Systemic Therapy For Breast Cancer Research Articles

Excision of both pretreatment marked positive nodes and sentinel nodes improves axillary staging after neoadjuvant systemic therapy in breast cancer.

BackgroundMarking the axilla with radioactive iodine seed and sentinel lymph node (SLN) biopsy have been proposed for axillary staging after neoadjuvant systemic therapy in clinically node‐positive breast cancer. This study evaluated the identification rate and detection of residual disease with combined excision of pretreatment‐positive marked lymph nodes (MLNs) together with SLNs.MethodsThis was a multicentre retrospective analysis of patients with clinically node‐positive breast cancer undergoing neoadjuvant systemic therapy and the combination procedure (with or without axillary lymph node dissection). The identification rate and detection of axillary residual disease were calculated for the combination procedure, and for MLNs and SLNs separately.ResultsAt least one MLN and/or SLN(s) were identified by the combination procedure in 138 of 139 patients (identification rate 99·3 per cent). The identification rate was 92·8 per cent for MLNs alone and 87·8 per cent for SLNs alone. In 88 of 139 patients (63·3 per cent) residual axillary disease was detected by the combination procedure. Residual disease was shown only in the MLN in 20 of 88 patients (23 per cent) and only in the SLN in ten of 88 (11 per cent), whereas both the MLN and SLN contained residual disease in the remainder (58 of 88, 66 per cent).ConclusionExcision of the pretreatment‐positive MLN together with SLNs after neoadjuvant systemic therapy in patients with clinically node‐positive disease resulted in a higher identification rate and improved detection of residual axillary disease.

291TiP - Correlation between the density of tumour-infiltrating lymphocytes, immune cell subsets in tumour stroma and response to systemic therapy in breast cancer

BackgroundThe density of tumor-infiltrating lymphocytes (TIL) is a predictive factor for response to neoadjuvant systemic therapy (NAST) in breast cancer. High TIL density correlates with higher complete pathologic remission (pCR) in triple negative and HER2 positive breast cancer. Additionally, not only TIL density but also subsets of immune cells in tumor stroma seem to play an important role in cancer and immune cell interaction and response to chemotherapy. Our aim is to determine TIL density and expression of CD 20, CD3, CD8, PD-L1, FOXP3 and PGM1 on core biopsy specimen and find a correlation with pCR. Trial designWe will conduct a prospective study on early breast cancer patients (n=180) treated with NAST. Patients with breast tumor >2cm will be suitable. All patients will underwent mammography, MR of breast, core biopsy of breast tumor, implantation of radiopaque marker into tumor, axillary ultrasound and fine needle biopsy of suspect nodes, CT scan of thorax and abdomen and bone scintigraphy. On core biopsy specimen histologic type, grade, estrogen and progesterone receptors, HER 2 status and MIB-1 will be determined. Additionally, TIL density will be determined on stromal part of tumor on H&E slides in accordance with International TIL Working Group. TIL density will be defined as the percentage of lymphocytes in tumor stroma: as a continuous variable and as two categories: low (0-59%) or high (60-100%). Immunohistochemical detection of CD 20, CD3, CD8, PD-L1, FOXP3 and PGM1 will be performed and each subpopulation of immune cells defined as percentage of all immune cells in tumor stroma. Patients with metastatic tumours and luminal A-like characteristics will be excluded. All other patients will undergo NAST with anthracyclines and taxanes and anti-HER2 therapy if indicated, followed by surgical treatment. The breast and axilla specimen will undergo pathologic examination. pCR will be defined as absence of invasive and carcinoma in situ in breast and axillary nodes. The primary objective will be correlation of CD20, CD3, CD8, PD-L1, FOXP3 and PGM1 with TIL density. The secondary objective will be correlation of subsets of immune cells in tumor stroma with pCR. Clinical trial identificationEudraCT: 2018-000 547-11. Legal entity responsible for the studyInstitute of Oncology Ljubljana. FundingSlovenian Research Agency P3-0321. DisclosureAll authors have declared no conflicts of interest.

