Setting For Breast Cancer Patients Research Articles

Assessment of the Predictive Role of Ki-67 in Breast Cancer Patients' Responses to Neoadjuvant Chemotherapy.

Neoadjuvant chemotherapy (NAC) in breast cancer (BC) is being considered for a broader range of cases, including locally advanced tumors and situations where downstaging could reduce extensive surgery. Several trials have explored predictive markers of pathological complete response (pCR). The role of Ki-67 as a predictor of pCR has been demonstrated in studies. However, the cut-off remains vague, given the lack of standardization of measurement methods. The aim of our study was to evaluate the predictive value of Ki-67 in response to NAC and to identify the cut-off values that exhibit the strongest correlation with best response. This retrospective study included 187 patients who had undergone surgery following NAC for BC at the CHU Souss Massa of Agadir between January 2020 and January 2023. Logistic regression was used to assess the correlation between Ki-67 and patients' characteristics. Optimal Ki-67 cutoff was identified by receiver operating characteristic curve. Kaplan-Meier curves were used to assess disease-free survival (DFS), and survival comparisons were assessed with the log-rank test. The median age was 51.8±10.7 years and 51.4% of tumors were smaller than 5 cm. Node invasion was found in 55.4%. Luminal B subtype was found in 49.7%, followed by human epidermal growth factor receptor-2 (HER-2)-positive in 27.4%, triple-negative in 14.3% and Luminal A in 8.6%. pCR occurred in 40% of patients overall. Subgroup analysis revealed a significant association between pCR and tumor size (p<0.001), lymph node involvement (p<0.001), grade 2 (p<0.001), vascular invasion (p<0.001), and positive HER-2 status (p = 0.022). In statistical analysis, pathological responses were improved in patients with Ki-67 >35% (p<0.001). DFS was 98.8% at 12 months. No statistical difference was found in DFS according to Ki-67 values and pCR status. Our results indicate that Ki-67 is a predictive marker for response in the neoadjuvant setting in BC patients. Our study showed that a Ki-67 cut-off >35% predicts a better pCR rate in response to NAC. However, this cutoff value remains controversial due to the absence of a standard method of measurement, with inter- and intra-observer variability. It would be necessary to validate this cutoff in other studies.

Heart toxicity effects (HTE) of anthracyclines-containing regimens (ACRs) in patients with breast cancer (BC) carrying mutational signature of homologous recombination deficiency (HRD).

10519 Background: BRCA1/2 genes ( BRCA) play a prominent role in the Homologous Recombination Repair (HRR) pathway. Following the technological progress and deeper knowledge on BRCA-related cancers, the demand for genetic testing is rapidly increasing. Beyond BRCA1/2, other genes are involved in the HRR, including ATM, PALB2, RAD51, and BARD1. Due to the important role in the cellular repair process, deleterious variants in HRR genes may cause inadequate DNA damage repair in cardiomyocytes. The role of BRCA1/2 as predisposing condition to cardiac dysfunction is debated, and the contribution by no- BRCA genes is still unknown. Methods: This is a multicenter, retrospective, study to investigate the risk of heart-insults from anthracyclines on adjuvant setting in BC patients carrying germline pathogenic or likely pathogenic variant (PV) (classes IV and V) in BRCA and no- BRCA HRR pathway genes. We collected genetic and clinical data, and evaluated the left ventricular ejection fraction (LVEF) at cardiac ultrasound, before starting ACR therapy, and at subsequent time points, according to clinical indications. Results: Three hundred and sixty (360) BC patients, aging 22 to 80, were included in this study; 131 patients were carriers of germline PVs in HRR pathway genes: 52 in BRCA1 gene (39.7%), 48 in BRCA2 gene (36.6%), and 31 harbored PVs in no- BRCA HRR pathway genes (23.7%), including PVs in PALB2, CHEK2, ATM, RAD51C, RAD50 and BARD1 genes. In the cohort of 229 patients without PVs, 47 showed variant of uncertain significance (VUS, class III), and 173 had genetic testing not informative. When LVEF between the groups was compared, the difference was not significant for the pre-treatment values. Notably, individuals carrying BRCA or other HRR gene deleterious variants, showed a statistically significant reduction of LVEF &gt; 5% at the second time-point (3 month), compared to the LVEF pre-treatment values (p = 0.001). A marked LVEF reduction was in mutated patients treated with risk-reducing bilateral salpingo-oophorectomy prior to age 40, body mass index &gt; 25, and type-II diabetes mellitus. The latter risk factor was probably related to increased risk developing insulin-resistance reported for BRCA-mutated patients. Conclusions: Our data suggest that PVs in BRCA or other genes involved in HRR pathway, can lead to impaired homologous recombination, thus increasing sensitivity of cardiac cells to DNA damaging chemotherapy in BC patients. In this subgroup of patients, other measurements such as the global longitudinal strain (GLS), and a more in-depth assessment of risk factors, could be proposed to optimize cardiovascular risk-management and to improve long-term survival.

