Palbociclib Plus Fulvestrant in Korean Patients from PALOMA-3 With Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer

In the PALOMA-3 trial, the median progression-free survival (PFS) was longer among patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) treated with palbociclib plus fulvestrant than those treated with placebo plus fulvestrant. This subgroup analysis examined the efficacy and safety of palbociclib among Korean patients enrolled in PALOMA-3 (n = 43 [palbociclib group, n = 24; placebo group, n = 19]). In both groups, > 40% of patients were pre/perimenopausal at enrollment. The median PFS was significantly prolonged with palbociclib vs. placebo (12.3 [95% confidence interval (CI), 9.1–not estimable] vs. 5.4 months [95% CI, 1.9–9.2]; hazard ratio, 0.40 [95% CI, 0.19–0.83]; one-sided p = 0.005), and the confirmed objective response was 21.1% and 11.8%, respectively (odds ratio, 2.0 [95% CI, 0.24–24.8]). Neutropenia was the most common adverse event associated with palbociclib. Overall, palbociclib plus fulvestrant was effective and generally safe among Korean patients with HR+/HER2− ABC, regardless of menopausal status.     

Feasibility Study of Docetaxel and Cyclophosphamide Six-Cycle Therapy as Adjuvant Chemotherapy for Japanese Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer Patients

Background: We compared treatment completion rates and safety of docetaxel and cyclophosphamide sixcycletherapy (TC6) with docetaxel followed by 5FU, epirubicin and cyclophosphamide (T-FEC) therapy inJapanese patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Materialsand Methods: We administered TC6 q3w or T-FEC q3w to HER2-negative breast cancer patients. The primaryendpoint of this trial was toxicity. As second endpoints, the treatment completion rate and relative dose intensitywere evaluated. Results: The TC6 and T-FEC group consisted of 22 and 21 patients, respectively. Concerninghematological toxicity, grade 3 or higher adverse reactions included neutropenia and febrile neutropenia. Asnon-hematological adverse events, exanthema and peripheral neuropathy were frequently reported in theTC6 group, whereas more patients of the T-FEC group reported nausea and vomiting. In TC6, the treatmentcompletion rate was 86.4% and the relative dose intensity of docetaxel was 93.2%. In T-FEC, the values were95.2% and 98.9%, respectively. Conclusions: These results suggest that TC6 is tolerable in Japanese, and thatthis regimen can also be performed in outpatient clinics. However, with the TC6 regimen, the compliance wasslightly lower than with the T-FEC regimen, and supportive therapy needs to be managed appropriately.     

A Phase II Open Label Study of Everolimus in Combination With Endocrine Therapy in Resistant Hormone Receptor-Positive HER2-Negative Advanced Breast Cancer

BackgroundTherapies targeting estrogen receptor signaling are standard for patients with hormone receptor (HR)-positive (HR⁺) metastatic breast cancer (MBC). Dysregulation of the phosphoinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is associated with treatment resistance. Addition of the mTOR inhibitor, everolimus, to exemestane doubled progression-free survival (PFS) in HR⁺/HER2⁻ MBC patients whose disease had previously progressed during endocrine therapy. In this phase II study, we used everolimus in addition to the most recent endocrine therapy during which a patient's disease progressed, in an attempt to restore and extend the benefit of the antiestrogen therapy in patients with HR⁺/HER2⁻ MBC.Patients and MethodsPatients with HR⁺ MBC who progressed on antiestrogen therapy received everolimus (10 mg orally daily) in combination with the antiestrogen therapy most recently administered. Treatment was administered in 4-week cycles and continued until disease progression or unacceptable toxicity. Blood and archival tumor specimens were collected for VeriStrat (Biodesix, Inc) and Foundation One (Foundation Medicine) assays, respectively. Accrual of 42 evaluable patients allowed detection of improvement in median PFS from 2.8 months (expected with hormonal treatment alone) to 5 months (power 80%, α = 5%).ResultsForty-seven patients were enrolled and treated. After a median follow-up of 22.2 months, median PFS was 6.6 months. Secondary efficacy end points included: overall response rate, 6%; clinical benefit rate, 40%; and median overall survival, 21.1 months. No unexpected toxicity was observed. Efficacy could not be correlated with PI3K/AKT/mTOR alterations or VeriStrat (Biodesix, Inc) prognostic signatures.ConclusionAfter progression during antiestrogen therapy, the addition of everolimus, without changing the hormonal therapy, resulted in a median PFS of 6.6 months, suggesting efficacy in patients with HR⁺/HER2⁻ MBC.     