Can Breast Magnetic Resonance Imaging Assess Tumor Response to Preoperative Accelerated Partial Breast Irradiation?

While Magnetic Resonance Imaging (MR) is commonly performed after neoadjuvant systemic therapy for breast cancer to assess tumor response to therapy, little is known about the tumor response on MR after preoperative radiation. We sought to evaluate the MR changes in patients with Stage IA luminal breast cancer after preoperative accelerated partial breast irradiation (APBI) treated in the prone position and compare the MR changes with tumor diameter on pathology. We hypothesize that following preoperative ABPI there will be a detectable change on MR in maximum contrast enhancement (MCE), time to contrast enhancement (CE) or CE tumor volume that will correspond to reduction in tumor size. Women ≥50 years of age with Stage IA luminal breast cancer enrolled on an IRB approved trial were studied. Using a Q-fix™ therapy positioning device prototype, a CT Simulation in the prone position and then an MR were acquired and fused to contour GTV. Preoperative APBI was 3850 cGy in 10 fractions BID with a minimum of 6-hours between fractions. Another CE-MR was obtained 4 weeks after APBI prior to breast conserving surgery (BCS) on a 3T MR. Gadolinium MR contrast agent was injected at standard dose and rate after completing the first series; 5 series were acquired at 90 second intervals after contrast injection. A visual and quantitative assessment using region of interest was performed to assess the intensity, kinetics and volume of the lesion CE. We used a slice selective segmentation approach to determine the 3D volume and the longest axis diameter. The MCE compared to baseline and the time to MCE was determined. An experienced reader performed a visual classification to assess the MR volume-based changes and kinetic enhancement changes. To estimate the change in invasive tumor size occurring under APBI, we compared the longest axis size on the baseline CE-MR to longest diameter on pathology. Thirteen patients had both MRs and pathology available. Median age was 66 years old (range 51-78). Median days between pre-therapy MR and ABPI was 13 (range 8-19). Median days from ABPI to second MR and BCS was 33 (range 21-40) and 40 (range 34-52), respectively. Eight (62%) patients had a reduction of MCE after APBI, 7 of which had a decrease in pathological size. Ten (77%) patients had an increase of time to MCE. The average reduction of the contrast enhanced tumor volume was 22%. The tumor diameter shrinkage from pre-treatment CE-MR to histology was on average 49%. In 4 patients we found a longest diameter reduction of less than <25%, while in 3 patients 25-50%, and >50% in 6 patients. The treatment effect of preoperative ABPI can be detected on CE-MR. Most irradiated tumors showed either a reduction in maximum contrast enhancement and/or longer time to maximum contrast enhancement. This study demonstrates that preoperative radiation induces changes on MR reflecting treatment effect on tumor vasculature and/or tumor necrosis. Future analysis will include a detailed pathological review.

The Effect of Bolus on Local Control for Patients Treated with Mastectomy and Adjuvant Radiotherapy

