Survival benefit and biomarker analysis of pyrotinib or pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer: a pooled analysis of two phase I studies.

BACKGROUND: Pyrotinib, a novel irreversible tyrosine kinase inhibitor (TKI), has demonstrated promising antitumor activity to improve the overall response rate and progression-free survival (PFS) in patients with HER2-positive metastatic breast cancer (MBC). However, the survival data of pyrotinib or pyrotinib plus capecitabine in HER2-positive MBC remains scarce. Thus, we summarized the updated individual patient data from the phase I trials of pyrotinib or pyrotinib plus capecitabine, to provide a cumulative assessment on long-term outcomes and associated biomarker analysis of irreversible TKIs in HER2-positive MBC patients. METHODS: We performed a pooled analysis of the phase I trials for pyrotinib or pyrotinib plus capecitabine based on the updated survival data from individual patients. Next-generation sequencing was performed on circulating tumor DNA for predictive biomarkers. RESULTS: A total of 66 patients were enrolled, including 38 patients from the phase Ib trial for pyrotinib and 28 patients from the phase Ic trial for pyrotinib plus capecitabine. The median follow-up duration was 84.2 months (95% CI: 74.7-93.7 months). The estimated median PFS in the entire cohort was 9.2 months (95% CI: 5.4-12.9 months) and median OS was 31.0 months (95% CI: 16.5-45.5 months). The median PFS was 8.2 months in the pyrotinib monotherapy cohort and 22.1 months in the pyrotinib plus capecitabine group, while the median OS was 27.1 months in the pyrotinib monotherapy group and 37.4 months in the pyrotinib plus capecitabine group. Biomarker analysis suggested that the patients harbored concomitant mutations from multiple pathways in HER2-related signaling network (HER2 bypass signaling pathways, PI3K/Akt/mTOR pathway and TP53) were observed with significantly poorer PFS and OS when compared to those with none or one genetic alteration (median PFS, 7.3 vs. 26.1 months, P = 0.003; median OS, 25.1 vs. 48.0 months, P = 0.013). CONCLUSIONS: The updated survival results based on individual patient data from the phase I trials of pyrotinib-based regimen revealed promising PFS and OS in HER2-positive MBC. Concomitant mutations from multiple pathways in HER2-related signaling network may be a potential efficacy and prognosis biomarker for pyrotinib in HER2-positive MBC. TRIAL REGISTRATION: ClinicalTrials.gov. (NCT01937689, NCT02361112).

Clinical N3 is an independent risk factor of recurrence for breast cancer patients achieving pathological complete response and near-pathological complete response after neoadjuvant chemotherapy.

Background: Although achieving pathological complete response (pCR) and near-pathological complete response (near-pCR) after neoadjuvant chemotherapy (NAC) in breast cancer predicts a better outcome, some patients still experience recurrence. The aim of our study was to investigate the predictive factors of recurrence in the pCR and near-pCR population. Methods: We reviewed 1,209 breast cancer patients treated with NAC between January 2010 and April 2021 in the Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS). A total of 292 patients achieving pCR and near-pCR were included in our analysis. pCR was defined as ypT0N0/ypTisN0. Near-pCR was defined as ypT1mi/1a/1bN0 or ypT0/isN1mi. Clinical features and follow-up information were collected. Survival and predictive factors of recurrence were analyzed. Results: Of the 292 patients, 173 were pCR and 119 were near-pCR. The median age was 46 years (range, 23-75 years). The predominant tumor subtypes were human epidermal growth factor receptor type 2 (HER2)-positive breast cancer (49.0%) and triple-negative breast cancer (TNBC) (30.8%). The median duration of follow-up was 53 months (range, 9-138 months). A total of 25 (8.6%) patients developed recurrence, with 9 (5.2%) in the pCR group and 16 (13.4%) in the near-pCR group. The vast majority of recurrence occurred within 36 months from onset of NAC. The 5-year recurrence-free survival (RFS) rate of patients achieving pCR was significantly higher than that of patients achieving near-pCR (94.6% vs. 85.6%, p = 0.008). However, the 5-year overall survival (OS) rate between the two cohorts had no statistical difference (94.3% vs. 89.6%, p = 0.304). Clinical N3 (cN3) before NAC was an independent risk factor of recurrence in patients who achieved pCR (p = 0.003) and near-pCR (p = 0.036). Tumor size before NAC, subtypes of breast cancer, and chemotherapy regimens showed no significant association with RFS both for patients who achieved pCR and for those who achieved near-pCR (p > 0.05). Conclusions: cN3 before NAC was an independent risk factor of recurrence in patients who achieved pCR and near-pCR. It is worthwhile to closely monitor patients with cN3, especially in the first 3 years.