Effect of Hormone Therapy on Long-term Outcomes of Patients with Human Epidermal Growth Factor Receptor 2- and Hormone Receptor-Positive Metastatic Breast Cancer: Real World Experience in China

Background: Among human epidermal growth factor receptor 2 (HER2)-positive breast cancer, more thanhalf are also hormone receptor (HR)-positive. Although HR is a predictive factor for the efficacy of hormonetherapy, there are still some uncertainties in regard to the effects on patients with HR-positive and HER2-positivemetastatic breast cancers due to the potential resistance to hormone therapy caused by co-expression of HRand HER2. There are no clinical trials directly comparing the efficacy of hormonal therapy with chemotherapy.Materials and Methods: To examine the real-world effect of hormone therapy on patients with HR-positiveand HER2-positive metastatic breast cancers, a cross-sectional study of a representative sample of the Chinesepopulation was conducted. The study included 113 patients who received first-line and second-line palliativetreatment between 2005 and 2010 in the Cancer Institute and Hospital, Chinese Academy of Medical Science.The effect of hormone therapy on overall survival (OS) was studied. Results: The patients who received hormonetherapy (n=51) had better overall survival in contrast to those who received chemotherapy with anti-HER2therapy (n=62) in first- or second-line treatment. The difference was of borderline statistical significance (51.8mvs 31.9m, p=0.065). In addition, the effect of hormone therapy did not differ significantly with other prognosticfactors, including age (≤50 years or >50 years), disease free survival (≥2 years or < 2 years) and site of metastasis(visceral or bone/soft tissue). On multivariate analysis, administration of hormone therapy was associated witha trend toward a favorable prognosis (p=0.148, HR=0.693, 95%CI 0.422-1.139). Age more than 50 years wasthe sole independent harmful prognostic factor (p<0.001, HR=2.797, 95%CI 1.676-4.668). Conclusions: Ourdata suggest that hormonel therapy may improve outcomes of the patients with ER-positive and HER2-positivemetastatic breast cancer.     

A Multicenter Phase II Study of Docetaxel 60 mg/m2 as First-Line Chemotherapy in Patients with Advanced or Recurrent Breast Cancer

PURPOSE: Docetaxel is an active agent as first-line chemotherapy in patients with advanced breast cancer at a dosage of 100 mg/m2. However, the efficacy of this agent as a first-line drug when used at a lower dosage is unclear. This study was performed to evaluate the clinical efficacy and safety of 60 mg/m2 docetaxel for the treatment of breast cancer. PATIENTS AND METHODS: This study enrolled 23 patients with advanced and/or metastatic breast cancer, who had not been treated with an anthracycline or taxane previously. Treatment with docetaxel was continued in patients showing a response until there was evidence of disease progression or unacceptable toxicity. RESULTS: Among 20 fully evaluated patients, the overall response rate was 50.0% and the median time to progression was 31 weeks. The most commonly observed adverse events were neutropenia (78.2%) and fatigue (60.9%). Fluid retention occurred in only 8.7% of the patients. Adverse events did not cause discontinuation of the treatment. CONCLUSION: Docetaxel achieved good disease control with mild adverse events in first-line treatment at a dosage of 60 mg/m2.     

Phase II Trial of Fulvestrant With Metronomic Capecitabine for Postmenopausal Women With Hormone Receptor-Positive,HER2-Negative Metastatic Breast Cancer

BackgroundIn this phase II study, we explored efficacy and toxicity of combined endocrine and low-dose metronomic chemotherapy therapy consisting of fulvestrant and capecitabine in estrogen and/or progesterone receptor-positive, HER2-negative MBC.Patients and MethodsPatients with ≤ 1 previous hormonal treatment in the metastatic setting received an injection fulvestrant loading dose 500 mg on day 1, 250 mg on days 15 and 29 followed by 250 mg every 28 days along with continuous oral capecitabine in divided doses. The total fixed daily dose of capecitabine was either 1500 mg or 2000 mg, depending on the patient’s weight (< 80 kg vs. ≥ 80 kg). Primary end points were PFS and TTP. Toxicity was assessed by continuous evaluations of treatment-emergent adverse events (AEs) and changes from baseline in laboratory values.ResultsForty-one women, with a mean age of 64.5 years, were enrolled. Patients completed a median of 11 monthly treatment cycles. Median PFS was 14.98 months (95% confidence interval [CI], 7.26-upper limit [UL] not estimated) and median TTP was 26.94 months (95% CI, 7.26-UL not estimated). Median overall survival was 28.65 months (95% CI, 23.95-UL not estimated). Treatment was well tolerated with < 10% Grade 3 palmar-plantar erythrodysesthesia. Overall, the most frequent AEs were palmar-plantar erythrodysesthesia, fatigue, and nausea.ConclusionFulvestrant with metronomic capecitabine demonstrates substantial activity in hormone receptor-positive MBC and is well tolerated. Combined chemoendocrine approaches should be further explored considering the low toxicity of the combination with meaningful TTP.     