Patterns of practice surveys have shown that about half of radiation oncologists routinely use bolus for postmastectomy radiotherapy (RT). Bolus use causes well recognized acute and late toxicities and leads to non-completion of adjuvant radiotherapy in a small fraction of patients. Whether bolus use improves local control is unknown. The null hypothesis of this study was that the use of bolus during radiotherapy would not improve local control. This study was conducted for a defined population of patients, in whom bolus was used routinely for chest-wall RT and was omitted routinely for RT with a breast reconstruction. As the decision to have a reconstruction was usually made by the patient in consultation with their surgeon(s) and not with their oncologists, this practice offered a pseudo-randomized opportunity to evaluate local control outcomes in patients treated with and without bolus. The study included newly diagnosed invasive breast cancers (pT1-4a, any-N, M0) treated with mastectomy and adjuvant RT. Patients with skin involvement (T-stage cT4b, c, d or pT4b, c, d) were excluded. In this population, local recurrence events are actively sought until 15 years after diagnosis with annual queries to the primary practitioners of all breast cancer survivors. The primary endpoint was the cumulative incidence of local recurrence using regional recurrence, distant recurrence and death as competing risks in patients treated with and without bolus. A multivariable analysis of local recurrence was conducted with T-stage, N-stage, lymphovascular invasion (LVI), margin status, triple-negative subtype, as well as use of bolus, hormone therapy and chemotherapy. The entire cohort consisted of 1,891 women diagnosed from 2007 to 2011, 789 treated with bolus and 1,102 treated without bolus. The median follow-up was 8.7 years. The median age in the reconstruction cohort was lower (54 versus 56 years, p=0.03, median test); however, there were no significant differences in the distribution of tumor characteristics (T-stage, N-stage, LVI, margin status) or treatment characteristics (hormone therapy, chemotherapy). The 10-year cumulative incidence of local recurrence was 1.8% (95%CI: 1.1 – 2.9%) with bolus and 1.7% (95%CI: 0.9 – 2.8%) without bolus. The multivariable analysis demonstrated that local recurrence was not significantly related to use of bolus (HR = 1.08, 95%CI: 0.5 – 2.2) or the other variables. In this population-based study of patients who received contemporary systemic therapy for breast cancer without skin involvement, the absolute risk of local recurrence was low. The use of bolus did not impact long-term local control after mastectomy and RT. This retrospective study provides the best current evidence that routine use of bolus during radiotherapy should be questioned in patients treated with mastectomy.

Prognostic and Clinicopathological Correlations of Cell Cycle Marker Expressions before and after the Primary Systemic Therapy of Breast Cancer

We aimed to analyze the expression of cell-cycle regulation markers – minichromosome maintenance protein 2 (MCM2), Ki-67, Cyclin-A and phosphohistone-H3 (PHH3) − in pre-treatment core-biopsy samples of breast carcinomas in correlation with known predictive and prognostic factors. Totally 52 core biopsy samples obtained prior to neoadjuvant therapy were analyzed. Immunohistochemistry was performed to analyze the expression of MCM2, Ki-67, Cyclin A and PHH3, which were correlated with the following clinicopathological parameters: clinical TNM, tumor grade, biological subtype, the presence of tumor infiltrating lymphocytes (TIL), pathological tumor response rate to the neoadjuvant therapy and patient survival. All investigated markers showed higher expression in high grade and in triple negative tumors (p < 0.01 and p < 0.05, respectively). Hormone receptor negative tumors showed significantly higher expression of Ki-67 (p < 0.01), MCM2 (p < 0.01) and Cyclin A (p < 0.01) than hormone receptor positive ones. Tumors with increased TIL showed significantly higher Ki-67 expression (p = 0.04). Pattern analysis suggested that novel cell-cycle marker-based subgrouping reveals predictive and prognostic potential. Tumors with high MCM2, Cyclin A or PHH3 expression showed significantly higher rate of pathological complete remission. Tumors with early relapse (progression-free survival ≤2 years) and shortened overall survival also show a higher rate of proliferation. Our cell cycle marker (Ki-67, MCM2, Cyclin A, PHH3) based testing could identify tumors with worse prognosis, but with a favorable response to primary systemic therapy. The pattern of cell-cycle activity could also be useful for predicting early relapse, but our findings need to be further substantiated in larger patient cohorts.

Does use of axillary ultrasound in clinically node-negative patients receiving neo-adjuvant systemic therapy for breast cancer lead to surgical overtreatment?