Treatment patterns and clinical outcomes in patients with metastatic breast cancer treated with palbociclib-based therapies: real-world data in the Han population.

BACKGROUND: This study aimed to reveal the treatment patterns and clinical outcomes of diverse palbociclib-based regimens in Han patients with estrogen receptor-positive (ER+) metastatic breast cancer in routine clinical practice. METHODS: The clinical data of patients with ER+ metastatic breast cancer treated with palbociclib were collected from the National Cancer Center database. The efficacy profile of palbociclib in this Han population was evaluated, especially for various combination regimens. The efficacy of palbociclib-based therapy in patients with prior everolimus treatment was also assessed. RESULTS: A total of 186 patients from 89 cities in 18 provinces in China were enrolled. The median progression-free survival (PFS) was similar among different palbociclib-combined groups ( P  = 0.566): 10.0 months (95% confidence interval [CI] 3.8-16.1) in the +exemestane group, 9.7 months (95% CI 6.3-13.1) in the +letrozole group, 7.8 months (95% CI 5.5-10.2) in the +fulvestrant group, 7.2 months (95% CI 3.2-11.3) in the +toremifene group, and 6.1 months (95% CI 1.2-11.0) in the +anastrozole group. Thirty-four patients (18.3%) had received everolimus for their metastatic disease before the prescription of palbociclib. The disease control rate was significantly lower in patients who had received previous everolimus than in the everolimus-naïve group (50.0% vs . 82.2%, P  < 0.001). Patients pre-treated with everolimus had significantly worse PFS than those in the everolimus-naïve group (3.4 months vs . 8.8 months, P   =  0.001). After propensity score matching, patients pre-treated with everolimus had similar PFS (4.4 months, 95% CI 0.5-8.2) compared with everolimus-naïve patients (6.1 months, 95% CI 4.7-7.5, P   =  0.439). CONCLUSIONS: Various palbociclib-based regimens have promising efficacy in ER+ metastatic breast cancer in real-world settings, even in patients who had been pre-treated with everolimus.

Development and External Validation of a Clinical Nomogram for Individually Predicting Survival of Metaplastic Breast Cancer.

BACKGROUND: Few studies have concerned the prognosis of metaplastic breast cancer (MpBC), a rare and diverse malignancy. A prognostic index estimating the MpBC survival would be attractive in clinical practice. PATIENTS AND METHODS: We retrospectively analyzed MpBC patients from the Surveillance, Epidemiology, and End Results (SEER) database. Prognostic factors were identified and the final nomogram was developed to predict the 1-, 3-, or 5-year overall survival (OS). Calibration curves were provided to internally validate the performance of the nomogram and discriminative ability was appraised by concordance index (C-index). RESULTS: A total of 1017 MpBC patients diagnosed between 2010 and 2015 were assigned into 3:1 as training set (n = 763) and SEER validation set (n = 254). An external validation was performed by an individual set of 94 MpBC patients from National Cancer Center in China from 2010 to 2018. The nomogram finally consisted of 7 independent prognostic factors and presented a good accuracy for predicting the OS with the C-index of 0.77 (95% CI: 0.751-0.786). Interestingly, the nomogram based on the western (including 92.5% non-Asian) SEER validation population (C-index of nomogram: 0.76, 95% CI: 0.737-0.796) also has an optimal discrimination in Asian population (C-index of nomogram: 0.70). The calibration plots of the nomogram predictions were also accurate and corresponded closely with the actual survival rates. CONCLUSION: This novel nomogram was accurate enough to predict the OS by using readily available clinicopathologic factors in MpBC general population, which could provide individualized recommendations for patients and clinical decisions for physicians.

Clinicopathological Characteristics and Prognosis of HER2-Low Early-Stage Breast Cancer: A Single-Institution Experience.