The impact of modern radiotherapy on long-term cardiac sequelae in breast cancer survivor: a focus on deep inspiration breath-hold (DIBH) technique.

One of the most feared side effects of radiotherapy (RT) in the setting of breast cancer (BC) patients is cardiac toxicity. This side effect can jeopardize the quality of life (QoL) of long-term survivors. The impact of modern techniques of RT such as deep inspiration breath hold (DIBH) have dramatically changed this setting. We report and discuss the results of the literature overview of this paper. Literature references were obtained with a PubMed query, hand searching, and clinicaltrials.gov. We reported and discussed the toxicity of RT and the improvements due to the modern techniques in the setting of BC patients. BC patients often have a long life expectancy, thus the RT should aim at limiting toxicities and at the same time maintaining the same high cure rates. Further studies are needed to evaluate the risk-benefit ratio to identify patients at higher risk and to tailor the treatment choices.

Abstract PS4-27: A prospective multicenter study evaluating the impact of the 21-Gene Breast Recurrence Score® upon physician treatment decision and cost in lymph node-positive breast cancer patients in Quebec

Abstract Background: Locoregional lymph node involvement has historically been used as the most important deciding factor for the administration of chemotherapy in the adjuvant setting of breast cancer patients. The 21-gene Breast Recurrence Score® assay (the assay) is emerging as an important tool to assist with chemotherapy decisions amongst hormone receptor (HR)-positive, node-positive breast cancer (BC) patients. Previous studies have suggested that node-positive patients with low Recurrence Score (RS) results do not benefit from chemotherapy. We wanted to better understand the impact of the assay upon physician treatment decisions and treatment cost in this patient cohort. Methods: We conducted a multicenter prospective observational trial for ER/PR-positive HER2-negative BC patients that have undergone surgical treatment for T1-T3 disease and 1-3 positive lymph nodes. Physicians were required to complete a questionnaire indicating treatment choice prior to and post availability of Recurrence Score results. Patients were enrolled in the study from the time of consent to 6 months after the start of adjuvant therapy. The primary endpoint was change in the physician’s recommendation for chemotherapy prior to and post assay results. Secondary endpoints include the change in recommendation for additional growth factor (GF) supportive therapy, change in physician’s expressed level of confidence, and changes in estimated cost of recommended treatments prior to and post assay results. Results: 70 patients were enrolled between March 2018 and September 2019 at five hospital centers, as part of the McPeak Sirois Group of Quebec. The median age of the cohort was 61 years (range, 38 to 82 years). 18.5% (n=13) of the cohort consisted of patients &amp;lt; 50 years, and 81.4% (n=57) were &amp;gt; or = to 50 years. 64.3% (n=45) of the patients had one positive lymph node and 35.7% (n=25) of the patients had 2 or 3 positive lymph nodes. 25.7% (n=18) of the patients had a RS &amp;lt; 11 and 68.6% (n=48) had a RS result between 11-25. For the entire cohort, we found that the proportion of patients for whom chemo-hormonal therapy was recommended was reduced by an absolute 67.1% by knowledge of the RS result (OR (odds of having chemo-hormonal therapy post-RS recommendation versus pre-RS recommendation) = 0.03 [95% CI: 0.01-0.08]; P&amp;lt;0.0001). The RS results led to an absolute reduction in physician recommendation in chemo-hormonal therapy by 38.5% for patients &amp;lt; 50 years, and by 73.7% of patients (OR=0.02 [95% CI: 0.01-0.06]; P &amp;lt;0.0001) for patients &amp;gt; or = to 50 years. Changes in treatment recommendation were identified for patients with one positive node, 73.3% (OR=0.02 [95% CI: 0.01-0.07]; P&amp;lt;0.0001); and for patients with two or three positive nodes, 56.0% (OR=0.06 [95% CI: 0.02-0.23]; P&amp;lt;0.0001). Recommendations for GF supportive therapy due to RS results decreased by 42.6% (OR=0.16 [95% CI: 0.07-0.34]; P &amp;lt;0.0001). Moreover, RS results led to an increase in confidence in physician treatment decisions for 68.6% of patients (OR=18.3 [95% CI: 7.90-42.28]; P &amp;lt;0.0001). We found that the cost of chemotherapy, in addition to anti-emetics and GF supportive therapy, decreased by 69.9% per patient (pre-RS mean, $3,968 CAN; versus post-RS mean, $1,196 CAN) (P &amp;lt;0.0001). Conclusions: Overall, we found that the 21-gene Breast Recurrence Score® assay changed physician treatment decisions in about two-thirds of all patients with hormone receptor-positive, node-positive BC, regardless of the number of positive nodes (up to 3). The assay increased physician confidence and was associated with an important decrease in treatment cost. Taken together, the assay is a cost-effective approach that can decrease the use of chemotherapy amongst HR-positive, node-positive BC patients in Quebec. Citation Format: Saima Hassan, Rami Younan, Erica Patocskai, Louise Provencher, Brigitte Poirier, Lucas Sideris, Pierre Dubé, Jean-Francois Boileau, Catalin Mihalcioiu, André Robidoux. A prospective multicenter study evaluating the impact of the 21-Gene Breast Recurrence Score® upon physician treatment decision and cost in lymph node-positive breast cancer patients in Quebec [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-27.