Increased use of neo-adjuvant chemotherapy (NAC) for breast cancer has raised uncertainty regarding staging of the axilla, particularly for patients with a clinically negative axillary physical examination (PE). We sought to determine whether axillary ultrasound (AUS) prior to NAC to identify occult nodal disease is beneficial in patients with a clinically negative examination by evaluating the difference in nodal burden on final pathology in those with abnormal vs normal AUS. A retrospective review of an institutional cancer registry identified patients who underwent NAC for breast cancer and had a pretreatment AUS. Differences in the number of positive lymph nodes (PLN) in patients with a normal axillary PE and abnormal vs normal AUS prior to NAC were determined. A total of 120 patients who received NAC had a negative axillary PE prior to treatment. Fifty-three had an abnormal AUS and biopsy-proven lymph node (LN) involvement. In patients with an abnormal AUS, median number of PLNs at surgery was 1 vs 0 for those with a normal AUS (mean difference of 2.12, P<.0001). Of those patients with an abnormal AUS and biopsy-proven LN involvement, 87% underwent axillary lymph node dissection (ALND) and nearly half had no PLN on final pathology (N=23, 43%). Patients with a clinically negative axilla and an abnormal AUS were more likely to have PLN at the time of surgery. However, almost half of those patients had no residual LN involvement. Routine AUS prior to NAC may lead to more extensive surgical management of the axilla.

Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of the Cancer Care Ontario Guideline.

To update the American Society of Clinical Oncology endorsement of the Cancer Care Ontario recommendations on the Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer. Two phase III trials-the Trial Assigning Individualized Options for Treatment (TAILORx) in women with hormone receptor-positive, node-negative tumors and the Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy (MINDACT) trial-provided the evidence for this update. Shared decision making between clinicians and patients is appropriate for adjuvant systemic therapy for breast cancer. For patients older than age 50 years and whose tumors have Oncotype DX recurrence scores less than 26, and for patients age 50 years or younger whose tumors have Oncotype DX recurrence scores less than 16, there is little to no benefit from chemotherapy. Clinicians may offer endocrine therapy alone for these patients. For patients age 50 years or younger with recurrence scores of 16 to 25, clinicians may offer chemoendocrine therapy. Patients with recurrence scores greater than 30 should be considered candidates for chemoendocrine therapy. Based on informal consensus, the Panel recommends that oncologists may offer chemoendocrine therapy to patients with Oncotype DX scores of 26 to 30.The MammaPrint assay could be used to guide decisions on withholding adjuvant systemic chemotherapy in patients with hormone receptor-positive lymph node-negative breast cancer and in select patients with lymph node-positive cancers. In both patients with node-positive and node-negative disease, evidence of clinical utility of the MammaPrint assay was only apparent in those determined to be at high clinical risk; the Panel thus did not recommend use of MammaPrint assay in patients determined to be at low clinical risk. Remaining recommendations from the 2016 ASCO guideline endorsement are unchanged.Additional information is available at www.asco.org/breast-cancer-guidelines.

Biomarkers involved in the neoadjuvant therapy response in triple-negative and Her2+ subtypes breast cancer.

e12098 Background: Neoadjuvant systemic therapy for breast cancer is used increasingly for patients with breast cancer. One of the more compelling theoretical arguments for primary systemic therapy is its value as an in vivo test for drug sensitivity. The oncogenesis of breast cancer, progression and development of metastasis is influenced by the deregulation of a multitude of processes. Several long non-coding RNAs (LncRNAs) and genes are important regulators of gene expression, acting at almost all regulatory levels: transcriptional, posttranscriptional, epigenetic, and protein translation. Our main objective was to identify the differential expression of genes and LncRNAs in paraffin-embedded breast cancer samples Her2+ and triple negative (TN) subtypes in responders (R) and non-responders (NR) patients (pts) to neoadjuvant therapy. Methods: The expression RNAs was analyzed by ClariomD Asssay (ThermoFisher). Results were analyzed with Transcriptome Analysis Console and with in-house scripts in R (version 3.5.1). Data were corrected and normalized using Robust Multichip Average method from the oligo package. Expression was summarized at gene level using the corresponding annotation for ClariomD array BrainArray. Expression analyses were performed with limma package. We defined R (RCB 0; n = 29) and NR (RCB III; n = 11) pts. Results: The differential expression (p &lt; 0.01) of two LncRNAs (RP1-213J1P_B.1 and AC053503.12), one miscellaneous RNA (miscRNA) (Metazoa_SRP) and five genes (STMND1, C8orf33, RP11-144G6.12, ZNF555, RGS2) were found between R and NR. Among others, we highlighted one of these LncRNAs (AC053503.12) and one gene (Metazoa_SRP) that were also identified in TN R (n = 11) vs NR (n = 6). In the Her2+subtype, STMND1 gene also showed a differential expression in R (n = 18) vs NR (n = 5). Conclusions: We found these LncRNAs, miscRNA and genes were involved in different cancer pathways and the their differential expression in R vs NR pts suggest that they could be involved in the response to neoadjuvant therapy in TN and Her2+ subtypes breast cancer. LncRNAs, miscRNA and genes differentially expressed are being independently analyzed by individual qPCR assays in the study cohort.