Background: Human epidermal growth factor 2 (HER2)-low breast cancer, which is defined as HER2 1+ or 2+ in immunohistochemistry without gene amplification, accounts for a considerable part of all breast cancers. However, it remains controversial whether HER2-low breast cancer is a distinct entity. Our aim was to compare the clinicopathological features and survival outcomes between HER2-zero and HER2-low early breast cancer. Methods: The study was a retrospective analysis that enrolled 1,039 patients with available HER2 expression data in a single institute from 2013 to 2014, of whom 262 HER2-positive patients were excluded from the subsequent analysis. The remaining patients were divided into HER2-zero and HER2-low groups. Each group was further categorized into a hormone receptor (HR)-positive and an HR-negative subgroup. Clinicopathological characteristics were collected and compared between HER2-zero and HER2-low groups. The primary endpoint was disease-free survival (DFS) and overall survival (OS), which were analyzed using the Kaplan-Meier method with log-rank test, landmark analysis, and Cox proportional hazards model. Results: A total of 777 non-HER2-positive patients were included in this analysis, of whom 126, 552, 53, and 46 patients were HR-positive/HER2-zero, HR-positive/HER2-low, HR-negative/HER2-zero, and HR-negative/HER2-low, respectively. No significant difference in DFS and OS was detected between the HER2-zero group and the HER2-low group when paired by HR status. Landmark analysis with a time point set at 5 years indicated that HR-positive/HER2-low patients had a better DFS compared with HR-positive/HER2-zero patients after 5 years (p = 0.0047). HER2-low status was an independent prognostic factor for DFS after 5 years [hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.13-0.75, p = 0.01]. Conclusion: The clinicopathological characteristics and prognosis of HER2-zero and HER2-low breast cancer were similar regardless of HR status. Patients with HR-positive/HER2-low tumors tended to have a better DFS than their HR-positive/HER2-zero counterparts after 5 years.

Chemotherapy Decision-Making and Survival Outcomes in Older Women With Early Triple-Negative Breast Cancer: Evidence From Real-World Practice.

Data regarding chemotherapy options and benefits in older women with early triple-negative breast cancer (TNBC) are limited. Our study aimed to assess the effects of adjuvant chemotherapy on recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS) rates in elderly TNBC patients. Patients aged ≥65 years diagnosed with stage I-III TNBC (except T1aN0) between 2010 and 2016 were retrospectively included. Multivariate Cox regression was performed to minimize bias. A total of 177 patients were included with a median age of 69 years (range, 65-86), almost all had a Charlson Comorbidity Index of 0-2, and 127 (71.8%) received chemotherapy. Patients who received chemotherapy were younger, had more advanced-stage disease and had better ECOG performance status (P<0.05). Among the 127 patients who were administered chemotherapy, 45 (35%) received taxane plus carboplatin, 36 (28%) received anthracycline-and-taxane-based regimens, and 23 (18%) received taxane-based regimens. The regimen options differed based on patient age and tumour stage (P<0.05). Nearly 80% of the patients completed ≥6 cycles of chemotherapy, and half had their dosage decreased. After adjustment for confounding factors, patients who received ≥6 cycles of chemotherapy were found to have improved RFS rates (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.09-0.87; P=0.027), and receipt of chemotherapy (≥1 cycle) was associated with better BCSS (HR, 0.19; 95% CI, 0.04-0.97; P=0.046) and OS (HR, 0.26; 95% CI, 0.08-0.87; P=0.029) rates. These results support the considering the risk for recurrence and performing individualized assessments when determining the appropriate chemotherapy approach for older women with early TNBC.

Targeted gene next-generation sequencing reveals genomic profile in a cohort of 46 Chinese patients with breast cancer.

BACKGROUND: The present study aimed to explore the genomic profile in a cohort of Chinese patients with breast cancer (BC), as well as provide potential strategies for clinic treatment in specific subset of BC patients. METHODS: Paired samples from 46 BC patients were subjected to DNA extraction and 537 gene targeted next-generation sequencing. RESULTS: In total, 742 somatic mutations were detected in these patients, which involved 303 genes. TP53 and PIK3CA were the most frequently mutated genes, with a mutation rate of 45.65% and 26.09%. C>T, T>C and C>A comprised the main single nucleotide base variation for this Chinese cohort. Triple negative breast cancer (TNBC) group had more TP53-mutated patients than the Non-TNBC group (p = 0.0229). In addition, the cohort was also divided into 'Young' and 'Old' groups based on the age of onset. Compared with the 'Young' group, the 'Old' group had more frameshift mutations (p = 0.0190), less missense mutations (p = 0.0269) and more HOXA11-mutated patients (p = 0.0197). Additionally, the HOXA11mt (HOXA11 gene mutated) group had more frameshift mutations than the HOXA11wt (HOXA11 gene without mutation) group (p < 0.0001). In KEGG (i.e. Kyoto Encyclopedia of Genes and Genomes) analysis, the HOXA11wt group had more gene mutations involved in the T cell receptor signaling pathway (p = 0.0197), Jak-STAT signaling pathway (p = 0.0380) and the HIF-1 signaling pathway (p = 0.0489) than the HOXA11mt group. In the present study, the heterogeneity of somatic mutations was revealed between different tumor subgroups, including TNBC/Non-TNBC, age of onset (Young/Old) and HOXA11 mutation (HOXA11mt /HOXA11wt ). CONCLUSIONS: The present study revealed the heterogeneity of gene mutation and clinical variables among BC subtypes and might provide guidance for developing a potential target for clinical treatment.