Bayesian approach for cure models with a change-point based on covariate threshold: application to breast cancer data

ABSTRACT In this study, a Bayesian approach was suggested to estimate a change-point according to a covariate threshold when some patients never experienced the event of interest. Gibbs sampler algorithm with latent binary cure indicators was used to simplify the implementation of Markov chain Monte Carlo method. Then, the accuracy of new model was demonstrated by simulation studies to compute the point and interval estimates of parameters. Finally, an effective threshold was suggested in age at surgery time to experience the metastasis when the model was applied for a data set of breast cancer patients.

ROCplot.org: Validating predictive biomarkers of chemotherapy/hormonal therapy/anti-HER2 therapy using transcriptomic data of 3,104 breast cancer patients.

Systemic therapy of breast cancer can include chemotherapy, hormonal therapy and targeted therapy. Prognostic biomarkers are able to predict survival and predictive biomarkers are able to predict therapy response. In this report, we describe the initial release of the first available online tool able to identify gene expression-based predictive biomarkers using transcriptomic data of a large set of breast cancer patients. Published gene expression data of 36 publicly available datasets were integrated with treatment data into a unified database. Response to therapy was determined using either author-reported pathological complete response data (n = 1,775) or relapse-free survival status at 5 years (n = 1,329). Treatment data includes chemotherapy (n = 2,108), endocrine therapy (n = 971) and anti-human epidermal growth factor receptor 2 (HER2) therapy (n = 267). The transcriptomic database includes 20,089 unique genes and 54,675 probe sets. Gene expression and therapy response are compared using receiver operating characteristics and Mann-Whitney tests. We demonstrate the utility of the pipeline by cross-validating 23 paclitaxel resistance-associated genes in different molecular subtypes of breast cancer. An additional set of established biomarkers including TP53 for chemotherapy in Luminal breast cancer (p = 1.01E-19, AUC = 0.769), HER2 for trastuzumab therapy (p = 8.4E-04, AUC = 0.629) and PGR for hormonal therapy (p = 8.6E-05, AUC = 0.7), are also endorsed. The tool is designed to validate and rank new predictive biomarker candidates in real time. By analyzing the selected genes in a large set of independent patients, one can select the most robust candidates and quickly eliminate those that are most likely to fail in a clinical setting. The analysis tool is accessible at www.rocplot.org.

Abstract P5-12-12: ROCplot.org: validating predictive biomarkers of response to chemotherapy/hormonal therapy/anti-HER2 therapy using transcriptomic data of 3,150 breast cancer patients

Abstract Prognostic biomarkers are capable to predict survival and predictive biomarkers are capable to predict therapy response. Systemic therapy of breast cancer can include chemotherapy, hormonal therapy, and targeted therapy. Here, we report the initial release of the first online available tool capable to identify gene expression based predictive biomarkers using transcriptomic data of a large set of breast cancer patients. Published gene expression data of 44 publicly available datasets was integrated with treatment data into a unified database. The classification is based on either author-reported pathological complete response (n=1,775) or relapse-free survival status at five years (n=1,329). Treatment data includes chemotherapy (n=2,108), endocrine therapy (n=971), and anti-HER2 therapy (n=267). The transcriptomic database includes 20,089 unique genes and 54,675 probe sets. Gene expression and therapy response are compared using receiver operating characteristics and Mann-Whitney tests. We demonstrate the utility of the tool by validating a set of established biomarkers including TP53 for chemotherapy in luminal breast cancer (p=5.2e-20, AUC=0.77), ERBB2 for trastuzumab therapy (p=8.4e-04, AUC=0.629), and PGR for hormonal therapy (p=8.6e-05, AUC=0.7). The tool is designed to validate and rank new predictive biomarker candidates in real time. By analyzing the selected genes in a large set of independent patients, one can select the most robust candidate and quickly eliminate those which are most likely to fail in a clinical setting. The analysis tool is accessible at www.rocplot.org/breast. Citation Format: Győrffy B, Fekete J. ROCplot.org: validating predictive biomarkers of response to chemotherapy/hormonal therapy/anti-HER2 therapy using transcriptomic data of 3,150 breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-12-12.

