The Exploration Of Prognostic Factors And Predictive Factors For Response To Neoadjuvant Therapy In Early-stage Breast Cancer

Background and aim:With the wide use of mammographic screening programs,the incidence of DCIS has markedly increased by five folds over the last 3 decades,accounting for approximately 20%to 25%of newly diagnosed malignancies of the breast in the United States currently.Ductal carcinoma in situ with microinvasion(DCISM)is an uncommon pathologic entity accounting for approximately 1%of all breast cancer cases.It remains poorly understood whether the biologic behavior and survival outcomes of microinvasive breast cancer are distinct from those of ductal carcinoma in situ(DCIS).We aimed to investigate the clinicopathological characteristics of DCISM and further evaluate the impact of microinvasion on survival.Methods:we conducted an observational study of female diagnosed with DCIS or DCIS with microinvasion(DCISM)from 1990 to 2012 using the Surveillance,Epidemiology,and End Results(SEER)database.Demographic,pathologic,treatment,and survival data were obtained and analyzed.Kaplan-Meier estimates and Cox regression analyses of cancer-specific survival(CSS)and overall survival(OS)were done.The log-rank test was used to compare the distribution between the DCIS and DCISM groups.Fine and Gray’s competing-risks regression models were conducted to assess CSS.Univariate and multivariate Cox proportional hazard regression models were used to calculate hazard ratio(HR)and identify factors that are associated with CSS and OS.Results:There were 87695 DCIS and 8863 DCISM identified.In DCISM group,patients appeared to be younger and more black patients were identified in comparison with DCIS group.Furthermore,DCISM was associated with more aggressive tumor characteristics like higher rates of oestrogen receptor(ER)and progesterone receptor(PR)negativity,HER2 positivity,and lymph node metastasis.With a median follow-up of 91 months,patients with DCISM had worse cancer-specific survival(CSS)(hazard ratio[HR],2.475;P<0.001)and overall survival(OS)(HR,1.263;P<0.001).In the multivariable analysis,microinvasion was an independent prognostic factor for worse CSS(HR,1.919;P<0.001)and OS(HR,1.184;P<0.001).The 10-year cancer-specific mortality rate was 1.49%in DCIS and 4.08%in DCISM(HR,2.771;P<0.001).The 20-year cancer-specific mortality rate was 4.00%in DCIS and 9.65%in DCISM(HR,2.482;P<0.001).Conclusions:The clinicopathology of microinvasive breast cancer is more aggressive than that of DCIS.Furthermore,microinvasion is a predictor of worse CSS and OS than those of DCIS.Deepening understanding of the nature of microinvasive breast cancer will be valuable for clinical treatment recommendations.Background and aim:Neoadjuvant chemotherapy is the standard treatment for locally advanced breast cancer patients and operable cases for breast conserving surgery.Pathologic complete response(pCR)to neoadjuvant therapy correlates with significantly improved disease-free and overall survival in early-stage HER2-positive breast cancer.Early indicators of pCR could conceivably be used to optimize treatment.This study aimed to reveal pCR-related genomic characteristics in both tumor tissues and circulating tumor DNA(ctDNA).Meanwhile,we monitored the dynamic change in the levels of ctDNA during the treatment and explore the association of ctDNA dynamics with pCR,so as to identify potential biomarkers predictive of sensitivity early in the treatment.Methods:We enrolled 36 hormonal receptor(HR)-negative HER2-positive breast cancer patients treated with neoadjuvant therapy a prospective study between January 2014 and June 2017.All patients received either 4-6 cycles of paclitaxel plus carboplatin in combination with trastuzumab or 4-6 cycles of paclitaxel plus epirubicin with or without trastuzumab.Naive tumor tissues,baseline plasma and plasma after 2 cycles of neoadjuvant treatment were sampled.Target-capture deep sequencing was performed to identify somatic genomic alterations.Results:TP53 and PIK3CA were the most frequently mutated genes in tumor tissues,detected in 77.3%(17/22)and 50%(11/22)of patients,respectively.The