Predictive value of topoisomerase II alpha protein for clinicopathological characteristics and prognosis in early breast cancer.

PURPOSE: Topoisomerase II alpha (TOP2A) has been identified as a proliferation marker, of which the most common method for detection is immunohistochemistry (IHC). However, the optimal cut-off of TOP2A expression regarding prognostic value remains controversial. This study was to identify the optimal cut-off value of TOP2A expression and its correlation with clinicopathological variables and prognosis in early stage breast cancer in China. METHODS: Between January 2013 and January 2015, a total of 1084 early breast cancer patients were enrolled. The optimal cut-off of TOP2A expression was assessed using the minimum P value approach. Correlations between TOP2A expression and clinicopathological characteristics were explored by the Spearman's correlation analysis, while the impact of TOP2A expression on disease-free survival (DFS) and overall survival (OS) was evaluated by the Kaplan-Meier methods. Univariate and multivariate Cox regression analyses were executed to identify statistically significant prognostic factors. RESULTS: The optimal cut-off value of TOP2A was recommended as 15%. Overall, 603 (55.6%) patients were TOP2A over-expression and 481 (44.4%) patients were TOP2A low expression. TOP2A over-expression was in positive associations with a higher Ki67 index (r = 0.83, P < 0.001), HER2 positive (r = 0.26, P < 0.001), a larger tumor size (r = 0.14, P < 0.001), and a higher histologic grade (r = 0.59, P < 0.001), and in a significantly negative correlation with hormone receptor (HR) positive expression (r = - 0.40, P < 0.001) in early breast cancer. TOP2A over-expression significantly associated with worse DFS (P = 0.001) and OS (P < 0.001) and was an independent prognostic factor for both DFS (hazard ratio [HR] = 2.04; 95% confidence interval [95% CI] 1.30-3.18, P = 0.0018) and OS (HR = 3.54; 95%CI 1.53-8.23, P = 0.003) in stage I-II breast cancer patients. CONCLUSION: To our knowledge, this is the first study to recommend the optimal cut-off value of TOP2A expression in breast cancer. The TOP2A expression is significantly correlated with HER2 status, Ki67 index, tumor size, histologic grade and HR status, and could be a surrogate indicator for poor prognosis of early breast cancer.

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.

BACKGROUND: To 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. METHODS: The 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. RESULTS: The 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. CONCLUSION: In 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.

Updated efficacy of adjuvant epirubicin plus cyclophosphamide followed by taxanes versus carboplatin plus taxanes in early triple-negative breast cancer in phase 2 trial: 8.1-year median follow-up.

BACKGROUND: Paclitaxel/docetaxel after doxorubicin plus cyclophosphamide (ECT) is considered as an adjuvant chemotherapy and improves the survival of early triple-negative breast cancer (TNBC) patients. We aim to assess whether carboplatin plus taxanes (TP) is non-inferior to ECT in prolonging the survival time. METHODS: TNBC patients were randomized (1:1) to receive ECT (90 mg/m2 epirubicin + 600 mg/m2 cyclophosphamide followed by 75 mg/m2 docetaxel or 175 mg/m2 paclitaxel every 3 weeks, n = 154) or TP (75 mg/m2 docetaxel or 175 mg/m2 paclitaxel + carboplatin AUC 5 every 3 weeks, n = 154). These expression of SPARC, PD-L1, and BRCA were studied. Patients were followed up for disease-free survival (DFS), overall survival (OS), and safety. RESULTS: We recruited 308 TNBC patients (median follow-up of 97.6 months). The median DFS and OS were not reached; the 8-year DFS rate of ECT and TP arms was 78.4% and 81.7%, respectively, while the 8-year OS rate were 87.2% and 89.1%, respectively. In the SPARC (> 50%) subgroup analysis, the TP arm had longer DFS (P = 0.049) and a tendency with better OS (P = 0.06) than ECT arm. No significant differences were observed in the DFS and OS between the ECT arm and TP arm in TNBC with SPARC (≤ 50%), PD-L1 (-) PD-L1 (+), and BRCA mutation or BRCA wild (all P values > 0.05). CONCLUSION: TP showed non-inferiority for DFS and OS compared with ECT in early TNBC. TP may be an effective alternative chemotherapy for TNBC patients whom the standard ECT regimen is not being used. TRAIL REGISTRATION: ClinicalTrials.gov identifier NCT01150513.

