PR Status Research Articles

Abstract OT1-04-01: ATNEC: A multi-centre, randomised trial investigating whether axillary treatment can be avoided in T1-3N1M0 breast cancer patients with no residual cancer in the lymph glands after neoadjuvant chemotherapy (clinicaltrials.gov: nct04109079)

Abstract Background: For patients who are node positive to start at presentation and are found to have a complete nodal tumour response (ypN0) post neoadjuvant chemotherapy (NACT), we do not yet know whether local axillary therapy can be modified based on the response to NACT. ATNEC randomised trial specifically address axillary management following NACT in patients with proven axillary node metastases. Methods: Design: ATNEC is a phase III, randomised (1:1), multi-centre trial, with embedded economic evaluation. Patients with proven axillary node metastases on needle biopsy receive NACT followed by sentinel node biopsy (SNB). If the sentinel nodes have converted to benign (ypN0), ATNEC randomly assigns patients to axillary treatment (nodal radiotherapy or axillary nodal clearance) vs. no axillary treatment (without further surgery). Aims: To assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy - who after NACT have no residual nodal disease on SNB - is non-inferior to axillary treatment in terms of disease free survival, and reduces the risk of lymphoedema at 5 years. Stratification: Institution, type of surgery (breast conserving surgery [BCS] vs mastectomy), receptor status (triple negative vs HER2 positive vs ER status positive and/or PR status positive and HER2 negative). Inclusion criteria:. • Age ≥ 18. • Male or female. • T1-3N1M0 breast cancer at diagnosis (pre-NACT). • FNA or core biopsy confirmed axillary nodal metastases at presentation. • ER and HER2 status evaluated on primary tumour. • Received standard NACT as per local guidelines. • Imaging assessment of the axilla at completion of NACT. • Dual tracer SNB after NACT and at least 3 nodes removed (sentinel nodes and marked node). o If a single tracer is used, the patient is eligible if the involved node is marked before NACT and at least 3 nodes removed (including the marked node). o If axillary node sampling is performed following failed localisation of sentinel nodes, patient is eligible if at least 3 nodes removed (including the marked node). o If node is not marked, or marked node is not removed, patient is eligible if the histology report shows evidence of down-staging with complete pathological response in at least one node and at least 3 nodes removed. • No evidence of nodal metastases post NACT (ypN0). Exclusion criteria:. • Bilateral invasive breast cancer. • SNB prior to NACT. • Previous ipsilateral axillary nodal surgery. • Previous cancer within last 5 years or concomitant malignancy. Radiotherapy Quality Assurance: ATNEC has in-built radiotherapy QA programme that is coordinated by National Radiotherapy Trials QA (RTTQA) group. Target accrual: 1900 Number of sites: 100 Trial Status: Recruiting. Trial is open to new sites. Disclaimer: This study is funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (Reference - HTA NIHR128311). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Citation Format: Amit Goyal, Sophie Cramp, Andrea Marshall, Duncan Wheatley, Natalie Hammonds, Shama Puri, Tara Homer, Luke Vale, Roeum Butt, Romaana Mir, Janice Rose, Helen Teresa Edwards, Samreen Ahmed, Abeer Shaaban, Beatrix Elsberger, Julie Bruce, Sophie Gasson, Valerie Speirs, Jacqui Shaw, Helen Higgins, Janet Dunn. ATNEC: A multi-centre, randomised trial investigating whether axillary treatment can be avoided in T1-3N1M0 breast cancer patients with no residual cancer in the lymph glands after neoadjuvant chemotherapy (clinicaltrials.gov: nct04109079) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-04-01.

The association between migraine and breast cancer risk: A systematic review and meta-analysis.

BackgroundMigraines is likely to play a protective role in the risk of breast cancer. Some studies have shown that there is an inverse relationship between migraine and breast cancer, and some studies have not found an association; therefore, results from previous studies have been inconclusive and we conducted a meta-analysis to evaluate association between migraine and breast cancer.MethodsPubMed, EMBASE, Scopus and Web of Science were searched to identify studies on the association between migraine and breast cancer from January 1, 2000 through March 12, 2021. The pooled relative risk (RR) and the 95% confidence intervals (CI) was used to measure this relationship by assuming a random effects meta-analytic model.ResultsA total of 10 studies were included. Our study revealed that there was statistically significant inverse relationship between migraine and breast cancer in case-control studies 0.68 [95% CI: 0.56, 0.82], but no significant relationship was found in cohort studies 0.98 [95% CI: 0.91, 1.06]. Also, migraine reduced the risk of ductal carcinoma 0.84 [95% CI: 0.73, 0.96], and lobular carcinoma 0.83 [95% CI: 0.73, 0.96]. With respect to ER_PR status no association between migraine and breast cancer was found. We found no evidence of publication bias.ConclusionOur analysis demonstrated a statistically significantly inverse relationship between migraine and total risk of breast cancer only in case-control studies. In summary, cohort studies do not support an inverse association between migraine and incident breast cancer. While in case-control studies, migraine has an inverse association with ductal carcinoma and lobular carcinoma of breast.

