Dataset Information

Miller-Payne Grading and 70-Gene Signature Are Associated With Prognosis of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early-Stage Breast Cancer After Neoadjuvant Chemotherapy.

ABSTRACT:

Introduction

HR+/HER2- breast cancer (BC) has a much lower pathological complete response (pCR) rate to neoadjuvant chemotherapy (NAC). Therefore, to better stratify the relapse risk for HR+/HER2- non-pCR populations, it is essential to accurate identification new prognostic markers.

Materials and methods

The study retrospectively analyzed 105 stage II-III patients who were diagnosed with HR+/HER2- BC and received NAC followed by breast and axilla surgery between 2013 and 2019 in Sun Yat-Sen University Cancer Center. The Miller-Payne (MP) grading system was used to evaluate pathological responses to NAC. The 70-gene signature was used to classify the prognosis signatures.

Results

Among the 105 patients, the study demonstrated that larger tumor size and lower progesterone receptor level at baseline and larger tumor size postoperative were statistically significantly associated with worse disease-free survival (DFS) (p = 0.004, p = 0.021, and p = 0.001, respectively). Among 54 patients who underwent the 70-gene assays, 26 (48.1%) had a low-risk signature; 28 (51.9%) patients had a high-risk signature. Patients with poor response (MP grades 1-2) were more likely to with a high-risk 70-gene signature than those with good response (MP grades 4-5). The final analysis showed that DFS was longer in the low-risk group than in the high-risk group [52.4 vs. 36.1 months of the median DFS, hazard ratio (HR) for recurrence, 0.29; 95% confidence interval (CI), 0.10-0.80; p = 0.018]. DFS was longer in the good response (MP grades 3-4) group than in the poor response (MP grades 1-2) group (94.7% vs. 60% of the patients free from recurrence; HR, 0.16; 95% CI, 0.05-0.47; p = 0.037). When stratified by MP grades combined with the 70-gene signature, subgroup analyses showed the good-response low-risk group with the best DFS, whereas the poor-response high-risk group showed the worst DFS (p = 0.048). Due to the short median follow-up time of 34.5 months (5.9-75.1 months), MP grades and the 70-gene signature did not show significant prognostic value for overall survival.

Conclusion

The study showed that analysis of MP grades combined with the 70-gene signature with residual NAC-resistant breast samples has a significant correlation with DFS.

SUBMITTER: Wang L

PROVIDER: S-EPMC8498026 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ImportanceAlthough neoadjuvant endocrine therapy (NET) is an alternative to chemotherapy for strongly hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (ERBB2)-negative breast cancer, evidence is currently lacking regarding the probable survival outcomes of NET in comparison with those of neoadjuvant chemotherapy (NACT) for this cancer.ObjectiveTo evaluate all-cause mortality among patients with strongly HR-positive and ERBB2-negative breast cancer treated with NET vs NACT.Design, setting, and participantsThis cohort study included patients with a diagnosis of invasive ductal carcinoma (IDC) with strong HR positivity and ERBB2 negativity, treated between January 1, 2009, and December 31, 2016, with follow-up from the index date (ie, date of IDC diagnosis) to December 31, 2018. The data came from the Taiwan Cancer Registry Database. Data were analyzed from January to November 2020.ExposuresNET vs NACT for IDC with strong HR positivity and ERBB2 negativity.Main outcomes and measuresThe primary end point was all-cause mortality. Propensity score matching was performed, and Cox proportional hazard models were used to analyze all-cause mortality among patients undergoing different neoadjuvant treatments.ResultsA total of 640 patients (297 [46.4%] aged 20-49 years) undergoing NET (145 patients [22.7%]) or NACT (495 patients [77.3%]) were eligible for further analysis. In the multivariate Cox regression analyses, the adjusted hazard ratio (aHR) for all-cause mortality among the NET cohort compared with the NACT cohort was 2.67 (95% CI, 1.95-3.51; P < .001). The aHRs for age were 1.13 (95% CI, 1.03-2.24), 1.25 (95% CI, 1.13-2.45), and 1.37 (95% CI, 1.17-3.49) for all-cause mortality among patients aged 50 to 59, 60 to 69, and 70 years or older, respectively, compared with those aged 20 to 49 years (P = .002); the aHR for all-cause mortality among premenopausal women was 1.35 (95% CI, 1.13-1.56) compared with postmenopausal women (P < .001); and that of patients with a Charlson Comorbidity Index score of 2 or greater was 1.77 (1.37-2.26) compared with those with a score of 0 (P < .001). The aHRs of all-cause mortality for clinical tumor stage 2, 3, and 4 compared with 1 were 1.84 (95% CI, 1.07-3.40), 1.97 (95% CI, 1.03-3.77), and 2.49 (95% CI, 1.29-4.81), respectively (P = .009). The aHRs for all-cause mortality by clinical nodal (cN) stages were 1.49 (95% CI, 1.13-1.99) and 1.84 (95% CI, 1.31-2.61) for cN stage 1 and cN stages 2 or 3, respectively, compared with cN stage 0 (P = .005); those for differentiation were 1.77 (95% CI, 1.24-2.54) and 2.31 (95% CI, 1.61-3.34) for differentiation grade 2 and differentiation grade 3, respectively, compared with differentiation grade 1 (P < .001).Conclusions and relevanceThe findings of this study suggest that for patients with strongly HR-positive and ERBB2-negative IDC, NACT may be considered the first choice for neoadjuvant treatment.