Risk Factors and Survival of Patients With Liver Metastases at Initial Metastatic Breast Cancer Diagnosis in Han Population.

The risk factors for morbidity and mortality in patients with breast cancer liver metastases (BCLM) upon initial metastatic breast cancer (MBC) diagnosis have not been adequately identified in Han population. Data of 3,161 female patients who were initially diagnosed with MBC from December 1991 to September 2019 and treated in the China National Cancer Center were extracted and a total of 2,263 MBC patients were included in our study, among which 550 patients had liver metastases. Multivariable logistic regression was performed to identify risk factors for the presence of liver metastases at initial MBC diagnosis. Univariable and multivariable Cox proportional hazards regression analyses were conducted to determine prognostic factors for the survival of BCLM patients. Patients with hormone receptor (HR)-negative, human epidermal growth factor receptor 2 (HER2)-positive (35.0% of the entire population) subtype had the highest incidence of liver metastases. De novo stage IV breast cancer, HR-/HER2+ and HR+/HER2+ subtypes were associated with higher odds of liver metastases and patients with lung metastases had lower risk of liver metastases at initial MBC diagnosis. The median overall survival of BCLM patients was 31.4 months and BCLM patients with HR+/HER2- subtype had the longest survival of 38.2 months. Older age, worse performance status, later stage of initial breast cancer, triple-negative subtype and lung metastases were significantly associated with a poorer prognosis in BCLM patients. Our study offers insights into the incidence and prognosis of BCLM patients at initial MBC diagnosis in Han population.

Comparison of capecitabine-based regimens with platinum-based regimens in Chinese triple-negative breast cancer patients with liver metastasis.

BACKGROUND: Capecitabine-based chemotherapy (CBC) presents potential value in patients with liver metastasis; platinum-based chemotherapy (PBC) has shown promising benefit in patients with triple-negative breast cancer (TNBC). For TNBC patients with liver metastasis, which treatment strategy is better remains to be further studied. The aim of this study was to report the first real-world data evaluating the efficacy and safety of PBC versus CBC in the first-line treatment in Chinese TNBC patients with liver metastasis. METHODS: TNBC patients with liver metastasis pretreated with anthracyclines/taxanes in 4 institutions of China between January 2010 and December 2019 were included. Objective response rate (ORR), overall survival, treatment pattern, and toxicity profile were assessed between PBC and CBC groups. RESULTS: A total of 59 TNBC patients with liver metastasis were identified. Among these, 33 were treated with PBC and 26 were treated with CBC. The ORR was higher in the CBC group than in the PBC group (57.7% versus 30.3%, P=0.035). Median overall survival was also greatly improved (19.2 versus 14.4 months, P=0.041). Docetaxel/cisplatin was more likely to be used for PBC, and paclitaxel/capecitabine was the main regimen for CBC. Multivariable Cox regression analysis indicated that CBC was an independent predictor for overall survival after adjustment for baseline factors including age, tumor size, nodal status, prior anthracyclines/taxanes use, and tumor grade (odds ratio =0.51; 95% confidence interval, 0.27-0.98; P=0.042). Adverse events were not different except gastrointestinal tract toxicities, hand-foot syndrome and hematologic toxicity. CONCLUSIONS: For TNBC patients with liver metastasis, capecitabin-based chemotherapy might be more suitable than the platinum-based regimen in the first-line treatment, as measured by objective response rate and overall survival. Further large-scale studies are warranted.

Primary Trastuzumab Resistance After (Neo)adjuvant Trastuzumab-containing Treatment for Patients With HER2-positive Breast Cancer in Real-world Practice.