pCR rate of PIK3CA-mutated patients(18.2%,2/11)was significantly lower than that of PIK3CA wild-type patients(72.7%,8/11),(P = 0.03).CtDNA was successfully detected in 26 of the 31 patients(83.9%)in whom somatic genomic alterations were identified.TP53 mutation,HER2 gene amplification and PIK3CA mutation were the most frequently somatic variants in the baseline plasma samples,detected in 54.8%(17/31),41.9%(13/31)and 32.3%(10/31)of patients,respectively.Further analysis of the post-treatment plasmas showed that the pCR rate among ctDNA-negative patients after 2-cycle therapy was 87.5%,significantly higher than that in ctDNA-positive patients(27.2%;P = 0.005).Conclusions:In this study,the PIK3CA-mutation in tumor tissues associates with an unfavorable pCR rate to neoadjuvant treatment.CtDNA-negative patients after 2-cycle therapy achieved a higher pCR rate.Analysis of ctDNA dynamics offers a promising way to early predict pCR in HER2-enriched breast cancer patients and as a new approach to select patients who will benefit from neoadjuvant therapy.Background and aim:Neoadjuvant chemotherapy is the standard treatment for locally advanced breast cancer and operable cases for breast conserving surgery.Regarding the response to neoadjuvant chemotherapy,a pathologic complete response(pCR)is associated with improved disease-free and overall survival,therefore the pCR is a strong indicator of benefit from chemotherapy.In current practice,HER2-positive breast cancer patients often benefit from the neoadjuvant chemotherapy plus trastuzumab(NC+T),with nearly 30-50%of patients achieving a pCR.Emerging data suggest a potential contribution of host adaptive immune response and immune microenvironment of tumor in mediating clinical responses in HER2-positive breast cancer.However,the peripheral blood(PB)T cell reporter(TCR)repertoire and its interaction with early-stage HER2-positive breast cancer patients treated with chemotherapy plus trastuzumab have not been systemically studied.We thus performed an extensive immunomonitoring in HER2-enriched breast cancer patients to identify immunological correlates of pCR induction.Methods:We investigated the TCR repertoire using next-generation deep sequencing of the complementarity determining region 3(CDR3)of the TCR(3 chain in the PB samples from 26 treatment-naive hormonal receptor(HR)-negative HER2-positive breast cancer patients before and after 2 cycles of chemotherapy plus trastuzumab.The patient population was obtained from a prospective study.All patients received either 4-6 cycles of paclitaxel plus carboplatin in combination with trastuzumab(TCH)or 4-6 cycles of paclitaxel plus epirubicin in combination with trastuzumab(ATH).Results:Patients who achieved a pCR(n = 11)had a lower TCR density in their pre-treatment PB(P = 0.0147)and a higher degree of overlap between the pre-and post-treatment PB TCR repertoires(P = 0.0488)than did patients who achieved a non-pCR(n = 15).The sequences of V segments of the TCR p chain demonstrated significantly lower frequencies of TCR β variable(TRBV)3-1,TRBV4-2,TRBV12-3,TRBV12-5,TRBV15,TRBV6-2,and TRBV7-7 genes in the pre-treatment PB samples of the pCR group than in the non-pCR group.Moreover,there were marked differences in the frequencies of V-J rearrangements:29 unique V-J rearrangements were in significantly lower frequencies in the pCR patients and TRBV25-1_TCR β joining(TRBJ)2-6,TRBV7-7_TRBJ2-3,TRBV5-4_TRBJ2-6,TRBV10-3_TRBJ2-1 and TRBV30_TRBJ2-3 were in significantly higher frequencies.There were no significant differences in TCR density,diversity,clonality or evenness between pre-and post-treatment PB samples.Conclusions:Based on the current study,patients who achieved a pCR had a lower TCR density in their pre-treatment PB and a higher degree of overlap.There were marked differences in the frequencies of some unique TRBV genes and V-J rearrangements in patients with a pCR and non-pCR.TCR repertoire in PB may be used as a predictor of response to neoadjuvant chemotherapy plus trastuzumab in HR-negative HER2-positive breast cancer patients and as a new approach to select patients who will benefit from neoadjuvant therapy.