Pathological underestimation and biomarkers concordance rates in breast cancer patients diagnosed with ductal carcinoma in situ at preoperative biopsy

Ductal carcinoma in situ (DCIS) often upgrade to invasive breast cancer at surgery. The current study aimed to identify factors associated with pathological underestimation and evaluate concordance rates of biomarkers between biopsy and surgery. Patients diagnosed with DCIS at needle biopsy from 2009 to 2020 were retrospectively reviewed. Univariate and multivariate analyses were performed to identify factors associated with pathological underestimation. Concordance rates between paired biopsy samples and surgical specimens were evaluated. A total of 735 patients with pure DCIS at biopsy were included, and 392 patients (53.3%) underwent pathological underestimation at surgery. Multivariate analysis demonstrated that tumor size > 5.0 cm [odds ratio (OR) 1.79], MRI BI-RADS ≥ 5 categories (OR 2.03), and high nuclear grade (OR 2.01) were significantly associated with pathological underestimation. Concordance rates of ER, PR, HER2 status and Ki-67 between biopsy and surgery were 89.6%, 91.9%, 94.8%, and 76.4% in lesions without pathological underestimation, and were 86.4%, 93.2%, 98.2% and 76.3% for in situ components in lesions with pathological underestimation. Meanwhile, in situ components and invasive components at surgery had concordance rates of 92.9%, 93.8%, 97.4%, and 86.5% for those biomarkers, respectively. In conclusion, lesions diagnosed as DCIS at biopsy have a high rate of pathological underestimation, which was associated with larger tumor size, higher MRI BI-RADS category, and higher nuclear grade. High concordances were found in terms of ER, PR, and HER2 status evaluation between biopsy and surgery, regardless of the pathological underestimation.

Survival Estimation, Prognostic Factors Evaluation, and Prognostic Prediction Nomogram Construction of Breast Cancer Patients with Bone Metastasis in the Department of Bone and Soft Tissue Tumor: A Single Center Experience of 8 Years in Tianjin, China.

Purpose Bone metastasis in breast cancer remains globally concerned. Accurate survival estimation would be beneficial for clinical decision-making, especially for the patients with potential indications of surgery. Based on a retrospective cohort from China, the study aimed to construct a prognostic prediction nomogram for breast cancer patients with bone metastasis. Methods Breast cancer patients with bone metastasis diagnosed between 2009 and 2017 in our department were retrospectively selected. The total cohort was divided into construction and validation cohorts (ratio 7 : 3). A nomogram was constructed to predict the probability of survival, and the performance of model was validated. Results A total of 343 patients were enrolled with 243 and 100 patients in construction and validation cohorts, respectively. The median overall survival for the total cohort was 63.2 (95% CI: 52.4–74.0) months. Elevated ALP (HR = 1.71, 95% CI: 1.16–2.51; P=0.006), no surgery for breast cancer (HR = 2.19, 95% CI: 1.30–3.70; P=0.003), synchronous bone metastasis (HR = 1.98, 95% CI: 1.22–3.22; P=0.006), and liver metastasis (HR = 1.68, 95% CI: 1.20–2.37; P=0.003) were independent prognostic factors for worse survival. The independent predictors and other five factors (including age at diagnosis, ER status, PR status, Her-2 status, and the performance of bisphosphonate) were incorporated to construct the nomogram. The C-index was 0.714 (95% CI: 0.636–0.792) and 0.705 (95% CI: 0.705) in the construction cohort and validation cohort, respectively. All the calibration curves were close to the 45-degree line, which indicated satisfactory calibration. Conclusion A retrospective study aiming at prognostic estimation of breast cancer patients with bone metastasis was designed. Four independent prognostic factors were identified and a prognostic nomogram was constructed with satisfactory discrimination and calibration. The model could be used in survival estimation and individualized treatment planning.

Shear Wave Elastography-Assisted Ultrasound Breast Image Analysis and Identification of Abnormal Data.

In this paper, shear wave elastography was used to study and analyze the images of the breast in-depth and identify the abnormal image data. Sixty breast lesions were evaluated, and quantitative metrics were reproducible in the static and dynamic modes of shear wave elastography with a higher interobserver agreement in dynamic qualitative metrics than in the static mode. There were no statistically significant differences between the two modes of imaging in quantitative metrics, and quantitative metrics were more effective than qualitative metrics. Postoperative immunohistochemical expression of ER, PR, HER-2, Ki-67, molecular typing, pathological type, histological grading, and axillary lymph node status of breast cancer was obtained based on pathological results. The correlation between mass size, patient age, and WiMAX values of breast cancer masses was analyzed using Pearson correlation, and the differences in SWVmax values of breast cancer masses between different expressions of immunohistochemical parameters ER, PR, HER-2, Ki-67, and axillary lymph node status were compared using tests. The variables with correlations and differences were included in the multiple linear regression analysis to assess the factors influencing the SWVmax values. The performance of TDPM, SPM, and TSPM was compared using PVA body models with different freeze-thaw cycles. The results showed that TSPM performed better than SPM in general, and TDPM showed excellent performance because of high temporal resolution and low random error, especially when the number of freeze-thaw cycles increased and the hardness of the PVA body mold increased. Measurements at different depths of inhomogeneous body models also showed that the TDPM method was less affected by depth, and the results were more stable. Finally, the reliability of the shear wave velocity (SWS) measured by the TDPM and SPM methods was investigated using porcine ligament tissue, and the results showed that the mean values of SWS goodness of fit for TDPM and SPM were 0.94 and 0.87, respectively, and the estimated elastic modulus of TDPM was very close to the mechanical test results.