Abstract 3264: Targeting bone marrow-resident dormant CTCs to overcome metastasis

Abstract Metastatic “seeding” is an early event initiated when cancer cells are shed from the primary tumor, enter into the blood stream as circulating tumor cells (CTCs), and travel to distant organs where they can remain dormant as disseminated cancer cells (DTCs) for indefinite lengths of time. The organ serving as the foremost reservoir for DTCs is the bone marrow (BM). Despite widespread knowledge that bone marrow-resident breast cancer cells (BMRCs) affect tumor progression, signaling mechanisms of BMRCs implicated in maintaining long-term dormancy have not been characterized. This is caused by the lack of biomarkers that can identify and isolate viable but dormant BMRCs not expressing neoplastic and/or proliferation markers. To overcome these hurdles, we developed a patient-derived CTC model of clinical dormancy. We hypothesized that a significant distinction exists between signaling pathways of BM-homing vs metastasis-competent CTCs upon transplantation in xenografts. The model was established by three sequential steps: (a) isolation of CTC-enriched cell populations from the peripheral blood of patients with metastatic breast cancer, followed by CTC implantation in NOD-SCID-gamma mice; (b) in vivo depletion of “normal” human cell lineages over 4-8 months (before onset of overt metastasis), and (c) capture and characterization of viable human CTCs from blood and BM of mice via multi-parametric flow cytometry. This strategy was implemented on a set of breast cancer patients stratified according to their primary tumor subtype (ER+/PR+, HER2+, and ER-/PR-/HER2-), and gene-signatures of putative ex vivo CTCs and BMRCs were obtained by whole genome transcriptomic arrays. First, comparative analyses of ex vivo vs de novo CTC-gene signatures identified increased mTORC2 along with decreased mTORC1 signaling activity as the most significant characteristic of human BM-resident CTCs. mTORC2/mTORC1 represent the two complementary arms of mTOR signaling - a critical pathway frequently dysregulated in breast cancer and implicated in cell survival and dormancy. Second, heightened mTORC2 downstream targets augmented quiescent CTC populations (Ki67-/RBL2+ cells) in paired metastatic vs primary breast cancer tissues. Third, IHC analyses of breast cancer CTC xenograft tissues showed that solitary BM and tissue-resident breast cancer CTCs had high mTORC2 activity. Finally, shRNA knockdown of Rictor-the essential component of mTORC2 actions, increased Ki67/PCNA expression and proliferation. Collectively, these findings suggest that the balance between mTORC1 vs mTORC2 signaling pathways regulate CTC-associated mitotic and/or dormancy characteristics. Further elucidation of mTOR-mediated CTC dormancy will provide novel strategies for therapeutic interventions in breast cancer patients having metastatic “seeding” but yet to develop overt metastasis. Citation Format: Debasish Boral, Haowen N. Liu, Wei Yin, Monika Vishnoi, Antonio T. Scamardo, David S. Hong, Dario Marchetti. Targeting bone marrow-resident dormant CTCs to overcome metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3264.

Trastuzumab-induced cardiotoxicity and its risk factors in real-world setting of breast cancer patients.

Cardiotoxicity is the most important side effect of trastuzumab treatment. Heart function monitoring is recommended during the treatment which has led to growing use of resources. The aim of this retrospective study was to determine the frequency and timing of trastuzumab cardiotoxicity and its risk factors in real-world setting. Single institute, retrospective collection of data on HER2+ breast cancer patients (n = 246) was carried out through a pharmacy search for patients who had received trastuzumab in 2006-2014. Clinical and pathological factors, treatment history, EF measurements, cardiac medications, cardiovascular disease history, cardiac symptoms, and survival data were collected from patient records. 32 patients (13%) had EF decline ≥ 10%, eleven (4.5%) had EF decline ≥ 20% within 1year after trastuzumab initiation, and trastuzumab was discontinued due to suspected cardiotoxicity in six patients (2.4%). 49 patients (19.9%) experienced symptoms related to cardiotoxicity during therapy, which accumulated among those with EF drop. Underlying cardiovascular diseases and multiple (≥ 2) cardiac medications were related to EF drop (≥ 20%) and trastuzumab discontinuation. Majority of EF drops (≥ 10%) and trastuzumab discontinuations were seen within 6months of trastuzumab initiation and recovery of EF drop to < 10% of the baseline was seen in most cases (62.5%). There was no statistically significant difference in the survival of patients according to EF drop. Trastuzumab cardiotoxicity seems to accumulate among patients with underlying cardiac conditions. EF monitoring could be targeted to risk groups without compromising of the cardiac health or survival of HER2-positive breast cancer patients.