Project description:BackgroundNeoadjuvant chemotherapy (NCT) is considered more effective in downstaging hormone receptor-positive (HR+) breast cancer than neoadjuvant endocrine therapy (NET), particularly in node-positive disease. This study compared breast and axillary response and survival after NCT and NET in HR+ breast cancer.MethodsBased on American College of Surgeons Oncology Group (ACOSOG) Z1031 criteria, women age 50 years or older with cT2-4 HR+ breast cancer who underwent NET or NCT and surgery were identified in the National Cancer Database 2010-2016. Chi-square and logistic regression analysis determined differences between the NCT and NET groups and therapy response, including downstaging and pathologic complete response (pCR, ypT0/is and ypN0).ResultsOf 19,829 patients, 14,025 (70.7%) received NCT and 5804 (29.3%) received NET. The NET patients were older (mean age, 68.9 vs. 60.3; P < 0.001) and had greater comorbidity (1+ Charlson-Deyo score, 21% vs. 16%; P < 0.001). Therapy achieved T downstaging (any) for 58% of the patients with NCT versus 40.5% of the patients with NET, and in-breast pCR was achieved for 9.3% of the NCT versus 1.3% of the NET patients (P < 0.001). Approximately half of the mastectomy procedures could have been potentially avoided for the patients with in-breast pCR (53.6% of the NCT and 43.8% of the NET patients). For the cN+ patients, N downstaging (any) was 29% for the NCT patients versus 18.3% for the NET patients (P < 0.001), and nodal pCR was achieved for 20.3% of the NCT versus 13.5% of the NET patients (P < 0.001). Among those with nodal pCR, axillary lymph node dissection (ALND) still was performed for 56% of the patients after NCT and 45% of the patients after NET.ConclusionsAlthough the response rates after NCT were higher, NET achieved both T and N downstaging and pCR. Neoadjuvant endocrine therapy can be used to de-escalate surgery for patients who cannot tolerate NCT or when chemotherapy may not be effective based on genomic testing.