Paraneoplastic Encephalitis Associated with Locally Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

Paraneoplastic neurologic diseases (PND) are rare but can occur in patients with common malignancies including breast cancer. In patients with hormone receptor (HR)-negative human epidermal growth factor receptor 2 (HER2)-positive breast cancer, PND have been reported in association with anti-Yo antibodies and with clinical presentation of paraneoplastic cerebellar degeneration. We describe the case of a woman with progressively altered mental status and seizures, ultimately requiring admission. Based on her clinical presentation, imaging findings, and evidence of neural-directed antibodies in her serum and cerebrospinal fluid, she was diagnosed with paraneoplastic limbic encephalitis (LE) due to an underlying HR-negative, HER2-positive breast cancer. She showed a transient response to immunosuppression but had more significant improvement after surgical resection and initiation of chemotherapy along with HER2-directed therapy. To the best of our knowledge, this is the first documented case of paraneoplastic LE in a patient with HR-negative, HER2-positive breast cancer likely caused by the production of an unclassified anti-neuronal antibody.     

Final Overall Survival Analysis of the SOGUG Phase 2 MAJA Study: Maintenance Vinflunine Versus Best Supportive Care After First-Line Chemotherapy in Advanced Urothelial Carcinoma

IntroductionThe MAJA study compared vinflunine (VFL) plus best supportive care (BSC) maintenance therapy versus BSC alone in advanced urothelial carcinoma responsive to first-line chemotherapy. The primary end point of progression-free survival was achieved. We present the final overall survival (OS) and long-term follow-up safety analyses.Patients and MethodsPatients were enrolled, and a subsequent post hoc analysis was performed on the basis of radiologic response or stabilization to first-line cisplatin/gemcitabine (CG) chemotherapy (4-6 cycles), according to Response Evaluation Criteria in Solid Tumors (RECIST). VFL + BSC versus BSC alone were randomly assigned until disease progression.ResultsAt final analysis, 58 patients (66.7%) had died while 29 (33.3%) had survived; the BSC arm had higher mortality (VFL + BSC, n = 26, 59.1% vs. BSC, n = 32, 74.4%). Median follow-up of surviving patients was 38.8 months (interquartile range, 23.8-61.6). Median OS was 16.7 months (95% confidence interval, 0-34.5) in VFL and 13.2 months (95% confidence interval, 6-20.4) in the BSC groups (hazard ratio, 0.736; 95% confidence interval, 0.44-1.24, P = .182). Post hoc group division did not affect median OS in either study arm.ConclusionFinal analysis supported a benefit of VFL in maintenance therapy in patients with disease control after first-line treatment with CG, with no unexpected long-term adverse effects. The study was insufficiently powered to show a significant OS advantage.     

ER阳性绝经后乳腺癌术后化疗联合内分泌治疗的临床探讨

目的:探讨化疗联合内分泌治疗对ER阳性绝经后乳腺癌患者术后生存率的影响.方法:将接受乳腺癌改良根治术后ER阳性的绝经后乳腺癌患者随机分为两组,联合组67例,术后应用CMF或CAF方案6个疗程后口服TAM 5年;内分泌组59例,术后口服TAM 5年.结果:临床Ⅱ、Ⅲ期及术后腋窝转移淋巴结≥4枚的患者两组5年无瘤生存率分别为82.7%、46.7%,58.3%、28.1%,63.9%、28.7%;5年总生存率分别为86.4%、49.5%,61.1%、33.8%,69.8%、34.8%(P＜0.05);而临床Ⅰ期和腋窝淋巴结转移＜4枚的患者两组5年无瘤生存率和总生存率无显著差异(P＞0.05).结论:ER阳性绝经后Ⅱ、Ⅲ期乳腺癌改良根治术后和腋窝转移淋巴结≥4枚的患者术后化疗联合内分泌治疗效果优于单纯内分泌治疗.     

Fulvestrant 500 mg Versus Exemestane in Postmenopausal Women With Metastatic Breast Cancer Resistant to Adjuvant Nonsteroidal Aromatase Inhibitors in Clinical Practice: A Multicenter Retrospective Study