Abstract P3-08-10: Development and validation of a broad-based second generation multi marker “Morphometric IHC” test for optimal treatment planning of stage 1 and 2 breast cancer patients in low resource settings

Abstract Aims: Assessment of 'risk of recurrence' in ER+ breast cancer patients based on clinical parameters and existing hormone receptor signaling pathway and/or proliferation based biomarkers is insufficient, leading to treatment of majority of patients with chemotherapy. First generation risk identification tests like OncotypeDx and Mammaprint are not impactful in India and SE Asia as are largely prognostic with limited chemotherapy-predictivity and are prohibitively expensive. A cost-effective 'predictive' test which will accurately estimate the 'risk of recurrence' for a 'broader' (node - &amp; +) set of breast cancer patients in low resource settings is urgently required. Materials and Methods: Using a retrospective training cohort of 300 node– and node+ patients, we developed 'CanAssist-Breast'- a Morphometric Immunohistochemistry based test comprising 5 biomarkers plus three clinical parameters (Tumor size, grade and node status) to arrive at 'CanAssist-Breast Score'. The risk stratification model was developed using cutting edge support vector based machine learning technology. CanAssist-Breast Score stratifies patients into an all actionable 'low or high' risk for recurrence, with no intermediate zone. CanAssist-Breast biomarkers include cancer stem cell markers, Cadherins, and ATP transporter proteins - all critical players in the various steps of chemotherapy resistance leading to metastasis. Results: We validated CanAssist-Breast in accordance with EGAPP recommendations which require that prognostic tests be validated both analytically and clinically prior to being utilized in patients. Analytical validation experiments were performed to assess 'variation' in the outcome prediction due to critical IHC variables. We tested inter-pathologists, sample, operator and laboratory site variation and found high concordance in the outcome predictions across all variables, confirming the robustness and reproducibility of the test. Extended clinical validation on 1000+ pre and post-menopausal cases shows NPV of 95%. The majority of patients in 'low risk' had Stage 2, Grade 2/3 disease over Stage 1, Grade 1 disease, demonstrating that CanAssist-Breast reclassifies patients who would be considered high risk clinically. In a head-to-head pilot study of 100 patients with Oncotype Dx, CanAssist-Breast test had about 80% concordance with Oncotype in the 'low risk' category. Importantly, CanAssist-Breast correctly stratified few recurred cases as 'high risk' which were called 'low risk' by Oncotype Dx and thus were not treated with chemotherapy. Conclusion: In conclusion, we have developed a robust, accurate and low-cost prognostic test to predict risk of recurrence and enable optimal treatment planning in patients with early stage Breast Cancer. Citation Format: SP S, Bakre MM, Ramkumar C, Basavaraj C, Attuluri A, Madhav L, Prakash C, Naidu N, Malpani S. Development and validation of a broad-based second generation multi marker “Morphometric IHC” test for optimal treatment planning of stage 1 and 2 breast cancer patients in low resource settings [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-08-10.

Diagnostic and prognostic impact of fluorine-18-fluorodeoxyglucose PET/CT in preoperative and postoperative setting of breast cancer patients.

The aim of this study was to assess the diagnostic and prognostic value of fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT in patients with breast cancer (BC) in the preoperative and the postoperative setting. Between 2011 and 2015, we prospectively enrolled 275 patients (mean age: 53 years) with BC (stage I-III; triple-negative or HER2-positive cancer). One-hundred and forty-nine (54.2%) patients underwent F-FDG PET/CT before neoadjuvant therapy and 126 (45.8%) after surgery and before any additional adjuvant therapy. The patients were followed for a median period of 44 (2-57) months. The different effects of PET/CT on the presetting and postsetting phase form a therapeutic and prognostic point of view were assessed by χ, by Kaplan-Meier, and Cox-regression analyses. In the preoperative setting, PET/CT provided additional diagnostic information in 42/149 (28%) patients. In particular, 17/70 (24%) patients at stage III were converted into stage IV and 4/68 (6%) at stage II were upstaged to IV. In the postoperative setting, PET/CT upstaged the disease in both stage IIIC and stage IV in 14/126 (11%) cases. At the end of follow-up, 28/271 (10%) patients died from BC and 40 (15%) had a recurrence of disease. On Kaplan-Meier analysis, patients with a positive PET/CT other than the primary tumor site showed both a worse overall survival and a worse disease-free survival compared with their counterpart (76 vs. 92%; P=0.063 and 65 vs. 100%; P<0.001). Conversely, in the postoperative setting, no differences in overall survival and disease-free survival were found between patients with positive and negative PET/CT findings (both P>0.05). On multivariate Cox-regression analysis, a positive PET/CT was a significant predictive factor of a poor prognosis in the preoperative setting. The significance was lost in the postoperative setting. In the preoperative setting, PET/CT can provide additional diagnostic and prognostic information. Conversely, in the postoperative setting, PET/CT adds diagnostic information, but does not provide any adjunctive prognostic assessment.