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.

Expected Monetary Impact of Oncotype DX Score-Concordant Systemic Breast Cancer Therapy Based on the TAILORx Trial.

TAILORx demonstrated that women with node-negative, hormone receptor-positive, HER2-negative breast cancers and Oncotype DX recurrence scores (RS) of 0-25 had similar 9-year outcomes with endocrine vs chemo-endocrine therapy; evidence for women aged 50 years and younger and RS 16-25 was less clear. We estimated how expected changes in practice following the trial might affect US costs in the initial 12 months of care (initial costs). Data from Surveillance, Epidemiology, and End Results (SEER), SEER-Medicare, and SEER-Genomic Health Inc datasets were used to estimate Oncotype DX testing and chemotherapy rates and mean initial costs pre- and post-TAILORx (in 2018 dollars), assuming all women received Oncotype DX testing and score-suggested therapy posttrial. Sensitivity analyses tested the impact on costs of assumptions about compliance with testing and score-suggested treatment and estimation methods. Pretrial mean initial costs were $2.816 billion. Posttrial, Oncotype DX testing costs were projected to increase from $115 to $231 million and chemotherapy use to decrease from 25% to 17%, resulting in initial care costs of $2.766 billion, or a net savings of $49 million (1.8% decrease). A small net savings was seen under most assumptions. The one exception was if all women aged 50 years and younger with tumors with RS 16-25 elected to receive chemotherapy, initial care costs could increase by $105 million (4% increase). Personalizing breast cancer treatment based on tumor genetic profiles could result in small cost decreases in the initial 12 months of care. Studies are needed to evaluate the long-term costs and nonmonetary benefits of personalized cancer care.

Abstract P1-15-22: Clinicopathological significance of diversity index for c-MYC copy number variation after primary systemic therapy in breast cancer

Abstract Background: Chemotherapy can alter tumor cell populations by exerting selection pressure. This study was performed to evaluate the change in Shannon diversity index for c-MYC copy number variation after primary systemic therapy (PST) and its clinical implications in breast cancer patients treated with PST. Materials and Methods: One hundred and forty-four breast cancer patients who had residual disease after anthracycline- or anthracycline and taxane-based PST were included in the study. Associations between Shannon index for c-MYC copy number variation in pre- and post-PST breast cancer samples and clinicopathologic features of tumors as well as patient survival were analyzed. Results: Among the 119 patients with both pre- and post-PST samples available for comparison, 17 (14.3%) underwent change in c-MYC amplification status and 40 (33.6%) in c-MYC copy number gain status with most cases showing positive to negative conversion. In the whole group, Shannon index for c-MYC copy number variation was decreased in post-PST specimens compared to pre-PST specimens. Especially, the chemo-responsive group showed a more significant decrease in Shannon index after PST. However, there was no difference in diversity indices between pre- and post-PST specimens in the chemo-resistant group. c-MYC copy number gain and high Shannon indices for c-MYC copy number variation in both pre- and post-PST specimens were associated with adverse clinicopathologic features of breast cancer. In survival analyses, high Shannon indices for c-MYC copy number variation in post-PST samples as well as pre-PST samples were revealed as an independent prognostic factor for decreased disease-free survival. Upon subgroup analysis according to hormone receptor status, high Shannon indices before and after PST were associated with adverse clinical outcome in hormone receptor-positive group but not in hormone receptor-negative subgroup. Conclusions: These results suggest that a change in Shannon index for c-MYC copy number variation after PST reflects chemo-responsiveness and that Shannon index after PST can be used as a prognostic factor in breast cancer patients who receive PST. Citation Format: Kim G, Chung YR, Kim HJ, Kim M, Ahn S, Park SY. Clinicopathological significance of diversity index for c-MYC copy number variation after primary systemic therapy in breast cancer [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 P1-15-22.