BACKGROUND: It is difficult to define patients with primary trastuzumab resistance (PTR) after (neo)adjuvant trastuzumab with minimal data and understanding of the actual prevalence, prognosis, and potential treatment strategies in the real-world setting. PATIENTS AND METHODS: The medical records of 1096 patients with human epidermal growth factor receptor 2-positive early-stage breast cancer who had received (neo)adjuvant trastuzumab-containing treatment from 2010 to 2016 in the Cancer Hospital and Chinese Academy of Medical Sciences were reviewed. PTR was defined as recurrence during adjuvant trastuzumab or within 12 months from their last (neo)adjuvant trastuzumab dosage. The cutoff date for data collection was September 1, 2018, with a median follow-up time of 46 months. RESULTS: A total of 126 recurrences were observed, and 75 (6.8%; 75/1096) of them were categorized as PTR; the remaining were non-PTR. The prognosis of patients in the PTR group was much inferior to those in the non-PTR group (27 months vs. not reached; P < .01). As expected, patients with PTR did possess a much lower response rate to first-line trastuzumab-containing therapy (27.3% vs. 61.9%; P = .02). Subgroup analyses indicated that patients in the PTR group seemed to get little survival benefit from the reuse of trastuzumab compared with those without trastuzumab (26 months vs. 28 months; P = .80). However, in the non-PTR group, re-treatment with trastuzumab in the metastatic setting prolonged the survival of patients compared to those without trastuzumab (not reached vs. 34 months; P = .04). CONCLUSION: This study verified the rationality of present definition of PTR after (neo)adjuvant trastuzumab. Patients with PTR did have a poor prognosis. Further research and clinical trials are required to establish the best treatment patterns for these patients.

Incidence, risk factors and survival of patients with brain metastases at initial metastatic breast cancer diagnosis in China.

PURPOSE: To characterize the incidence, risk factors and survival of patients with brain metastases at initial diagnosis of metastatic breast cancer (MBC) in China. METHODS: The China National Cancer Center database was used to identify 2087 MBC patients diagnosed between 2003 and 2015. Clinicopathological features, treatment and survival information were extracted. Multivariable logistic and Cox regression were performed to determine factors predictive of brain metastases at MBC diagnosis and survival, respectively. RESULTS: Brain metastases occurred in ninety patients (4.3%) at MBC diagnosis, and in 27 patients (2.5%), 42 patients (7.2%) and 21 patients (5.2%) with hormone receptor positive, human epidermal growth factor receptor 2 negative (HR + HER2-), HER2-positive and triple negative breast cancer (TNBC), respectively. HER2-positive subtype (OR = 2.38; 95% CI 1.40-4.04; p < 0.0001), TNBC subtype (OR = 1.89; 95% CI 1.02-3.51; p = 0.005), and metastases to all three sites of bone, liver and lungs (OR = 3.23; 95% CI 1.52-6.87; p = 0.002) were shown to increase the risk of BM at MBC diagnosis. Median survival after BM was 23.7 months. First-line tyrosine kinase inhibitors (TKI) improved survival compared to trastuzumab-based regimen (44.9 vs 35.4 months, p = 0.09). Factors that independently decreased BM death risk were ECOG<2, brain metastases only and multidisciplinary treatment. CONCLUSION: HER2-positive and TNBC subtypes have a higher incidence of BM at initial MBC diagnosis. Brain screening might be considered in patients with HER2-positive disease at MBC diagnosis, and further prospective randomized study is warranted.

In Real Life, Low-Level HER2 Expression May Be Associated With Better Outcome in HER2-Negative Breast Cancer: A Study of the National Cancer Center, China.

BACKGROUND: To characterize the clinical and pathological features and survival of patients with human epidermal growth factor receptor 2 (HER2)-low breast cancer in China. METHODS: The China National Cancer Center database was used to identify 1,433 metastatic breast cancer patients with HER2-negative disease diagnosed between 2005 and 2015. Clinicopathological features, survival, and prognosis information were extracted. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Prognostic factors associated with OS were analyzed using Cox regression model with 95% confidence interval (95% CI). RESULTS: There were 618 (43.1%) and 815 (56.9%) HER2-low and HER2-zero tumors out of 1,433 tumors, respectively. The proportion of hormone receptor (HR)-positive tumors was significantly higher in HER2-low tumors than in those with HER2-zero tumors (77.8% vs. 69.2%, p < 0.001). Patients with HER2-low tumors survived significantly longer than those with HER2-zero tumors in the overall population (48.5 months vs. 43.0 months, p = 0.004) and HR-positive subgroup (54.9 months vs. 48.1 months, p = 0.011), but not in the HR-negative subgroup (29.5 months vs. 29.9 months, p = 0.718). Multivariate regression analysis revealed that HER2-low tumors were independently associated with increased OS in HER2-negative population (HR: 0.85, 95% CI: 0.73-0.98, p = 0.026). CONCLUSION: Our findings demonstrate that HER2-low tumors could be identified as a more distinct clinical entity from HER2-zero tumors, especially for the HR-positive subgroup. A more complex molecular landscape of HER2-low breast cancer might exist, and more precise diagnostic algorithms for HER2 testing could be investigated, thus offering new therapeutic targets for breast cancer treatment.