Expression of Poly(Adenosine Diphosphate-Ribose) Polymerase Protein in Breast Cancer.

The use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors for breast cancer (BC) therapy is the subject of debate, and there is an urgent need to understand much the expression and prognostic role of the PARP1 protein. In this study, we have compared the expression of PARP between BC and benign breast disease (BBD) patients and also analyzed the association of PARP expression with clinicopathological parameters in BC. The study consists of 30 patients with newly diagnosed operable BC who were planned for surgery without neoadjuvant chemotherapy and 15 patients of BBD as a control between 2019 and 2021. Immunohistochemical analyses were performed prospectively on tissue samples. Anti-human PARP1 rabbit polyclonal antibody gives strong nuclear positivity. Internal control was the adipose tissue and the BBD acted as the external control. PARP1 expression was evaluated using the multiplicative quickscore method. The mean age for BC patients was 51.30 ± 10.694 years (range: 25-75 years) while BBD was below 30 years. Overexpression of PARP was present in 25 (83.3%) and weak expression in 5 (16.7%) of BC patients compared to BBD, only 2 (13.3%) patients demonstrated an overexpression of PARP, and 13 (86.6%) patients showed weak expression which showed significant association (P < 0.001). In BC, nuclear PARP (nPARP) overexpression was seen in 22 (73.3%) patients and weak expression of nPARP in 8 (26.7%), whereas 5 (16.7%) patients showed cytoplasmic overexpression. On comparing expression of PARP with clinicopathological parameters, PARP overexpression was significantly associated with older population (age >50 years) (P = 0.002), postmenopausal women (P = 0.029), higher TNM stage (Stage II and III) (P = 0.014), higher histological grade (grade 2) (P = 0.043), and presence of lymphovascular invasion (P = 0.015). Enhanced PARP1 expression is closely correlated with positive estrogen receptor status (P = 0.001) and PR status (P = 0.001). Overall PARP and nPARP overexpression was significantly associated with ER- (P = 0.006 and P = 0.008) and PR-positive (P = 0.006 and P = 0.008) patients. The PARP and nPARP overexpression was significantly associated with nontriple-negative BC patients (P = 0.001 and P = 0.001). We have not come across any study in the literature to compare PARP expression in BC and BBD patients. On the basis of our observations, we concluded that PARP overexpression is a poor prognostic marker in BC.

PROX1 promotes breast cancer invasion and metastasis through WNT/β-catenin pathway via interacting with hnRNPK.

Background: The progressive, multifactorial and multistep dynamic process of metastasis is the primary cause of breast cancer (BC) lethality. PROX1 (Prospero-related homeobox 1), as a type of transcription factor that plays a key role in the formation of lymphatic vessels in animal embryonic development, has been proven to promote or suppress cancer in a variety of malignant tumors. However, molecular mechanisms behind PROX1 induced breast cancer metastases remain elusive.Methods: Changes of PROX1 expression and clinical significance of PROX1 in BC were evaluated by BC tissue, as well as public database. The functional role of PROX1 in metastases BC was analyzed by transwell assay in vitro, and by lung metastases model of nude mice in vivo via lentivirus mediated knockdown assays. Mechanism studies were performed by public database screening, western blot and PCR assay, immunoprecipitation, immunofluorescence staining and luciferase promoter assays.Results: In this study, we found that PROX1 was upregulated in breast cancer tissues; increased PROX1 expression in breast cancer was associated with tumor size, lymph node metastasis, ER and PR status. Meanwhile, PROX1 can promote breast cancer invasion and metastasis in vitro and in vivo. Furthermore, PROX1 can interact with hnRNPK to activate WNT/β-catenin signaling in breast cancer cells. Moreover, the interaction of PROX1 and hnRNPK inhibits the ubiquitination of hnRNPK, and subsequently activates WNT pathway to promote the invasion and metastasis of breast cancer.Conclusions: In conclusion, our findings indicated PROX1 contributes to breast cancer EMT and metastasis and serves as a candidate diagnostic biomarker and promising therapeutic target for breast cancer.

A Study Protocol for Assessment of Outcomes of Adjuvant versus Neoadjuvant Chemotherapy in Stage-IIIA of Breast Cancer

Background: Locally advanced breast cancer (LABC) includes stage III along with stage IV breast cancer and consists of operable and inoperable advanced breast cancer and metastatic disease. LABC is among the most common breast malignancies with increasing incidence now a days. In India, it accounts for 30-35% of all cases. The use of neo-adjuvant chemotherapy (NACT) for the treatment of LABC offers benefits like initiation of early systemic treatment, the drugs can be delivered via intact vasculature, the tumours can be down staged which helps to convert inoperable tumours into operable tumours and renders tumours suitable for breast conserving surgery (BCS). This study is aimed to compare the outcomes of neoadjuvant and adjuvant chemotherapy using taxane based drugs for locally advanced breast cancers.&#x0D; Methodology: This was an observational study will be undertaken in AVBRH. Total 40 patients will be enrolled in the study. Confirmed patients of breast malignancy either by FNAC or true cut histopathology with advanced breast malignancy confirmed on FNAC or true cut histopathology and planned for neo-adjuvant chemotherapy will be included in the study. For all the patients HER2, PR and ER status will be checked via immunohistopathology. Data will be analysed with appropriate statistical tests.&#x0D; Results: We expect neoadjuvant chemotherapy to have better surgical outcomes compared to neoadjuvant chemotherapy. &#x0D; Conclusion: Neoadjuvant paclitaxel based chemotherapy can be a better option for patients undergoing BCS (breast conserving surgery).

