 at two large teaching hospitals in the Netherlands were reviewed. We registered patient and tumor characteristics together with data on previous adjuvant treatment, palliative endocrine treatment, comorbidities, clinical benefit (defined as ≥6 months progression‐free survival), toxicity, and the reason for stopping chemotherapy. Patients with progressive disease (PD) or death within 30 days after starting CT were censored from analysis. A total of 54 patients with a median age of 77.6 years (range 75‐90) were treated with palliative chemotherapy for MBC. Of them, 20 patients (37%) were aged ≥ 80 years. There was clinical benefit in 28 patients (52%). Median progression‐free survival and median overall survival were 6.0 and 14.0 months, respectively. One year after the diagnosis of MBC, 27 patients (50%) were still alive and 15 patients (28%) lived longer than 2 years. Reasons for stopping CT were progressive disease (n = 32) or toxicity (n = 13). Most patients (n = 48) died of MBC while two patients died of toxicity. In selected patients with MBC aged 75 years or older, single‐agent palliative chemotherapy is feasible and may have clinical benefit.     

Real world initial palliative treatment patterns and clinical outcomes in premenopausal patients with hormone receptor-positive,HER2-negative metastatic breast cancer: A study of the National Cancer Center,China

BackgroundTo observe whether guideline non-adherence in initial palliative treatment choices for premenopausal hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (MBC) patients result in worse clinical outcomes in the Chinese population.MethodsThe China National Cancer Center database was used to identify 2194 patients diagnosed between 2004 and 2015. A total of 451 premenopausal patients with HR + HER2- MBC were included. Clinicopathological features and survival information were extracted. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared using log-rank test.ResultsThe number of patients receiving initial chemotherapy, endocrine therapy and chemo-endocrine therapy were 222 (49.2%), 80 (17.7%), and 149 (33.0%), respectively. Patients receiving initial chemotherapy were more likely to be luminal B subtype, had more de novo stage IV disease and more liver metastasis, compared with patients receiving initial endocrine therapy. Both PFS and OS were significantly longer for chemo-endocrine therapy group (median PFS 18.9 months and OS 75.0 months), than for endocrine therapy group (median PFS 11.7 months and OS 53.5 months), and chemotherapy group (median PFS 7.1 months and OS 43.9 months). In multivariate analysis, none of the three treatment strategies were independently associated with PFS or OS.ConclusionIn real world, a high percentage of premenopausal patients with HR + HER2- disease received chemotherapy as initial palliative treatment in China, which was not associated with worsened survival. Further studies with larger sample size across China are needed to explore the relationship between this guideline non-adherence and clinical outcomes.     

HER2阳性转移性乳腺癌治疗年度进展

乳腺癌是我国女性发病率最高的恶性肿瘤,其中HER2阳性转移性乳腺癌在晚期乳腺癌占比为25%~30%。HER2阳性乳腺癌患者预后差,如何提高HER2阳性转移性乳腺癌的治疗效果,包括优化靶向治疗、化疗药物的选择、后线治疗的策略等具有重要的临床意义。本文基于2017年各大乳腺癌会议,针对HER2阳性转移性乳腺癌在临床中的常见问题,阐述HER2阳性转移性乳腺癌治疗策略的新进展。     

Treatment of metastatic breast cancer with liver transplantation

Resection of liver metastases is accepted as an appropriate treatment for colorectal metastases in suitable patients. Liver transplant is not often used for malignant disease as there is a high incidence of undetectable micrometastases elsewhere and recurrence is likely. The effects of immunosuppression may also enhance the growth of malignant cells at other sites. We report a case where a young patient with undiagnosed breast cancer with axillary and liver metastases underwent liver transplantation and is effectively leading a normal life 33 months after transplant.     

Outcomes of metastatic breast cancer patients in relationship to disease‐free interval following primary treatment of localized disease; a pooled analysis of two clinical trials

The aim of the current study is to assess the impact of disease‐free interval (DFI) following treatment of primary localized breast cancer on the outcomes of patients with subsequent metastatic breast cancer treated with first‐line docetaxel chemotherapy. This study is a combined analysis of patient‐level raw data of 604 metastatic breast cancer patients referred for docetaxel first‐line chemotherapy in two clinical trials. Overall survival and time to progression were evaluated according to DFI through Kaplan‐Meier analysis. Multivariate analysis of factors affecting overall survival and time to progression was then conducted through Cox regression analysis. For the overall cohort, shorter DFI is associated with worse overall survival (P < 0.0001). When classified by the hormone receptor status, the shorter interval was associated with worse overall survival in both hormone receptor positive and negative patients (P = 0.009; P = 0.018; respectively). Likewise, shorter DFI is associated with shorter time to progression (P < 0.0001) in the overall cohort. When classified by the hormone receptor status, the shorter interval was associated with shorter time to progression for hormone receptor negative but not positive patients (P = 0.001; P = 0.070; respectively). In multivariate Cox regression analysis, the following factors were associated with worse overall survival: shorter DFI (P < 0.0001), poorer ECOG performance score (P = 0.008) and lower body mass index (P = 0.018). Likewise, in multivariate Cox regression analysis, the following factors were associated with shorter time to progression: shorter DFI (P < 0.0001) and hormone receptor negative status (P = 0.025). Shorter DFI was associated with worse overall survival and shorter time to progression among patients receiving first‐line docetaxel chemotherapy.     