Project description:BACKGROUND:The integration of residual cancer burden (RCB) and post-treatment Ki67 as residual proliferative cancer burden (RPCB) has been proposed as a stronger predictor of long-term outcome in unselected patients with breast cancer (BC) undergoing neoadjuvant chemotherapy (NACT), as compared with RCB. However, no specific analysis in hormone-receptor-positive (HR+) human epidermal growth receptor 2-negative (HER2-) BC is available so far. MATERIALS AND METHODS:A cohort of 130 patients with HR+/HER2- BC who underwent NACT between 2000 and 2014 was included. Archival surgical specimens were evaluated for RCB. RPCB was calculated by combining RCB and Ki67 as previously described. Patients were categorized in four RCB and RPCB categories (pathological complete response and tertiles). Disease-free survival (DFS) and overall survival (OS) estimates were determined by Kaplan-Meier analysis and compared using the log-rank test. Overall change of ?2 and c-indexes were used to compare the performance of the prognostic models. RESULTS:RPCB was calculated for 85 patients. After a median follow up of 8.5?years, RCB was associated with OS (p = .048) but not with DFS (p = .152); RPCB was instead significantly associated with both DFS and OS (p = .034 and p < .001, respectively). In terms of OS, RPCB provided a significant amount of prognostic information beyond RCB (??2 5.73, p < .001). In addition, c-index for OS prediction was significantly higher for RPCB as compared with RCB (0.79 vs. 0.61, p = .03). CONCLUSION:This is the first study evaluating RPCB in patients with HR+/HER2- BC treated with NACT. In this independent cohort, RPCB was a strong predictor of DFS and OS. The better performance of RPCB versus RCB was in part due to the ability of RPCB to discriminate a subgroup of patients with a particularly worse prognosis after NACT, who may be candidates for clinical trials evaluating novel adjuvant strategies. IMPLICATIONS FOR PRACTICE:The present work validated residual proliferative cancer burden (RPCB) as a strong predictor of long-term outcome in patients with hormone receptor-positive human epidermal growth receptor 2-negative (HR+/HER2-) breast cancer (BC) treated with neoadjuvant chemotherapy. In addition, results from the present study suggest RPCB as a promising tool to identify patients with HR+/HER2- BC who might potentially benefit from the inclusion in clinical trials evaluating novel or escalated postneoadjuvant treatment strategies because it allowed to discriminate a subgroup of patients with particularly poor prognosis despite having received subsequent endocrine therapy in the adjuvant setting.

Project description:The aim of this study was to compare the gene expression profile changes breast tumors after the treatment with Anthracyclines and Taxanes. To this end, an oligonucleotide microarray was performed (Affymetrix’s HG-U133 Plus 2.0 array). This gene expression study was carried out on the biopsied tumor samples previous being treated with chemotherapy, and subsequently compared with themselves once treatment schedule ended. The post-chemotherapy biopsy was obtained from the surgical piece. The goal of this study was the finding of several genes related to apoptosis, proliferation, differentiation, survival and transformation-related genes and correlating their differences in expression with the degree of response to chemotherapy, determined by the Miller and Payne histological grading system. After informed consent, patients with a histologically confirmed diagnosis of breast cancer and scheduled chemotherapy treatment based on Anthracyclines and Taxanes (Treatment A: Epirubicin 90 mg/m2-Cyclophosphamide 600 mg/m2, 3 cycles bi-weekly and Paclitaxel 150 mg/m2-Gemcitabine 2500 mg/m2, 6 cycles bi-weekly ± weekly Herceptin 4 mg/Kg during the first week, 2 mg/Kg for the remaining 11 cycles; Treatment B: Doxorubicin 60 mg/m2-Pemetrexed 500 mg/m2, 4 cycles tri-weekly and Docetaxel 100 mg/m2, 4 cycles tri-weekly; Treatment C: Doxorubicin 60 mg/m2-Cyclophosphamide 600 mg/m2, 4 cycles tri-weekly and Docetaxel 100 mg/m2, 4 cycles tri-weekly ) were recruited for this study. Pre-chemotherapy and post-chemotherapy biopsies were examined by a pathologist who determined the Miller & Payne grade for each patient. Matching pairs of pre-chemotherapy and post-chemotherpy samples were divided into 3 groups according to Miller & Payne grade: group of bad response (Miller & Payne grades 1 and 2), group of mid response (Miller & Payne grade 3) and group of good response (Miller & Payne grades 4 and 5). Gene expression analysis was performed in paired samples as follows: mid response group post-chemotherapy biopsy vs pre-chemotherapy biopsy (Mid final vs initial). For this assay were necessary 20 samples being chosen according to histopathologic criteria (Miller & Payne grade 3). Other comparisons in which this group of samples was involved include: Initial Good vs Mid, Initial Bad vs Mid, Final Bad vs Mid and Final Good vs Mid. This gene expression profiling was carried out making use of Affymetrix’s GeneChip technology, with the Affymetrix’s HG-U133 Plus 2.0 array from this provider. All the protocols and apparatus were recommended by Affymetrix. Total RNA from frozen mammary tumors was directly extracted by a RNeasy Mini kit and homogenized by QIAshredder columns under manufacturer’s instructions. The quality and quantity of the obtained RNA, was checked out through agarose electrophoresis and later spectrophotometry at 260/280 nm. Biotinylated cRNA was synthesized following the IVT labeling kit from Affymetrix and purified by the GeneChip Sample Cleanup Module from Affymetrix. Once again, the quality and quantity of the obtained cRNA, was checked out through agarose electrophoresis and posterior spectrophotometry at 260/280 nm. After hybridization, slides were washed and scanned following the manufacturer’s standard protocol. Intensity values were normalized by Robust Multichip Average method and subsequently these were filtered for remove the control sequences and those with a hybridization signal near to background. The spike controls were: BioB, BioC, BioD and Cre; because BioB was the less presented in the samples, it was used to estimate the sensitivity of the experiment. The housekeeping control was GAPDH. After non-supervised PCA analysis and clustering, gene expression statistical significances were identified by two regression models taking into account the pathologic response to chemotherapy and if the sample was obtained before or after chemotherapy treatment. Supervised PCA analysis and clustering were performed with processed data. Partek Genomics Suite v7.3.1 (Partek) software was employed for the statistic analysis and clustering.