Prognostic Model and Nomogram for Estimating Survival of Small Breast Cancer: A SEER-based Analysis.

BACKGROUND: Different clinicopathologic characteristics could contribute to inconsistent prognoses of small breast neoplasms (T1a/T1b). This study was done to conduct a retrospective analysis and establish a clinical prediction model to predict individual survival outcomes of patients with small carcinomas of the breast. MATERIALS AND METHODS: Based on the Surveillance, Epidemiology, and End Results (SEER) database, eligible patients with small breast carcinomas were analyzed. Univariate analysis and multivariate analysis were performed to clarify the indicators of overall survival. Pooling risk factors enabled nomograms to be constructed and further predicted 3-year, 5-year, and 10-year survival of patients with small breast cancer. The model was internally validated for discrimination and calibration. RESULTS: A total of 17,543 patients with small breast neoplasms diagnosed between 2013 and 2016 were enrolled. Histologic grade, lymph node stage, estrogen receptor or progesterone receptor status, and molecular subtypes of breast cancer were regarded as the risk factors of prognosis in a Cox proportional hazards model (P < .05). A nomogram was constructed to give predictive accuracy toward individual survival rate of patients with small breast neoplasms. CONCLUSIONS: This prognostic model provided a robust and effective method to predict the prognosis of patients with small breast cancer.

Development and validation of a nomogram for predicting survival of advanced breast cancer patients in China.

BACKGROUND: There is a lack of prognostic models predicting the overall survival (OS) of advanced breast cancer (ABC) patients in China. METHODS: Data from the China National Cancer Center database that recorded 4039 patients diagnosed with breast cancer between 1987 and 2019 were extracted and a total of 2263 ABC participants were enrolled in this study, which were further randomized 3:1 and divided into training (n = 1706) and validation (n = 557) groups. The nomogram was built based on independent predictors identified by univariate and multivariate cox regression analyses. The discriminatory and predictive capacities of the nomogram were assessed by Harrell's concordance index (C-index) and calibration plots. RESULTS: Univariate and multivariate analyses found that age, Eastern Cooperative Oncology Group (ECOG) score, T-stage, N-stage, tumor subtype, the presence of distant lymph node (DLN)/liver/brain metastasis, local therapy, efficacy of first-line therapy and metastatic-free interval (MFI) were significantly related to OS (all P < 0.05). These variables were incorporated into a nomogram to predict the 2-year and 3-year OS of ABC patients. The C-indexes of the nomogram were 0.700 (95% confidence interval [CI]: 0.683-0.717) for the training set and 0.686 (95% CI: 0.652-0.719) for the validation set. The calibration curves revealed satisfactory consistency between actual survival and nomogram prediction in both the internal and external validations. The nomogram was capable of stratifying patients into different risk cohorts. CONCLUSIONS: We constructed and validated a nomogram that might serve as an efficient tool to provide prognostic prediction for ABC patients and guide the physicians to make personalized treatment decisions.

Platinum-based chemotherapy in advanced triple-negative breast cancer: A multicenter real-world study in China.

Platinum-based chemotherapy (PBC) has proven benefits in phase III studies for advanced triple-negative breast cancer (TNBC) patients; however, real-world data of large samples from multiple centers are lacking. Our study was to compare the effectiveness of PBC and non-PBC in advanced TNBC patients in multicenter real-world settings. Totally, 495 patients with advanced TNBC receiving PBC (n = 350) or non-PBC (n = 145) at four cancer centers in China between 2003 and 2019 were included. Treatment responses and outcomes were compared between the two groups from first-line to third-line treatment. Of patients with PBC, 249 (71.1%) received PBC from first-line chemotherapy, 86 (24.6%) from second-line and 15 (4.3%) from third-line treatment. In first-line treatment, PBC was superior to non-PBC in objective response rate (ORR, 53.0% vs 32.1%, P < .001) and median progression-free survival (PFS, 8.4 vs 6.0 months, P = .022), whereas overall survival (OS) was similar (19.2 vs 16.8 months, P = .439). When comparing patients receiving non-PBC doublets (n = 221) with those receiving PBC doublets (n = 249), the same trend was observed in ORR (32.6% vs 53.0%, P < .001), median first-line PFS (6.5 vs 8.4 months, P = .041) and median first-line OS(17.8 vs 19.2 months, P = .568). Paclitaxel/docetaxel + platinum was more likely to be used, followed by gemcitabine + platinum. In second/third-line treatment, PBC yielded a similar response and survival compared to non-PBC. Adding PBC in the first-line therapy was better than that in the latter-line of treatment in terms of ORR, PFS and OS (P < .001). Toxic effects of PBC were tolerable and the most common adverse event was neutropenia (38.6%). PBC doublets exhibited superior efficacy and manageable toxicity compared to non-PBC doublets in the first-line treatment for Chinese mTNBC patients.

Carboplatin plus taxanes are non-inferior to epirubicin plus cyclophosphamide followed by taxanes as adjuvant chemotherapy for early triple-negative breast cancer.

PURPOSE: Platinum plays an important role in the treatment of triple-negative breast cancer (TNBC) in neoadjuvant and metastatic settings. However, its role in an adjuvant setting remains unclear. METHODS: In this non-inferior randomized phase 2 trial, we randomly assigned 308 chemotherapy-naive patients with histologically confirmed TNBC after primary surgery to receive either six cycles of TP (docetaxel: 75 mg/m2 or paclitaxel 175 mg/m2 d1; carboplatin AUC = 5, day 1), or four cycles of EC (epirubicin: 90 mg/m2; cyclophosphamide: 600 mg/m2, day 1) followed by four cycles of T (docetaxel: 75 mg/m2 or paclitaxel 175 mg/m2, day 1). The primary end point was the disease-free survival (DFS) rate at 5 years. Both regimens were repeated every 3 weeks. The prognostic and predictive value of germline breast cancer gene mutations and programmed death ligand-1 (PD-L1) expression was evaluated. RESULTS: At a median follow-up of 66.9 months, the 5-year DFS rate was 85.8% in the EC-T arm, and 84.4% in the TP arm (p non-inferiority = 0.034, p log-rank = 0.712). The 5-year overall survival (OS) rate was 94.4% in the EC-T arm and 93.5% in the TP arm (p = 0.770). Patients in the TP arm showed better compliance and experienced significantly lower frequencies of G3/4 neutrocytopenia and G3/4 alopecia, but higher rates of G1-4 thrombocytopenia than those in the EC-T arm. Patients with PD-L1 expressing tumors showed significantly improved DFS and OS. CONCLUSIONS: This study indicates that carboplatin plus taxanes could be a feasible adjuvant chemotherapy for patients with early TNBC who are cannot tolerate intensive chemotherapy with anthracycline.

Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer: A real-world retrospective study in Chinese patients.

OBJECTIVE: To assess the long-term effectiveness and safety of trastuzumab in adjuvant therapy for Chinese patients with early-stage human epidermal growth factor 2 (HER2)-positive breast cancer in a real-world setting. METHODS: This retrospective observational study analyzed the medical records of HER2-positive breast cancer patients between 2000 and 2012 at the Chinese Academy of Medical Sciences. Patients who received adjuvant chemotherapy alone or adjuvant chemotherapy followed by/combined with trastuzumab were included. The Kaplan-Meier method was used to estimate disease-free survival (DFS) and overall survival (OS). Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated using the Cox regression model. RESULTS: Of the 1,348 patients analyzed, 909 received chemotherapy alone and 439 received chemotherapy plus trastuzumab. The 3-year, 5-year and 10-year DFS rates were 83.70%, 76.38% and 68.94%, respectively, in the chemotherapy-alone cohort, and 90.21%, 86.19% and 83.45% in the chemotherapy plus trastuzumab cohort. The 3-year, 5-year and 10-year OS rates were 96.10%, 91.40% and 81.88% in the chemotherapy-alone cohort, and 98.17%, 94.91% and 90.01% in the chemotherapy plus trastuzumab cohort. The chemotherapy plus trastuzumab group had a significantly lower risk of disease recurrence and death than the chemotherapy-alone group (DFS: HR=0.50, 95% CI, 0.37-0.68; P<0.001; OS: HR=0.53, 95% CI, 0.34-0.81; P=0.004) after adjusting for covariates. In the 439 patients treated with trastuzumab, multivariate analysis suggested that lymph node positivity, higher T stages, and hormone receptor-negative status were significantly associated with higher risks of disease recurrence, and lymph node positivity and hormone receptor-negative status were significantly associated with higher risks of death. Grade 3/4 adverse events (incidence ≥1%) were more common in patients receiving trastuzumab (54.44%vs. 15.73%). CONCLUSIONS: Early-stage HER2-positive breast cancer patients treated with trastuzumab plus adjuvant chemotherapy have a significant survival benefit compared with chemotherapy-alone in real-world settings. Lymph node positivity, hormone receptor-negative status, and higher T stages may be associated with higher risks of recurrence, and effective therapy for patients with these factors is required.