BackgroundFulvestrant 500 mg and exemestane are widely used agents in first-line therapy for metastatic breast cancer (MBC) of estrogen receptor (ER)-positive (ER⁺) postmenopausal MBC after failure of adjuvant nonsteroidal aromatase inhibitor (NSAI) treatment. Although fulvestrant 250 mg had similar efficacy compared with exemestane (Evaluation of Faslodex versus Exemestane Clinical Trial study) and fulvestrant 500 mg was superior to fulvestrant 250 mg (Comparison of FASLODEX In Recurrent or Metastatic Breast Cancer study), no direct comparison between fulvestrant 500 mg and exemestane has been conducted. The aim of this study was to compare the efficacy and safety of fulvestrant 500 mg and exemestane in daily practice.Patients and MethodsWe retrospectively evaluated the medical records of all patients with ER⁺ HER2⁻ MBC who received fulvestrant 500 mg or exemestane 25 mg as first-line therapy for MBC from 2015 to 2017 in 4 institutions. A total of 120 patients were available for analysis. Both agents accounted for 50% (60) patients.ResultsThe median progression-free survival (PFS) of the fulvestrant group was significantly longer than that in the exemestane group (6.2 months [95% confidence interval (CI), 5.0-7.4] versus 4.8 months [95% CI, 3.0-6.7], P = .024). In subgroup analysis, for patients with visceral metastasis or primary endocrine resistance, no significant difference considering PFS was observed in the 2 groups (P = .563 and .769). No significant difference of Grade 3/4 adverse events was observed in the 2 groups (3 patients, 5% versus 2 patients, 3.3%; P = .648).ConclusionFulvestrant 500 mg showed better efficacy than exemestane in first-line therapy for MBC of ER⁺ postmenopausal women after failure of adjuvant NSAI treatment. For patients with visceral metastasis or primary endocrine resistance, both treatments showed poor outcomes, indicating a need for further alternatives (targeted therapy or chemotherapy). Both agents were well tolerated in terms of toxicities.     

The Significance of p-AKT1 as a Prognostic Marker and Therapeutic Target in Patients With Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor-2-Positive Early Breast Cancer

PurposePhosphorylated AKT1 (p-AKT1) at Ser473 is a functional isoform of AKT and a key component of the PI3K/mTOR/AKT pathway. This study aimed to evaluate the prognostic significance of p-AKT1 (Ser473) based on the molecular subtypes of breast cancer.MethodsTo investigate the prognostic value of p-AKT1 (Ser473), we performed a retrospective chart review of patients with breast cancer. Data on p-AKT1 (Ser473) positivity, hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) expression status, and other clinicopathological factors were obtained. Furthermore, the therapeutic effect of blocking p-AKT1 (Ser473) in breast cancer cells was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell apoptosis assay, apoptosis protein array, and western blot analysis.ResultsA total of 3,044 patients were evaluated, and the median follow-up time was 43 (range: 0–125) months. In patients with HR-positive and HER2-positive disease, the p-AKT1 (Ser473)-positive group had worse disease-free survival (DFS) than the p-AKT1 (Ser473)-negative group (hazard ratio, 1.9; 95% confidence interval, 1.1–3.5; p = 0.024). In the multivariate analysis, p-AKT1 (Ser473) remained a significantly worse prognostic factor in patients with HR-positive/HER2-positive breast cancer (p = 0.03). There was no difference in DFS according to p-AKT1 (Ser473) status among patients with other breast cancer subgroups. In vitro analysis showed that blocking p-AKT1 (Ser473) levels enhanced trastuzumab-induced cell death in HR-positive/HER2-positive and p-AKT1 (Ser473)-positive breast cancer cells.Conclusionp-AKT1 (Ser473) is a prognostic marker for poor outcomes in patients with HR-positive/HER2-positive breast cancer and may have a potential value as a therapeutic target.     

Hormone Receptor/Human Epidermal Growth Factor Receptor 2-positive breast cancer: Where we are now and where we are going

Near 75% of all breast cancers (BC) express estrogen receptors (ER) and/or progesterone receptors (PgR), while up to 20% of BC show an overexpression/amplification of Human Epidermal Growth Factor Receptor 2 (HER2). Around 50% of all HER2-overexpressing BC show the coexistence of both HER2 overexpression/amplification and ER and/or PgR overexpression. Numerous in vitro and in vivo studies suggest the existence of a cross-talk between their downstream pathways, which seem to affect the natural history, response to therapy and outcome of patients affected by this subset of BC. Meta-analyses or subgroup analysis of numerous neo-/adjuvant trials demonstrated significant clinical implications deriving from ER/HER2 co-existence, consisting in a different pattern of relapse and dissimilar outcome in response to anti-HER2 therapy. However, only two randomized trials in early disease and three in advanced disease specifically addressed the issue whether a combined approach with both hormonal and anti-HER2 therapy would have a better therapeutic impact in this subset of BC compared to the lone anti-HER2 or hormonal therapies (HT). None of these trials demonstrated improvements in overall survival, even though several efficacy end-points such as progression free survival, in advanced setting, or pCR rates in neoadjuvant setting, often favored the combined hormonal and anti-HER2 therapeutic approach. In the next few years, a certain number of ongoing randomized trials, both in neoadjuvant and advanced setting, will evaluate the efficacy of new anti-HER2 drugs, T-DM1 and pertuzumab, in combination with HT, helping to improve the therapeutic strategy for this specific subtype of breast tumors.