Abstract P4-12-08: Use of an aptamer library based next generation omics platform for the development of a novel trastuzumab predictive assay

Abstract Introduction: Previous attempts to use individual aptamers as diagnostic reagents have failed to consistently achieve performance comparable to antibodies. Here we report a novel systems biology approach using poly-ligand aptamer libraries to identify responders and non-responders to traztuzumab-based regimens in metastatic breast cancer. Methods: To overcome the fundamental limitation of the individual aptamer binding affinities, large libraries (106 species) were created so that potentially thousands of aptamers could bind to each of a multitude of targets related to the whole cellular changes in response to trastuzumab therapy. A set of breast cancer patients, which received trastuzumab mono- or combined therapy for at least 7 months were classified as “Responders” (R); cases with particular regimen discontinued in the period not exceeding 5 months were classified as “Non-Responders”(NR). A library of 2x1012 unique 90-mer ssDNA oligodeoxynucleotides (ssODN) was trained on FFPE tissue of both R and NR patients. Partitioning of aptamer libraries was done by microdissection of the tumor tissue, after incubation of aptamer library with the entire tissue section, to drive selection pressure toward cancer cells. A total of 10 cases of R and NR, 6 Her2+ cases each, were used to train separate aptamer libraries, with 1 positive and 2 counter selection cases per enrichment. Enriched libraries were screened on 20 R and 20 NR cases (11 Her2+ cases each) by adopting modified immunohistochemistry protocol. Each library was used as an independent reagent (similar to an antibody in IHC) across all 40 cases to evaluate the efficacy of the aptamer library to distinguish differences between the R and NR groups. Staining (DAB chromogen) profiles were scored from 0 to 3+ (nuclear and cytoplasmic staining) by a pathologist without any knowledge of the clinical outcomes. Initial validation was done by t-test using raw histological scores. Four libraries showed significant p-values between groups of responders and non-responders, a classification algorithm was constructed and evaluated using area under the receiver-operator characteristic curve (AUC). The datasets of two best-performing libraries were combined into one model using logistic regression to further improved the classifier performance. Results: Of seventeen trained libraries, eight were evaluated and four showed significant correlation to clinical benefit with a minimum accuracy of 75% for each library when evaluated independently. Furthermore, two libraries showed exceptional performance (ROC curve AUC of 0.86 and 0.77). Combination of the profiling data from these two libraries using logistic regression resulted in an AUC of 0.985. A prospective validation of aptamer histochemical theranostic testing has been initiated. Summary: Enriched aptamer libraries appear to distinguish trastuzumab responsiveness in metastatic breast cancer. This technology could be used as an additional technique beyond FISH testing to determine sensitivity to anti-HER2 agents. The demonstrated platform is applicable to virtually any disease where the safe and effective use of corresponding drug is yet to be improved. Citation Format: Spetzler D, Domenyuk V, Santhanam R, Wei X, Stark A, Wang J, Gatalica Z, Miglarese M, Vidal G, Schwartzberg LS. Use of an aptamer library based next generation omics platform for the development of a novel trastuzumab predictive assay [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 P4-12-08.

Prognostic values of Ki-67 in neoadjuvant setting for breast cancer: a systematic review and meta-analysis.

To assess the prognostic values of Ki-67 in neoadjuvant setting for breast cancer patients. PubMed and EMBASE were searched. Revman software was used to conduct random-effect model meta-analysis. 49 studies (14,076 patients) were included. High Ki-67 before and after neoadjuvant chemotherapy were associated with worse overall survival (OS; before: hazard ratio [HR]: 2.29; 95% CI: 1.42-3.69; after: HR: 2.24; 95% CI: 1.82-2.75) and disease-free survival (DFS; before: HR: 1.54; 95% CI: 1.23-1.95; after: HR: 2.08; 95% CI: 1.83-2.37). Low/no reduction or increase might be associated with worse DFS (HR: 2.13; 95% CI: 1.51-3.02) and OS. Ki-67 before and after neoadjuvant chemotherapy, as well as the change could predict the prognosis for breast cancer patients.

The predictive value of Ki-67 before neoadjuvant chemotherapy for breast cancer: a systematic review and meta-analysis.