Overview of Patients with Metastatic Brain Tumors from Breast Cancer at H. Adam Malik Hospital, Medan in 2017-2021

Abstract&#x0D; Introduction: The incidence of breast cancer based on Globocan in 2018, reached 2,088,849 cases (11.6%), with a mortality rate of 626,679 cases (6.6%). Breast cancer is one of the most common causes of a metastatic brain tumor. Approximately 10%-16% of patients with breast cancer develop brain metastases during the course of their disease. Current case management guidelines for patients with metastatic brain tumors from breast cancer are radiotherapy to the entire brain, with or without surgical resection, or stereotactic radiosurgery. Hormone receptor ([HR]; estrogen receptor [ER], progesterone receptor [PR]) and HER2 expression serve as predictors of response to hormone-targeted therapy and HER2, respectively.&#x0D; Method: The study was a descriptive study with a retrospective cohort design in which the researchers identified 78 patients with breast cancer brain metastases (either for diagnostic purposes or for therapeutic purposes at RSUP HAM Medan between 2017 and 2021. Data were collected from SIRS RSUP HAM Medan. Data related to clinicopathology were collected from medical records, including demographic characteristics, tumor characteristics, biomarker status, recurrence of metastatic brain tumors based on Magnetic Resonance Imaging (MRI) examination, and data on therapeutic regimens in cases of brain metastases of breast cancer. ER and PR status were determined by immunohistochemical examination. the intensity of the HER2 3+ immunohistochemical staining was considered positive&#x0D; Result: The mean age at breast cancer diagnosis was 46 years (range: 24-73 years). Most patients had invasive ductal histology (n=73, 94%). In addition, 56% of patients had T3 (n=34) T4 disease in 56% of patients (n=44) and 68% of patients (n=53) had positive axillary lymph nodes. Among patients with known HR and HER2 status, a total of 56% of tumors were ER negative (ER-; n=44), 62% were PR negative (n=48), and 44% were HER2-positive (HER2+; n= 34). With regard to the four subtypes formed by the combined values of HR and HER2 status, 21% (n=16) of tumors were HR+HER2+, 27% (n=21) were HR+HER2-, 23% (n=18) were HR+/ HER2-, and 28% (n=23) were triple negative (TN).&#x0D; Discussion: In the current study, investigators found that apart from patient age and number of brain metastases, HER2 status was a strong predictor of survival outcome after brain metastases. Patients with HER2-positive characteristics had a longer life expectancy than patients with HER2-negative disease. Considering the intracranial antitumor effect of anti-HER2 therapy, it is important to establish HER2 status not only in primary tumors but also in brain metastases to aid in consideration of the choice of therapeutic modality&#x0D; Conclusion: This study showed that younger age, brain metastases from solitary breast cancer, and HER2 positive from breast tumors were independent predictors of better survival in patients with breast cancer brain metastases

Associations between the Levels of Estradiol-, Progesterone-, and Testosterone-Sensitive MiRNAs and Main Clinicopathologic Features of Breast Cancer.

Despite the existing advances in the diagnosis and treatment of breast cancer (BC), the search for markers associated with the clinicopathological features of BC is still in demand. MiRNAs (miRs) have potential as markers, since a change in the miRNA expression profile accompanies the initiation and progression of malignant diseases. The receptors for estrogen, androgen, and progesterone (ER, AR, and PR) play an important role in breast carcinogenesis. Therefore, to search for miRNAs that may function as markers in BC, using bioinformatic analysis and the literature data, we selected 13 miRNAs whose promoter regions contain binding sites for ER or AR, or putative binding sites for ER, AR, and PR. We quantified their expression in MCF-7 cells treated with estradiol, progesterone, or testosterone. The levels of miRNAs sensitive to one or more of these hormones were quantified in BC samples (n = 196). We discovered that high expression levels of miR-190b in breast tumor tissue indicate a positive ER status, and miR-423 and miR-200b levels differ between patients with and without HER2 amplification. The miR-193b, -423, -190a, -324, and -200b levels were associated with tumor size or lymph node status in BC patients, but the presence of these associations depended on the status and expression level of ER, PR, HER2, and Ki-67. We also found that miR-21 expression depends on HER2 expression in ER- and/or PR-positive BC. The levels of miRNA were significantly different between HER2 0 and HER2 1+ tumors (p = 0.027), and between HER2 0 and HER2 2+, 3+ tumors (p = 0.005).

A pre-operative prognostic model predicting all cause and cause specific mortality for women presenting with invasive breast cancer

PurposeThe aim of this study is to develop a pre-operative prognostic model based on known pre-operative factors. MethodsA database of ultrasound (US) lesions undergoing biopsy documented US lesion size, stiffness, and patient source prospectively. Women with invasive cancer presenting between 2010 and 2015 were the study group. Breast and axillary core results and ER, PR and HER receptor status were collected prospectively. Assessment of US skin thickening, US distal enhancement and presence of chronic kidney disease (CKD) was performed retrospectively. Patient survival and cause of death were ascertained from computer records. Predictive models for (i) all-cause mortality (ACM) and (ii) breast cancer death (BCD) were built and then validated using bootstrap k-fold cross-validation. A comparison of predictive performance was made between a full cause-specific Cox model, a sub cause-specific Cox model, and a full Fine-Gray sub-distribution hazard model. Results1136 patients were included in the study. The median follow-up time was 6.2 years. 125 (11%) women died from breast cancer and 155 (14%) died from other causes. For the prediction of BCD, the cause-specific Cox sub-model performed the best. The time dependent AUC begins above 0.91 in year one to 3 reducing to 0.83 in year 6. The factors included in the Cox sub model were tumour size, skin thickening, source of detection, tumour grade, ER status, pre-operative nodal metastasis and CKD. ConclusionWe have shown that a model based on preoperative factors can predict BCD. Such prediction if externally validated and incorporating treatment data could be useful for treatment planning and patient counselling.

Systemic Immune-Inflammation Index Is a Prognostic Factor for Breast Cancer Patients After Curative Resection.

BackgroundThe preoperative systemic immune-inflammation index (SII) is correlated with prognosis in several malignancies. The aim of this study was to investigate the prognosis value of SII in patients with resected breast cancer.Materials and MethodsA total of 784 breast cancer patients who underwent surgical resection were consecutively investigated. The optimal cutoff value of SII was evaluated using the receiver operating characteristic (ROC) curve. The collection of SII with clinicopathological characteristic and prognosis was further evaluated.ResultsThe optimal cutoff value for SII in the prediction of survival was 514 according to ROC curve analysis. A high SII was significantly correlated with younger age (P = 0.037), PR status (P < 0.001), and HER2 status (P = 0.035). Univariate analysis revealed that SII (P < 0.001), T-stage (P < 0.001), lymph node involvement post-surgery (P = 0.024), and histological grade (P < 0.001) were significantly related to DFS, and SII (P < 0.001), T-stage (P = 0.003), lymph node involvement post-surgery (P = 0.006), and histological grade (P < 0.001) were significantly associated with OS. In multivariate analysis, a high SII was an independent worse prognostic factor for DFS (HR, 4.530; 95% CI, 3.279-6.258; P < 0.001) and OS (HR, 3.825; 95% CI, 2.594-5.640; P < 0.001) in all the enrolled patients. Furthermore, subgroup analysis of molecular subtype revealed that SII was significantly associated with prognosis in all subtypes.ConclusionPreoperative SII is a simple and useful prognostic factor for predicting long-term outcomes for breast cancer patients undergoing surgery.

Overall survival and progression-free survival with cyclin-dependent kinase 4/6 inhibitors plus endocrine therapy in breast cancer: an updated meta-analysis of randomized controlled trials.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) have been recommended as standard therapeutic strategies for hormone receptor-positive (HR+), human epidermal growth factor receptor type 2-negative (Her2-) advanced breast cancer (ABC). While the benefits to progression-free survival (PFS) rates have been confirmed, whether the combination of CDK4/6i and ET leads to overall survival (OS) rate improvements remains controversial. This study aimed to assess the long-term efficacy and safety of CDK4/6i in HR+, Her2- ABC patients and identify a population suitable for treatment with CDK4/6i by subgroup analysis. Electronic literature databases (MEDLINE, EMBASE and the Cochrane Library) were searched for relevant randomized controlled trials (rcts) published from Jan 2014 to Jan 2020. In addition, abstracts and presentations from all major conference proceedings were reviewed. All rcts that compared the efficacy and safety of CDK4/6i plus ET with ET alone in HR+, Her2- ABC patients were selected. The pooled analyses of hazard ratios (hrs) for PFS and OS, and risk ratios (rrs) for the objective response rate (ORR) and adverse events (aes) were obtained with the random-effects model. A total of 6 rcts and 3421 HR+, Her2- ABC patients were enrolled for OS outcome analysis, while all 8 trials and 4580 patients were included for PFS outcome analysis. The pooled hrs for the OS and PFS were 0.76 (95% CI: 0.67-0.84) and 0.55 (95% CI: 0.50-0.59), respectively, and were consistent in the subgroup analysis. Moreover, CDK4/6i meaningfully improved the ORR in both the intention-to-treat population (RR=1.47; 95% CI: 1.29-1.67) and patients with measurable disease (RR=1.47; 95% CI: 1.30-1.67); however, CDK4/6i increased the incidence of grade 3/4 aes (RR=2.69; 95% CI: 2.43-2.97). The combination of CDK4/6i and ET was superior to ET alone in terms of OS and PFS regardless of the drugs administered, the treatment line, age distribution, race, PR status, menopausal status, metastasis site and endocrine resistance status.

A simplified breast cancer prognostic score: comparison with the AJCC clinical prognostic staging system

There have been many breast cancer prognostic models proposed in the last few decades, varying in their methods of development and validation, predictors, outcomes, and patients included. Most models were developed to assess prognostic outcomes for early breast cancers. In this study, we established a simplified prognostic score to predict survival outcomes in all breast cancer patients. A total of 36,152 breast cancer patients diagnosed between 2010 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were used as the training dataset. Multivariate analyses were performed to identify independent factors for disease-specific survival (DSS). A prognostic score was calculated by summing the point values based on the magnitude of the hazard ratio for all independent factors. The authors institutional cohort (n = 4982) was used as the validation dataset. The prognostic score model consisting of histologic grade, ER, PR, HER2, and TNM status demonstrated a similar predictive power when compared to the revised 8th AJCC Clinical Prognostic Staging system in both training and validation datasets, whereas the addition of age and race did not facilitate stratification of prognostic groups. Pairwise comparison of hazard ratios showed a significant difference in all categories when compared to their proximate groups in both prognostic schemes in the SEER database, while the prognostic score model demonstrated a slightly better discriminating power in the validation dataset. Thus, the proposed prognostic score showed at least a comparable predicting power for survival outcomes in breast cancer patients receiving standard-of-care treatment when compared to the AJCC Clinical Prognostic Stage. This prognostic model provides a convenient and alternative modality in clinical practice thus warranting further validation using larger cohorts with longer follow-up.

Effect of postmastectomy radiotherapy on survival outcomes of patients with metaplastic breast cancer

To evaluate the effect of postmastectomy radiotherapy (PMRT) on the overall survival (OS) and breast cancer-specific survival (BCSS) of patients with metaplastic breast cancer (MpBC) in comparison with those of patients with invasive ductal breast carcinoma (IDC). We selected the patients with pathologically confirmed MpBC and IDC who either received PMRT or not from the archived cases (from January, 1998 to December, 2016) in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. In total, 31 982 patients were selected, including 308 patients with MpBC and PMRT, 629 with MpBC and PMRT, and 31 045 with IDC and PMRT. All the included patients were above 18 years of age without distant metastases or a second primary cancer and underwent radical surgery. Baseline characteristics of the patients were compared among the 3 subgroups, and multivariate Cox regression and Kaplan-Meier analyses were performed for analyzing the prognostic factors of MpBC, OS, and BCSS. The majority (81.2%) of patients with MpBC were older than 50 years, had pathological grade III (68%), and were negative for ER (75.9%) and PR (79.8%) and in stage T2-3 (71.3%) and N0-1 (85.6%). Multivariate Cox regression analysis showed that age, T stage, N stage, PMRT, and chemotherapy were significantly associated with the prognosis of patients with MpBC (P < 0.05), while pathological grade, ER status, or PR status did not significantly affect the prognosis (P>0.05). Kaplan-Meier analysis showed that the patients with MpBC and PMRT had better OS (HR=1.394, 95% CI: 1.125-1.727; P < 0.05) and BCSS (HR=1.390, 95% CI: 1.074-1.800; P < 0.05) than those with MpBC who did not receive PMRT; but after PMRT, the patients with MpBC had worse OS (HR=1.626, 95%CI: 1.386-1.908; P < 0.001) and BCSS (HR=1.710, 95% CI: 1.418-2.062; P < 0.001) as compared with those with IDC. MpBC has unique clinicopathological features. In patients with MpBC, age, T stage, N stage, radiotherapy and chemotherapy are all the prognostic factors affecting the survival outcomes, and PMRT can improve the OS and BCSS of the patients.

Safety and Short-Term Efficacy of CART Cells in Treatment of Diffuse Large B-Cell Lymphoma with Follicular Transformation

Background：Tissue transformation to Diffuse large B-cell lymphoma(DLBCL) occurs in some patients with follicular cell lymphoma(FL), and these patients have a poor prognosis, and some patients do not respond well to chemotherapy, relapse or disease progression. In recent years, many clinical trials have found that CART cells are have a relatively good effect on relapsed and refractory DLBCL, but what about the effect on DLBCL transformed by FL?Methods：A total of 13 patients with diffuse large B-cell lymphoma transformed from follicular cell lymphoma who received CART cell therapy in our hospital from January 2020 to January 2021 were observed. All patients had stage III/IV disease (7 patients with stage III and 6 patients with stage IV). Among them, 10 were germinal centers and 3 were non-germinal centers. There were 8 males and 5 females, with a median age of 44 years (33-70 years old), who had undergone more than 2 chemotherapy cycles before admission to our hospital, and the median chemotherapy cycle was 10 cycles (7-19 years old). Among them, 3 had previously undergone other clinical drug trials, 1 had undergone CD20 CART cell immunotherapy, and 1 had undergone radiotherapy. At admission, ECOG was 0-3, and all patients had measurable lesions with a median size of 5cm (1.4cm-12.0cm). After preconditioning, CART cells were reinjected, 12 cases were reinjected with murine anti-CD19-CART, and 1 case was reinjected with humanized anti-CD19-CART. Median volume 3.07×10^6/kg (0.46×10^6/kg -5.43×10^6/kg). The cytokine release syndrome(CRS) and the therapeutic effect of 3 months/6 months after reinfusion were observed, and the endpoint was disease progression or death.Results：The main treatment related adverse reaction was cytokine release syndrome. Among them, there were 12 I CRS, 1 II CRS, and no treatment-related deaths. The short-term efficacy of 3 months after treatment: 4/13CR（30.8%）, 7/13PR（53.8%）, 2/13 SD/PD(15.4%) and ORR was 11/13 (84.6%). The efficacy of 6 months after treatment: 10/13CR（76.9%）, 0/13PR（0%）and ORR was 10/13 (76.9%). One patient with 3-months CR developed disease at 11 months and died at 12 months, and one patient with 3- months PR developed disease at 5 months and died at 8 months. The remaining 6patients with 3- PR have now achieved CR。the median follow-up time was 10 months (6-19months). Of the 2 patients who did not respond to treatment have achieved PR after subsequent treatment.Conclusions: It can be seen from this study that CART cells have obvious efficacy and good safety in the treatment of DLBCL transformed by FL. It should be noted that 7 patients had PR status at 3 months after treatment, 6 patients had CR at 6 months after treatment, and 1 patient had disease progression. Efficacy evaluation of patients with DLBCL with potential transformation from FL after CART cell therapy should be appropriately delayed, except that 6 months may be the best time to evaluate the efficacy. At present, the observation time is short, PFS and OS have not been observed, and long-term observation with a larger sample is under way. DisclosuresNo relevant conflicts of interest to declare.

The Presence of SETBP1, RUNX1 or EZH2 Mutation in MDS/MPN Is Associated with Absence of Response to Hypo-Methylating Agents

INTRODUCTION: The management of myelodysplastic syndrome/myeloproliferative overlap neoplasms (MDS/MPN) remains challenging due to their molecular complexity. Hypo-methylating agents (HMA) have been used for cytoreduction and preparation of patients for allogeneic blood or marrow transplantation (BMT). However, less than 50% patients have a meaningful response to HMA and predictive factors for response remain unknown. The aim of our study is to examine molecular predictors of response to HMA in patients with MDS/MPN.PATIENTS AND METHODS: We performed a retrospective analysis of 150 patients evaluated at our center for chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML) and unclassifiable MDS/MPN (MDS/MPN-U) between 1/1/2010 and 12/31/2020. Forty-three individuals who were treated with HMA during chronic phase and had next generation sequencing (NGS) using the established 63-genes panel were identified. Complete and partial remission (CR and PR), and marrow response (MR) were assessed based on the MDS/MPN International Working Group response criteria. Univariate logistic regression analysis was used to associate the number of somatic mutations or high-risk (HR) mutations (NRAS, SETBP1, RUNX1, EZH2, TP53, ASXL1, STAG2), and other disease specific factors at the time of the initiation of HMA with response categories. Multivariable analysis for modeling response were conducted via Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression approach, where the predictors were selected based on 5-fold cross validation with turning parameter selected to minimize deviance of logistic regression model. Kaplan-Meier was used to assess the overall survival based on the CR/PR status at 6 months from the initiation of HMA in landmark analysis. Cox-regression analysis considering the occurrence of CR/PR as a time-varying covariate was used to assess the impact of CR/PR on overall survival.RESULTS: Fifteen women and 28 men with a median age 67 years (range: 45 - 85 years) and a median follow up of 1.5 years (range: 91 days - 5.2 years) were included. Twenty five (58.1%) had CMML, 15 (34.9%) had MDS/MPN-U and 3 (7%) had aCML. Thirty-four patients (79.1%) received azacitidine (median number of cycles: 4.5, range: 1 - 65) and 9 patients (20.9%) received decitabine (median number of cycles: 4, range: 3 - 21). Seventeen patients (39.5%) underwent BMT following HMA therapy. The incidence of AML transformation was 16%. No patients had CR while 56% achieved a PR and 42% had an MR. Univariate analysis showed that ≥2 HR mutations (OR 0.19, 95% CI 0.05-0.67), SETBP1 mutation (OR 0.16, 95% CI 0.02-0.76), RUNX1 mutation (OR 0.1, 95% CI 0.01-0.48) and a mutation in at least one out of the SETBP1, RUNX1 and EZH2 genes (OR 0.05, 95% CI 0.01-0.21) were associated with absence of PR. ≥2 HR mutations (OR 0.23, 95% CI 0.05-0.9), and the presence of a mutation in one out of the SETBP1, RUNX1 and EZH2 genes (OR 0.16, 95% CI 0.03-0.62) were associated with absence of MR on univariate analysis. Finally, older age as a continuous variable was associated with PR (OR 1.09, 95% CI 1.01-1.19) and MR (OR 1.12, 95% CI 1.03-1.24). Presence of a mutation in one of the SETBP1, RUNX1 and EZH2 genes with age adjusted was selected from LASSO approach and significantly predicted the absence of PR (OR 0.05, 95% CI 0.01-0.27), and MR (OR 0.19, 95% CI 0.04-0.91) (Table 1). Using the landmark of 6 months after the initiation of treatment, Kaplan-Meier analysis showed that PR at 6 months was associated with superior overall survival (P=0.010) compared to patients with no response (Figure 1). Similarly, Cox-regression analysis revealed that the occurrence of PR following the initiation of treatment was associated with better overall survival (HR 0.26, 95% CI 0.9-0.13, P=0.010).CONCLUSIONS: Mutations in SETBP1, RUNX1 or EZH2 genes predicted absence of response to HMA among patients with MDS/MPN independent of other factors including karyotype, blast percentage and R-IPSS. These findings suggest that the molecular profile of MDS/MPN patients can potentially identify patients with HMA-refractory phenotype. Multi-institutional studies of larger cohorts are required to verify these results and develop novel treatment strategies especially for patients with high-risk mutations in MDS/MPN.Figure 1. Kaplan-Meier estimates of OS by PR status at 6 months in landmark analysis. P-value was based on log-rank test. [Display omitted] DisclosuresLevis: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria; Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas and FujiFilm: Research Funding; Pfizer: Consultancy, Honoraria; Takeda: Honoraria. Jain: Syneos Health: Research Funding; CTI Biopharma: Research Funding; CareDx: Other: for advisory board participation; Bristol Myers Squibb: Other: for advisory board participation; Targeted Healthcare Communications: Consultancy.

Can Estrogen Receptor, Progesterone Receptor, and Proliferative Index be Considered as Isolated Prognostic Factors of Overall Survival in Early luminal Breast Cancer?

BACKGROUND: There are a number of proven molecular and pathological markers important for the prognosis for OS of early luminal type breast cancer, but there are still some deficiencies mainly due to the non-linear relationship between the markers and the outcome of the disease. METHODS AND PATIENTS: In this retro-prospective study, clinical and pathological data were provided from 336 patients with breast cancer who underwent breast surgery and treatment between January 2010 and December 2013, and followed until December 2018. The aim of the study was an evaluation of ER, PR, and Ki-67 as independent prognostic factors for OS of early luminal breast cancer. RESULTS: Early luminal breast cancers were not predictive of ER expression status (p = 0.699, p = 0.356), whereas only early Luminal B was predictive for PR expression (&gt;10%: 72.2%). Ki-67 in most of the cases of early Luminal B was with expression of &gt;14–20% (p = 0.056). Patients with ER of 1–10% survived over 80 months (p = 0.0020) in early Luminal A, but ER expression status did not show prognostic significance for OS of early Luminal B (p = 0.775). PR status did not show prognostic significance for OS in early luminal types (p = 0.257, p = 0.622). ER &gt;1%/PR &gt;1% was protective in early Luminal B (p = 0.00043), but not in early Luminal A. CONCLUSION: Our results suggest ER, but not PR as independent prognostic factor for OS but only of early Luminal A. We did not prove Ki-67 as independent prognostic factor for OS of highly proliferative early breast cancer.

MRNA coexpression patterns of Wnt pathway components and their clinicopathological associations in breast and colorectal cancer

Aberrant Wnt signaling is implicated in carcinogenesis triggering efforts for the development of new therapeutic agents, many of which have entered clinical trials. We extend our previous analysis of WNT3, FZD7, LEF1 expression levels in breast and colorectal cancer including WNT2, FZD4 and β-catenin expression, in an effort to delineate their relative expression levels along with concurrent expression patterns and possible prognostic value. We analyzed 82 breast and 102 colorectal carcinomas for relative mRNA expression levels of the investigated genes by RT-PCR relative quantification with the ΔΔCt method. Statistical analysis was performed in order to determine associations of relative mRNA expression and linear correlations. β-catenin expression was determined by immunochemistry. Regarding breast carcinomas, decreased relative mRNA expression levels of WNT2, FZD4 were found frequently and WNT2 expression was correlated with ER/ PR status (p = 0.045/p = 0.028), whereas β-catenin with grade (p = 0.026). In colorectal carcinomas, increased relative mRNA expression levels of WNT2 and FZD4 were found in 59% and 32% of cases respectively, whereas β-catenin showed decreased mRNA expression levels in 57% of cases and a correlation with pN-category (p = 0.037). Linear correlations were observed between WNT2/FZD4 (R=0.542, p < 0.001), WNT2/β-catenin (R=0.254, p = 0.010), FZD4/β-catenin (R=0.406, p < 0.001) expression and a correlation between mRNA expression and membranous/cytoplasmic β-catenin emerged (p = 0.039/0.046). Our results suggest a possible clinical significance for Wnt pathway gene expression levels in both tumour types. The concurrent expression of the investigated genes as well as the different expression profiles, underlines the complexity of this pathway and the necessity of patient selection in order to maximize the efficacy of drugs targeting Wnt pathway.

Development of a prediction model based on LASSO regression to evaluate the risk of non-sentinel lymph node metastasis in Chinese breast cancer patients with 1\u20132 positive sentinel lymph nodes

This study aimed to develop an intraoperative prediction model to evaluate the risk of non-sentinel lymph node (NSLN) metastasis in Chinese breast cancer patients with 1–2 positive sentinel lymph nodes (SLNs). The clinicopathologic data of 714 patients with 1–2 positive SLNs were investigated. Univariate and multivariate analyses were performed to identify the risk factors of NSLN metastasis. A new mathematical prediction model was developed based on LASSO and validated in an independent cohort of 131 patients. The area under the receiver operating characteristic curve (AUC) was used to quantify performance of the model. Patients with NSLN metastasis accounted for 37.3% (266/714) and 34.3% (45/131) of the training and validation cohorts, respectively. A LASSO regression-based prediction model was developed and included the 13 most powerful factors (age group, clinical tumour stage, histologic type, number of positive SLNs, number of negative SLNs, number of SLNs dissected, SLN metastasis ratio, ER status, PR status, HER2 status, Ki67 staining percentage, molecular subtype and P53 status). The AUCs of training and validation cohorts were 0.764 (95% CI 0.729–0.798) and 0.777 (95% CI 0.692–0.862), respectively. We presented a new prediction model with excellent clinical applicability and diagnostic performance for use by clinicians as an intraoperative clinical tool to predict risk of NSLN metastasis in Chinese breast cancer patients with 1–2 positive SLNs and make the final decisions regarding axillary lymph node dissection.