Project description:PurposeTo develop a scoring system for hormone receptor-positive (HR+) breast cancer patients who are expected to achieve axillary pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). To confirm the correlation between axillary status and survival rate in HR+ breast cancer after NAC.MethodsWomen from the Shanghai Jiao Tong University Breast Cancer Database (SJTU-BCDB) who underwent NAC for cT1-4N1-3M0 primary HR+ breast cancer between 2009 and 2018 were included in the study. In this case, patient follow up was performed until 2022 for those with complete data before and after NAC. The main outcome measures were the axillary pCR rate, overall survival (OS), and disease-free survival (DFS). The patients were randomly assigned to a test set (n = 175) and a validation set (n = 68) in a 7 : 3 ratio. A prediction risk score was then developed based on the odds ratios from the multivariate analysis of the test set (n = 175) before being validated in the validation set (n = 68). Finally, the Kaplan-Meier curves were used to explore the survival on this score system.ResultsFrom the database, 243 women were included, and the median follow-up period was 47.5 months (95% confidence interval: 41.9-53.1). The axillary pCR rate was 18.9% (46 of 243), with the independent predictors of residual positive axillary lymph nodes (LNs) being lymphovascular invasion (LVI), breast conserving surgery (BCS), Ki67 < 14%, HER2 negativity, positive lymph nodes in ultrasound (US) before surgery, and stage III histological grade (All, P < 0.05). Using the above predictors of the model, the receiver operating characteristic (ROC) curve was used for calibration and inspection, with values for the test and validation sets being 0.847 (P < 0.001; 95% CI: 0.769, 0.925) and 0.813 (P < 0.001; 95% CI: 0.741, 0.885), respectively. The total risk score ranged from 0 to 6 for the multivariate analysis, and from this range, a risk score of 0-2 was defined as a low-risk group, while scores of 3-6 were defined as the high-risk one. By constructing the survival curve, it was found that the 5-year OS rates for the low-risk and high-risk groups were 89.0% and 84.2% (P = 0.236). Similarly, the 5-year DFS rates for the low-risk and high-risk groups were 80% and 68.5% (P = 0.048), respectively. In addition, axillary pathological stages were significantly correlated with the overall survival (OS) and disease-free survival (DFS) (All, P < 0.05).ConclusionThe prediction model showed good performance for HR + breast cancer. LVI, BCS, low Ki-67, HER2 negativity, suspected positive LNs before surgery, and stage III histological grade were all risk factors for residual positive axillary LNs. However, unlike pathological stages, achieving pCR in the axillary LNs does not affect the survival status.

Project description:PurposeThe phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer.Patients and methodsI-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week.ResultsMK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform).ConclusionThe Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.