To review the predictive values of Ki-67 before neoadjuvant chemotherapy (NAC) for breast cancer patients. PubMed and EMBASE were searched. Random-effect model meta-analysis was conducted using Revman software. High Ki-67 was associated with more pathological complete responses (pCRs) events (odds ratio: 3.10; 95% CI: 2.52-3.81; 53 studies, 10,848 patients) regardless of HR+, HER2+ and triple-negative breast cancer types, the definitions of pCR and cut-off points for Ki-67. Ki-67 could predict pCR in those who received anthracyclines plus taxanes, and anthracyclines only, and those from Asia and Europe. High Ki-67 before NAC was a predictor for pCR in neoadjuvant setting for breast cancer patients.

Pre-operative MRI exhibits limited utility in axillary staging for breast cancer

IntroductionMagnetic resonance imaging (MRI) is commonly utilized in treatment planning of breast cancer patients. While axillary lymph node findings are routinely reported in these studies, the utility of these findings remains unclear. MethodsIn this retrospective study from 2008–2014, women diagnosed with invasive breast cancer who did not undergo neoadjuvant therapy were reviewed. MRI characteristics of axillary findings were compared to the final pathologic results. Results210 of 338 female patients met inclusion criteria and comprised our patient cohort. MRI was found to have a sensitivity and specificity of 45% and 84%, respectively. The negative predictive value was 78% with an accuracy of 72% and a false negative rate of 14%. MRI was more often accurate in younger patients (p<0.04, CI 0.52–1.19) and those whom had a larger number of lymph nodes harvested (p<0.0001, CI −10.8 to −0.2). True positives had significantly larger primary tumors and a larger number of positive lymph nodes on final pathology. ConclusionMRI of the axilla is not a reliable tool for axillary staging in women with breast cancer. MicroabstractThe significance of magnetic resonance imaging (MRI) findings of the axilla after routine preoperative imaging is poorly understood. We evaluated the perioperative course including axillary findings on MRI and compared them to the final axillary pathology of 210 women with invasive breast cancer. MRI did not show adequate predictive capability in determining women with invasive cancer progression to the axilla. Clinical practice pointsPreoperative magnetic resonance imaging of the breast is often obtained for women diagnosed with breast cancer. Findings in the axilla are often commented on in the radiology reports of these studies. There is limited data evaluating the significance of axillary finding in breast cancer imaging. The current literature differs in two important ways from the findings revealed in this study. First, the majority of the current literature focuses on imaging obtained using axillary specific protocols. These findings to not contribute transferable information for the typical clinical practice as these protocols are not commonly ordered or performed. Second, currently available studies have small cohorts, typically less than one hundred patients, or are systematic reviews. This study provides analysis of 210 patients over 6 years and represents the largest single study cohort that evaluates the clinical significance of axillary findings obtained during preoperative MRI of the breast.The findings reported here will aid clinicians when completing the preoperative work up for women diagnosed with breast cancer. Further, the subgroup analysis of our true positives presents an opportunity to potentially identify a new set of breast cancer patients that would have a greater benefit from neoadjuvant chemotherapy and thus spare them the morbidity of axillary lymph node dissection.

Influences on quality of prescribing in breast cancer patients

This article presents a discussion on both positive and negative influences on quality of prescribing in clinical practice. It explores how such influences have an impact on breast cancer patients on adjuvant hormonal therapy. Since hormonal therapy in the adjuvant setting for breast cancer patients is associated with a reduction in both recurrence and mortality rates, the impact of quality prescribing can result in a meaningful long-term outcome for this particular group of patients. In Ireland, nurse prescribing is a relatively new development and continues to develop. Guiding the registered prescribing nurse in practice, prescribing duties are undertaken in line with a dual framework incorporating both legislative and professional mandates. Although these guidelines serve to direct and ensure quality prescribing, no governing mandate meets all the complexities and challenges faced in clinical practice.

Magnetic resonance imaging in the preoperative setting for breast cancer patients with undetected additional disease

ObjectiveThe last few years have witnessed a significant increase in the preoperative use of Magnetic Resonance Imaging (MRI) for staging purposes in breast cancer (BC) patients. Many studies have confirmed the improvement that MRI can provide in terms of diagnostic assessment, especially with regard to additional disease foci. In the present study, we address the advantages and disadvantages of MRI in the preoperative setting for BC patients. Patients and methodsThere were 1513 consecutive breast MRI studies performed in patients with either primary or recurrent BC, who were scheduled for surgery. ResultsBeyond the primary lesion, 10.4% of our cases had additional disease at the final histological assessment. MRI overall sensitivity, when considering tumour size and additional foci together, was 74.3%, and 80.3% when considering additional foci exclusively. MRI specificity for additional disease was 95.3%, positive predictive value was 77.4%, and negative predictive value was 94.6%. Nevertheless, 5% of cases had additional tumours that were missed by MRI or, conversely, had additional foci on MRI that were not confirmed by histology. Age (p=0.020) and lobular carcinomas (p=0.030) showed significance in the multivariate analysis by logistic regression, using the presence of additional foci diagnosed by MRI as a dependent variable. ConclusionPreoperative MRI seems to have a role in preoperative tumour staging for breast cancer patients, as it discloses additional disease foci in some patients, including contralateral involvement. However, given the lack of absolute accuracy, core-needle biopsy cannot be neglected in the diagnosis of such additional malignant foci, which could result in a change in surgical treatment.