Ribociclib therapy in peritoneal carcinomatosis secondary to HER2‐negative metastatic breast cancer: A clinical case with a positive outcome

Although metastatic breast cancer can be fatal, a series of randomized double‐blind placebo‐controlled phase 3 trials (MONALEESA studies) have shown that ribociclib is an effective anticancer drug for the treatment of advanced breast cancer with bones, liver, lungs, and brain as major metastatic sites. Here, we report the clinical case of a woman with peritoneal carcinomatosis secondary to HER2‐negative estrogen receptor–positive breast cancer successfully treated with ribociclib and letrozole. After 9‐month follow‐up, total body computed tomography imaging showed resolution of hypodense areas surrounding the hepatic hilus with concomitant reduction in both bile duct dilatation and peritoneal effusion, and abdominal lymphadenopathy was excluded. Notably, therapy was well tolerated throughout the treatment with no side effects.     

Primary tumor resection in metastatic breast cancer: A propensity‐matched analysis, 1988‐2011 SEER data base

Primary tumor resection (PTR) in metastatic breast cancer is not a standard treatment modality, and its impact on survival is conflicting. The primary objective of this study was to analyze impact of PTR on survival in metastatic patients with breast cancer. A retrospective study of metastatic patients with breast cancer was conducted using the 1988‐2011 Surveillance, Epidemiology, and End Results (SEER) data base. Cox proportional hazards regression models were used to evaluate the relationship between PTR and survival and to adjust for the heterogeneity between the groups, and a propensity score‐matched analysis was also performed. A total of 29 916 patients with metastatic breast cancer were included in the study, and 15 129 (51%) of patients underwent primary tumor resection, and 14 787 (49%) patients did not undergo surgery. Overall, decreasing trend in PTR for metastatic breast cancer in last decades was noted. Primary tumor resection was associated with a longer median OS (34 vs 18 months). In a propensity score‐matched analysis, prognosis was also more favorable in the resected group (P = .0017). Primary tumor resection in metastatic breast cancer was associated with survival improvement, and the improvement persisted in propensity‐matched analysis.     

Gemcitabine-oxaliplatin combination in heavily pretreated metastatic breast cancer: a pilot study on 43 patients

To investigate the efficacy and the safety of gemcitabine and oxaliplatin combination in metastatic breast cancer (MBC), in patients heavily treated with anthracycline and taxane. A retrospective study including all MBC patients, treated by two different schedules of GemOx between February 2001 and December 2003 in the medical oncology department of Saint-Louis hospital. Forty-three consecutive patients were included. Median involved organs was 2. The median number of regimen of previous metastatic chemotherapy administered was 3. The median number of cycle administered was 5, with a median dose by cycle of 1,000 or 2,000 mg/m(2) of gemcitabine (D1D2 or D1D8 schedule, respectively) and 100 mg/m(2) of oxaliplatin. Of the 40 evaluable patients, three achieved a partial response giving an overall response rate of 7.5% and 11 demonstrated stable disease, giving a stabilization rate of 27.5%. Median overall survival in all treated patients was 10.6 months and median progression-free survival in all evaluated patients was 3.0 and 10.5 months for the partial responders. Hematotoxicity was prevalent, sometimes severe, with grades 3 and 4 neutropenia, thrombocytopenia, and anemia in 42%, 19%, and 14% of the patients. Grades 3 and 4 peripheral neuropathy were developed by 9% of the patients, but was not limiting. The present study reports the results of two exploratory schedules of the GemOx combination in advanced breast cancer patients. The D1D8 schedule was the most promising and deserves further clinical studies.     

Efficacy and safety of palbociclib plus endocrine therapy in North American women with hormone receptor‐positive/human epidermal growth factor receptor 2‐negative metastatic breast cancer

Palbociclib is a cyclin‐dependent kinase 4/6 inhibitor indicated for treatment of hormone receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer in combination with endocrine therapy. We investigated the efficacy and safety of palbociclib in patients enrolled in North America during two‐phase 3 trials: PALOMA‐2 (n = 267, data cutoff: May 31, 2017) and PALOMA‐3 (n = 240, data cutoffs: April 13, 2018, for overall survival, October 23, 2015, for all other outcomes). In PALOMA‐2, treatment‐naïve postmenopausal patients with advanced breast cancer were randomized 2:1 to palbociclib (125 mg/d; 3 weeks on/1 week off [3/1]) plus letrozole (2.5 mg/d, continuous) or placebo plus letrozole. In PALOMA‐3, patients who progressed on prior endocrine therapy were randomized 2:1 to palbociclib (125 mg/d; 3/1) plus fulvestrant (500 mg, per standard of care) or placebo plus fulvestrant; pre/perimenopausal patients received ovarian suppression with goserelin. Palbociclib plus endocrine therapy prolonged median progression‐free survival vs placebo plus endocrine therapy in North American patients (PALOMA‐2: 25.4 vs 13.7 months, hazard ratio, 0.54 [95% CI, 0.40–0.74], P < .0001; PALOMA‐3: 9.9 vs 3.5 months, hazard ratio, 0.52 [95% CI, 0.38–0.72], P < .0001). Objective response and clinical benefit response rates were greater with palbociclib vs placebo in North American patients in both trials. While overall survival data are not yet mature for PALOMA‐2, median overall survival was increased in PALOMA‐3 (32.0 vs 24.7 months, hazard ratio, 0.75 [95% CI, 0.53–1.04]), though this did not reach statistical significance (P = .0869). Safety profiles in North American patients were similar to those of the overall populations; neutropenia was the most common treatment‐emergent adverse event. No new safety signals were observed. In summary, palbociclib plus endocrine therapy is an effective treatment option for North American women with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer.