Z-M Shao

Weekly paclitaxel plus carboplatin is an effective nonanthracycline-containing regimen as neoadjuvant chemotherapy for breast cancer

BACKGROUND To evaluate the activity and safety of nonanthracycline-containing weekly PCb [paclitaxel (Taxol) plus carboplatin] regimen in neoadjuvant treatment of breast cancer. PATIENTS AND METHODS Eligible patients were assigned to receive four cycles of PCb with dose of paclitaxel 80 mg/m(2) and carboplatin at an area under the curve of 2 mg x min/ml, given day 1, day 8 and day 15 of every 4 weeks. Pathological complete remission (pCR) was defined as no invasive cancer in breast and axillary samples. RESULTS Overall, 107 consecutive patients received weekly PCb treatment from December 2007 to December 2008, and one was diagnosed with bilateral breast cancer. A total of 85.2% of patients were initially diagnosed with stage III diseases. Clinical response rate was 86.1% with complete remission rate 32.4%. Twenty-one patients achieved pCR after neoadjuvant treatment, with pCR rate 19.4%. The incidence of grade 3-4 neutropenia was 40.2% and only one patient was reported with febrile neutropenia. Severe anemia and thrombocytopenia occurred in 4.7% and 0.9%, respectively, of patients. Peripheral neuropathy was frequent but never severe. Patients with estrogen receptor-negative, progesterone receptor-negative, triple-negative or human epidermal growth factor receptor 2 (Her2)-positive subtype disease had higher pCR. CONCLUSIONS Weekly PCb regimen was very active and tolerable as neoadjuvant treatment of breast cancer. This weekly PCb regimen should consider as a reasonable nonanthracycline-containing option in the neoadjuvant treatment of breast cancer.

Treatment outcomes and unfavorable prognostic factors in patients with occult breast cancer.

AIMS The purpose of this study was to evaluate the treatment outcomes and prognostic factors in patients with occult breast cancer (OBC). METHODS We retrospectively analyzed 95 patients with OBC who were treated at our facility between January 1998 and June 2010. Of the 95 patients, 64 underwent mastectomy plus axillary lymph node dissection (ALND) with or without post-mastectomy radiation (Mast + ALND group), 13 underwent ALND followed by ipsilateral breast radiotherapy (BR + ALND group) and the remaining 18 were treated with ALND (ALND group). RESULTS Patients who underwent Mast + ALND or BR + ALND had significantly improved rates of locoregional recurrence-free survival (LRFS) and recurrence/metastasis-free survival (RFS) than patients who only underwent ALND (p < 0.05). There were no significant differences in the LRFS (p = 0.718), RFS (p = 0.935) and breast cancer-specific survival (BCSS) (p = 0.991) rates between the patients who underwent Mast + ALND compared with those who received BR + ALND. Multivariate analysis revealed that patients with four or more involved lymph nodes had significantly worse outcomes (p = 0.042, HR = 4.63, 95% CI = 1.66-32.47 for BCSS and p = 0.038, HR = 3.62, 95% CI = 1.08-20.77 for RFS). CONCLUSIONS Patients with OBC who received ALND and subsequent breast radiotherapy had similar outcomes to patients who underwent mastectomy. The presence of four or more involved lymph nodes may independently predict poor outcomes of OBC.

PPAR signaling pathway may be an important predictor of breast cancer response to neoadjuvant chemotherapy

PurposeNeoadjuvant chemotherapy for advanced breast cancer may improve the radicality for a subset of patients, but others may suffer from severe adverse drug reactions without any benefit. To predict the responses to chemotherapy, we performed a phase II trial of neoadjuvant chemotherapy using a weekly PCb [paclitaxel (Taxol) plus carboplatin] regimen for stage II/III breast cancer and assessed the correlation between baseline gene expression and the tumor response to treatment.MethodsA total of 61 patients with stage II-III breast cancer were included and administered four cycles of preoperative PCb. We performed a gene expression analysis using Affymetrix HG-U133 Plus 2.0 GeneChip arrays in 31 breast cancer tissues. Differentially expressed genes (DEGs) were identified by the significance analysis of microarrays (SAM) program using a false discovery rate of 0.05. The Functional Annotation Tool in the DAVID Bioinformatics Resources was used to perform the gene functional enrichment analysis. The other 30 patients (15 pCR and 15 non-pCR patients) were available as an independent validation set to test the selected DEGs by quantitative real-time PCR analysis (qRT-PCR).ResultsBy analyzing six pathological complete response (pCR) patients and 25 patients with non-pCR, 300 probes (231 genes) were identified as differentially expressed between pCR and residual disease by the SAM program when the fold change was >2. The gene functional enrichment analysis revealed 15 prominent gene categories that were different between pCR and non-pCR patients, most notably the genes involved in the peroxisome proliferator-activated receptor (PPAR), DNA repair and ER signal pathways and in the immune-related gene cluster. The qRT-PCR analysis results for the genes in the PPAR pathway (LPL, SORBS1, PLTP, SCD5, MMP1 and CSTA) in independent validation set were consistent with the results from the microarray data analysis.ConclusionIn the present study, we identified a number of gene categories pertinent to the therapeutic response. We believe that the PPAR pathway may be an important predictor of genes that are involved in the chemotherapy response.

Comparison of molecular analysis and touch imprint cytology for the intraoperative evaluation of sentinel lymph nodes in primary breast cancer: Results of the China Breast Cancer Clinical Study Group (CBCSG) 001c trial

BACKGROUND To validate the clinical value of the One-Step Nucleic Acid Amplification (OSNA) Breast Cancer System for the intraoperative detection of sentinel lymph node (SLN) metastases in early-stage breast cancer patients in a Chinese population, a prospective, multicenter trial, the China Breast Cancer Clinical Study Group (CBCSG)-001c trial, was conducted. The present study focused on the prospective comparison of the performance between OSNA and touch imprint cytology (TIC). METHODS The retrieved SLNs were divided into sections. Alternate slices from the tissue blocks were subjected either to OSNA analysis or to postoperative histopathology evaluation through serial sectioning. TIC was performed on every sample surface of each tissue block and was used by the surgeon to determine whether to perform an immediate ALND. RESULTS A total of 552 patients qualified for the analysis. The sensitivity, specificity, and overall accuracy of OSNA were 87.8%, 89.6%, and 88.4%, respectively, on a per-patient basis compared with those of TIC, which were 81.3%, 96.9%, and 92.0%, respectively. OSNA detected more micrometastasis-involved nodes than TIC (52.8% vs. 25.0%; p = 0.029) on a per-node basis. Tissue allocation bias (TAB) was the main cause of discordant results. The performance of TIC varied significantly among the institutes, while the performance of OSNA was steady. CONCLUSIONS Both OSNA and TIC can serve as qualified intraoperative assessments of SLNs. For institutes lacking the support of experienced cytopathologists, OSNA can be the first choice for the intraoperative assessment. In addition, OSNA can be applied as a complement to histopathology assessment. However, the results of the present study do not support the routine application of OSNA in the entire SLNs in place of pathology with serial sectioning.

Biomarker assessment of the CBCSG006 trial: A randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer.

Background CBCSG006 trial reported the superior efficacy of cisplatin plus gemcitabine (GP) regimen than paclitaxel plus gemcitabine (GT) regimen as first-line treatment of metastatic triple-negative breast cancer (mTNBC). This study focused on the updated survival data and the explorations of potential biomarkers for efficacy. Patients and methods Germ-line mutations of homologous recombination (HR) panel, BRCA1/2 included, were evaluated in 55.9% (132/236) patients. PD-L1 expression was evaluated in 48.3% (114/236) patients. A nonparametric sliding-window subpopulation treatment effect pattern plot (STEPP) methodology was used to analyze the absolute survival benefits. All statistical tests were two-sided. Results Median progression-free survival (PFS) was 7.73 [95% confidence interval (CI) 6.46-9.00] months for GP arm and 6.07 (95% CI 5.32-6.83) months for GT arm (P = 0.005). No significant difference in overall survival (OS) was observed. There was significant interaction between HR status and treatment for PFS and status of HR deficient significantly correlated with higher objective response rate (ORR) and longer PFS in GP arm than in GT arm (71.9% versus 38.7%, P = 0.008; 10.37 versus 4.30 months, P = 0.011). There was no significant interaction between germ-line BRCA1/2 (gBRCA1/2) status and treatment for PFS. Patients with gBRCA1/2 mutation had numerically higher ORR and prolonged PFS in GP arm than in GT arm (83.3% versus 37.5%, P = 0.086; 8.90 versus 3.20 months, P = 0.459). There was no significant interaction between PD-L1 status and treatment for PFS, and no significant differences in ORR, PFS or OS between two arms regardless of PD-L1 status. In STEPP analysis, patients with lower composite risks had more absolute benefits in PFS than those with higher composite risks. Conclusions GP regimen has superior efficacy than GT regimen as first-line chemotherapy for mTNBC patients. Germ-line mutations of BRCA1/2 and HR panel are possible biomarkers for better performance of cisplatin-based regimens. A composite risk model was developed to guide patient selection for GP treatment in TNBC patients. Trial registration ClinicalTrials.gov, NCT01287624.

Diffusion-Weighted MRI in Predicting the Efficacy of Neoadjuvant Chemotherapy of Breast Cancer.

Objective: To approach the apparent diffusion coefficient(ADC) obtained on diffusion weighted imaging (DWI) in predicting the response of breast cancer to neoadjuvant chemotherapy. Methods: 53 locally advanced breast cancer patients participated in this prospective study on neoadjuvant chemotherapy. All patients were treated with weekly neoadjuvant paclitaxel plus carboplatin for 4 cycles. DWI and ADC value were examined before chemotherapy(the first time point), after the first and the forth cycle of chemotherapy(the second and the third time point). Patients were categorized as high responders if their ADC at the second time point were higher by 2 times the standard deviation than the mean pre-chemotherapy ADC, and otherwise the patients were considered as low responders. Logistic regression was conducted to examine the independent factors predictive of clinical complete response(CR) and pathologic complete response(pCR). Results: CR was documented in 13 patients (24.5%); partial response in 36 patients (67.9%); stable disease in 4 patients (7.5%) and no patient had progressive disease. 11 patients(20.8%) have achieved pCR. There was a strong positive correlation between the percentage changes in ADC value at the third time points and the degree of the tumor reduction. A significant increase in ADC value was observed at the second time point compared with the first time point (1.104±0.117×10 -3 mm 2 /s, 1.220±0.158×10 -3 mm 2 /s, P P >0.05). Logistic regression revealed that percentage changes of ADC value at the second time point were significantly associated with CR( P =0.022, hazard ratio[HR] =1.08, 95% confidence interval[CI]: 1.01∼1.16) and pCR( P =0.022, HR =1.11, 95%CI: 1.02∼1.21). The AUC value of the receiver operating characteristic curve were 0.721(95%CI: 0.512∼0.931, P =0.017) and 0.775(95%CI: 0.598∼0.952, P =0.005) in the two diagnostic tests for CR and pCR, and the sensitivity and specificity were 76.9%, 63.6% and 77.5%, 90.5%, respectively. According to categorizing system described above, 10 patients(18.9%) were considered as high responders and 43 patients(81.1%) low responders. 7 patients(70%) of the high responders have achieved clinical CR and pCR while for the low responders there were only 6 patients(14.0%) and 4 patients (9.3%) proven to have CR and pCR. The difference have both reached statistical significance( P =0.001, P P =0.006, HR=42.26, 95%CI: 2.86∼624.08) and pCR( P =0.013, HR=25.19, 95%CI: 2.00∼318.91). Taking this categorizing system as a dignostic test, the sensitivity and specificity were 53.8% and 92.5% for CR and 63.6% and 92.9% for pCR, respectively. Conclusions: The change of ADC value obtained on DWI after the first cycle of neoadjuvant chemotherapy occured prior to the morphologic changes of the tumor and at this time ADC value could to some extent predict the efficacy of neoadjuvant chemotherapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4025.

Abstract P1-06-07: Clinical and molecular relevance of intra-tumor genetic heterogeneity in breast cancer: Integrative analysis of data from The Cancer Genome Atlas

Background: Intra-tumor heterogeneity (ITH) plays a pivotal role in driving breast cancer progression and therapeutic resistance. Emerging evidence has indicated that the extent of genetic heterogeneity may serve as a clinically useful biomarker. While several studies have suggested the prognostic value of ITH in several cancer types, the clinical significance of genetic ITH and molecular portraits that correlated with different ITH levels were poorly understood in breast cancer. The establishment of algorithms estimating genetic ITH based on sequencing of bulk tumor DNA offered us an opportunity to explore the clinical implication of ITH in large breast cancer cohorts and, for the first time, to use integrative genomic analyses to reveal molecular portraits related to intra-tumor genetic heterogeneity. Methods: We assessed 916 female breast cancer patients from The Cancer Genome Atlas. Mutant-allele tumor heterogeneity (MATH) values were calculated from whole-exome sequencing data. We used integers nearest to the tertiles of the MATH values as cutoff points to divide the patients into three groups nearly equal in size. The association between MATH value and clinical characteristics was evaluated, followed by survival analyses in these different MATH groups. We then compared the rates of total non-silent somatic mutations among the different MATH groups, and further determined the mutations independently associated with high MATH by logistic regression adjusting for T classification and clinical subtypes. Similar methods, superadding somatic copy number alteration (SCNA) burden in logistic model, were used to evaluate SCNA events that were significantly associated with high MATH level. Gene enrichment between the high and rest MATH groups was analyzed using Gene Set Enrichment Analysis. Results: The patients were divided into low (MATH value lower than 33), intermediate (MATH between 33 and 46) and high (MATH higher than 46) MATH groups. High T stage, African American race, and triple-negative or basal-like subtype were associated with a higher MATH level (all P Conclusion: Our study extended the knowledge concerning the clinical role of ITH in breast cancer, especially the distinct pattern of prognostic values in different clinical subtypes, which may help promote the clinical utilization of genetic ITH. Our attempt at exploring the molecular features related to ITH might provide clues for the source and consequences of ITH, inspiring subsequent experiments investigating the laws underling tumor heterogeneity. Citation Format: Ma D, Jiang Y-Z, Liu X-Y, Liu Y-R, Yu K-D, Shao Z-M. Clinical and molecular relevance of intra-tumor genetic heterogeneity in breast cancer: Integrative analysis of data from The Cancer Genome Atlas [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-06-07.

Abstract P1-07-13: The mutation detection and a high throughput screening of driver mutations in PI3K/AKT pathway based on next generation sequencing

Background The deregulation of the PI3K/AKT signaling pathway is essential to malignant cellular processes of breast cancer, including proliferation, apoptosis, and drug response. Oncogenic activating somatic mutations in the PI3K/AKT pathway are pervasive. However, it remains difficult to discriminate between driver and passenger mutations. This study was conducted to identify the landscape of genetic mutations in the PI3K/AKT pathway using Amplicon Sequencing in a Chinese population. Notably, we developed a Gateway-based mutation barcoding (GaMB) library which enables a high-throughput mutation-phenotype screen for specific vulnerable mutations that contribute to the cancer development and drug resistance. Method We collected 149 breast cancer specimens in a Chinese population and performed Ion Torrent Amplicon Sequencing for the key genes in PI3K/AKT pathway: PIK3CA, PIK3R1, AKT1, AKT2, AKT3, PTEN, PDK1, and the canonical tumor suppressor gene TP53, at 1000× coverage. Next, we established a high-throughput GaMB library that contained all of the PIK3CA mutations, either newly identified in Chinese population or reported in TCGA and COSMIC database, and tagged each mutations with a specific barcode. We then applied this library to functional screening processes using proliferation and drug response selection (doxorubicin or BKM-120) assays through which we screened the functional mutations with specific characteristics. The genomic DNA of the pooled surviving cells from the library, as well as the original cells before the screenings, was extracted and used for PCR amplification of the barcode regions, and then detected using Illumina Miseq sequencing to analyze the functional mutations. We then validated the cellular 2D- & 3D- proliferation abilities and the status of PI3K/AKT pathway activation in presence of identified mutations, respectively. Result Mutations in the PIK3CA (44%), PIK3R1 (37%), AKT3 (15%) and PTEN (12%) genes were the most prevalent. Mutations in PIK3CA were present in 65 samples (43.6%) which is similar to that reported in TCGA database. PIK3R1 (37%) was found significantly mutated, with a novel recurrent mutation, N595S, being identified in 24 patients. Similarly, AKT1 (10.1%), AKT2 (10.1%), and AKT3 (14.8%) mutations were present at a higher frequency in our population than has been reported in the TCGA and COSMIC database. In the PIK3CA-GaMB library, our highest-ranking mutations included the previously validated deleterious mutations H1047R and E545K and several mutations of uncertain significance, including E39K, G1049R, N345I, N345K, M1043V, and H1047T. In the validation assays, we found a high phenotype-consistency of these identified mutations using these functional validation techniques. The breast cancer cells harboring identified mutations exhibit a relatively higher proliferation ability and tolerance to chemotherapy and pathway inhibitors. Conclusion This study identified the landscape of genetic mutations in the PI3K/AKT pathway using Amplicon Sequencing in a Chinese population. A novel developed GaMB screening platform may allow the rapid identification of significant mutations that dominate breast cancer development and drug responses during treatment. Citation Format: Chen L, Yang L, Yao L, Hu X, Shao Z. The mutation detection and a high throughput screening of driver mutations in PI3K/AKT pathway based on next generation sequencing [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-13.

Abstract P6-09-29: Clinicopathological characteristics and survival outcomes in invasive papillary carcinoma of the breast: A population-based study

Background Invasive papillary carcinoma (IPC) is defined as having papillary architecture in >90% of the invasive component. The overall incidence of IPC is low, accounting for less than 1-2% of all newly diagnosed cases of invasive breast cancer. Limited data are available that contribute to a comprehensive summarization of the clinicopathological characteristics and prognostic factors that are associated with IPC. We aimed to determine the clinicopathological characteristics and prognostic factors of IPC in a large population and help physicians to acquire a better understanding of the disease and make better informed therapeutic decisions. Methods We identified 233,171 female patients in the Surveillance, Epidemiology, and End Results (SEER) database who had IPC (n = 524) or infiltrating ductal carcinoma (IDC) (n = 232,647). The demographics and tumour and treatment characteristics of IPC were compared to those of IDC. A Cox proportional hazards model was used to investigate the effects of baseline characteristics on disease-specific survival (DSS). We performed a 1:1 (IPC: IDC) matched case-control analysis using the propensity score-matching method. A forest plot of hazard ratios (HRs) that was used to illustrate the exploratory subgroup analyses. Results Generally, IPCs occurred in older women (≥50 years old) and presented with smaller sizes, lower grades, higher rates of oestrogen receptor (ER) and progesterone receptor (PR) positivity, and reduced lymph node (LN) involvement and were less likely to be treated with mastectomy than patients with IDC. The five-year DSS rates were significantly better in IPC than in IDC (97.5% vs. 93%, respectively; P Conclusions This study is currently the largest analysis of IPC. We investigated a large cohort of patients with IPC and found that this rare tumour type presents unique clinicopathological characteristics and is associated with a higher rate of breast-conserving surgery and favourable prognoses than are observed in the overall IDC population. However, this advantage was diminished after we adjusted for demographic and clinicopathological factors. Therefore, patients diagnosed with this rare variant should be made aware that its biological features are not as favourable as once thought. Therapeutic decisions should not be made based solely on this rare entity and evidence-based treatment guidelines should be strictly followed. Improving our understanding of the clinical and biological features of IPC may lead to more individualized and tailored therapies for breast cancer patients. Citation Format: Zheng Y-Z, Hu X, Shao Z-M. Clinicopathological characteristics and survival outcomes in invasive papillary carcinoma of the breast: A population-based study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-29.

Abstract P1-14-18: Postmastectomy radiotherapy improves the outcomes of stage III breast cancer patients with negative lymph nodes after neoadjuvant chemotherapy

Purpose: The aim of this study is to evaluate the role of postmastectomy radiotherapy (PMRT) in clinical stage II and III breast cancer patients who achieved negative node status (pN0) after neoadjuvant chemotherapy (NAC). Material and methods: We retrospectively analyzed the outcomes of 143 patients with pN0 after NAC and mastectomy at Fudan University Shanghai Cancer Center. In total, 103 (72%) patients received PMRT, and 40 (28%) patients did not. Univariate and multivariate survival analyses were performed to evaluate the effect of PMRT on locoregional recurrence-free survival (LRRFS) and overall survival (OS) of the two groups. Results: There were no differences between the two groups with respect to age, nuclear grade, estrogen receptor (ER) status, HER2/neu receptor status, lymphovascular space invasion (LVSI) status or pathological tumor size. However, a significantly higher proportion of patients in the irradiated group (64%) had clinical lymph node involvement than in the nonirradiated group (45%). After a median follow-up time of 49 months, 10 locoregional recurrence events occurred. For the entire cohort of patients, use of radiation therapy improved the 5-year LRRFS rate (94.5% vs. 80.2%; P =0.032) but not the 5-year OS rate (92.2% vs. 88.7%; P =0.617). In the subset of patients who presented with clinically stage II disease, the 5-year LRRFS and 5-year OS did not differ significantly between the PMRT and no-PMRT group (96.3% vs. 91.3%; P = 0.190 and 96.2% vs. 91.3%; P = 0.199, respectively). For patients with stage III disease at diagnosis, a trend was seen toward better local regional control with PMRT (the 5-year LRRFS rate was 92.7% vs. 64.2%; P = 0.063), although the benefit from radiation with respect to OS was not significant (5-year OS rate was 88.1% vs. 85.2%; P = 0.657). On multivariate Cox regression analyses, the clinical tumor size (hazard ratio [HR], 3.27; 95% confidence interval [CI], 1.05-10.18; P = 0.041), pathologic breast tumor response (HR, 1.82; 95% CI, 1,11-3.77; P = 0.046) and delivery of radiation therapy (HR, 1.27; 95% CI, 1.08-9.25; P = 0.047) were independent predictors of locoregional recurrence. Conclusions: For patients who achieved pN0 after NAC, PMRT seemed to provide a clinical benefit for breast cancer patients with stage III disease. Omission of PMRT in patients with stage II disease did not increase the risk of locoregional recurrence and death. Citation Format: He M, Li J, Ni X-J, Chen S, Jiang Y-Z, Di G-H, Shao Z-M. Postmastectomy radiotherapy improves the outcomes of stage III breast cancer patients with negative lymph nodes after neoadjuvant chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-18.