High-circulating Tie2 Is Associated With Pathologic Complete Response to Chemotherapy and Antiangiogenic Therapy in Breast Cancer

Vascular endothelial growth factor (VEGF) is a central mediator of angiogenesis in breast cancer. Research in antiangiogenic cancer treatment has been marked by the development of the monoclonal antibody bevacizumab, which targets VEGF in many solid tumors. As patients do not equally benefit from bevacizumab, it has become necessary to define the profile of patients who will benefit from the drug. We have conducted a prospective phase II study in 39 patients using bevacizumab in breast cancer in the neoadjuvant setting, and found improved pathologic complete response (pCR) when bevacizumab was added to chemotherapy in patients with hormone receptor negative and invasive ductal carcinoma. Blood samples were collected at baseline and serially while patients were on treatment. Circulating angiogenesis-related proteins angiopoietin (ANG)1, ANG2, basic fibroblast growth factor, IL-1a, matrix metalloproteinase 9, platelet derived growth factor - BB, platelet endothelial cell adhesion molecule -1, Tie2, VEGF, and vascular endothelial growth factor receptor 2 were measured at baseline and during treatment. This correlative study was conducted to identify specific serum angiogenic factor profiles that might be associated with pCR in the neoadjuvant setting in breast cancer patients receiving bevacizumab and chemotherapy. Elevated baseline serum Tie2 and basic fibroblast growth factor were associated with pCR in response to this combination. Changes in serum levels of these proteins were seen during treatment but were not significantly different between the pCR and non-pCR groups. Baseline-circulating Tie2 levels may help distinguish patients who will have pCR from those who will not and may form the basis for future development of antiangiogenic therapy in breast cancer. Larger studies are needed to validate these findings. ClinicalTrials.gov Identifier: NCT00203502.

Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines.

BackgroundStudies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30 % response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this study was to lay the groundwork for development of predictive biomarkers for irinotecan treatment in BC.MethodsWe established BC cell lines with acquired or de novo resistance to SN-38, by exposing the human BC cell lines MCF-7 and MDA-MB-231 to either stepwise increasing concentrations over 6 months or an initial high dose of SN-38 (the active metabolite of irinotecan), respectively. The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers and protein expression, and inhibition of the breast cancer resistance protein (ABCG2/BCRP) drug efflux pump.ResultsWe found that the resistant cell lines showed 7–100 fold increased resistance to SN-38 but remained sensitive to docetaxel and the non-camptothecin Top1 inhibitor LMP400. The resistant cell lines were characterized by Top1 down-regulation, changed isoelectric points of Top1 and reduced growth rates. The gene and protein expression of ABCG2/BCRP was up-regulated in the resistant sub-lines and functional assays revealed BCRP as a key mediator of SN-38 resistance.ConclusionsBased on our preclinical results, we suggest analyzing the predictive value of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2071-1) contains supplementary material, which is available to authorized users.

Acupuncture in the Postoperative Setting for Breast Cancer Patients: A Feasibility Study

Acupuncture is used to treat a variety of symptoms and conditions associated with cancer and cancer treatments. The present study was performed to evaluate the feasibility of providing acupuncture in the hospital setting for breast cancer patients and to evaluate the short-term effect of acupuncture on stress, anxiety, and pain. This was an open label study conducted at Mayo Clinic Hospital, Methodist and Saint Marys Campus, Rochester, Minnesota. A total of 20 adult breast cancer patients undergoing mastectomy and/or breast reconstruction were recruited and offered daily acupuncture intervention beginning postoperative day 1 and continuing for the duration of the hospital stay. Outcome measures included the Symptom Visual Analog Scale (VAS) and Satisfaction Question and Was-it-Worth-it (WIWI) Questionnaire. It was found that acupuncture is a feasible option for postoperative breast cancer patients. In addition, it can significantly decrease the levels of anxiety (p = 0.0065), tension/muscular discomfort (p < 0.001) and pain (p = 0.023). The association between acupuncture and relaxation was found to be statistically borderline (p = 0.053). This feasibility study showed that acupuncture can be integrated into a busy postsurgical clinical practice. These results also suggest that acupuncture may be an important intervention in the postoperative setting for breast cancer patients.