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 P3-03-16: Intraoperative evaluation of sentinel lymph nodes after neoadjuvant systemic therapy in breast cancer

Abstract Introduction: Intraoperative evaluation of sentinel lymph nodes (SLN) in breast cancer patients are performed using Touch preparation (TP) and/or frozen section (FS). Touch preparation for intraoperative evaluation of SLN is quick and known to be a highly sensitive and specific method for detection of metastasis. Detecting metastases in SLN intraoperatively can be challenging in patients who receive neoadjuvant systemic therapy (NST). In our hospitals, we have been routinely evaluating SLN intraoperatively in patients who have undergone (NST), including those with known metastasis to an axillary lymph node (LN) prior to therapy. Objective: To compare the sensitivity and specificity of TP and frozen section (FS) in the intraoperative evaluation of SLN in the neoadjuvant setting. Material and Methods: This retrospective review study was approved by the institutional review board. Four hundred ninety-eight SLN from 142 patients were included in this study. The intraoperative results for TP and FS were compared with the final pathology results. Relevant clinical and pathological findings such as type of surgery, tumor grade, histologic subtype, and size of metastasis were reviewed. Results: Of the 498 SLN evaluated intraoperatively, 341 were by TP only, 57 by FS only and 100 by both. Of the 341 SLN examined by TP only, 313 (92%) were interpreted as negative and 28 (8%) as positive for carcinoma intraoperatively. Eighteen LN turned out to be false negative (FN) with no false positives (FP) (sensitivity=62%, specificity=100%). In the false negative cases, 12 LN had micrometastasis, 6 macrometastasis and 1 showed isolated tumor cells (ITC). The size of the macrometastatic ranged from 3 mm to 10 mm. Of the 57 LN examined by FS only, 48 were true negative and 9 were true positive (sensitivity=100%, specificity=100%). Of the 100 LN evaluated by both TP and FS, 59 were interpreted as negative and 41 as positive for carcinoma. There were 8 false negatives and 1 false positive (sensitivity=83%, specificity=98%). Of the 8 false negatives, 7 showed micrometastasis and 1 LN had ITC. Discussion: In neoadjuvant cases, both the primary tumor as well as lymph node metastases can show therapy effect such as fibrosis, necrosis and/or histiocytic aggregates. Evaluating SLN in NST cases can be challenging secondary to these effects. The TP slides are often paucicellular in SLN with treatment effect. Residual tumor cells are often trapped in a fibrotic scar and do not transfer onto the TP slide leading to low sensitivity. Therefore, for optimal intraoperative evaluation of SLN in NST cases, frozen section with or without touch preparation, is recommended. Citation Format: Sahoo S, Mir M, Sarode V, Fang Y, Peng Y, Gwin K, Hwang H. Intraoperative evaluation of sentinel lymph nodes after neoadjuvant systemic therapy in breast cancer [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 P3-03-16.

Abstract P6-21-05: Concurrent exercise and chemotherapy in preclinical breast cancer models

Abstract The benefits of exercise following a cancer diagnosis is increasingly recognized. Increased physical activity is associated with reduced breast cancer recurrence and breast cancer specific mortality. However, the mechanisms underpinning this effect are still under investigation. The role of exercise as an adjunct to systemic therapy for breast cancer remains unclear. We hypothesize that exercise may exert an anti-tumor effect and a change in tumor immune cell infiltration. Methods We evaluated the effect of exercise alone and in combination with chemotherapy in preclinical patient-derived TNBC xenografts (PDX) established in Nude mice and PyMT mouse tumor models. Mice were individually housed in boxes equipped with running wheels and randomized to 1) clamped wheels (sedentary controls), 2) doxorubicin (Dox, 2mg/kg/week), 3) exercise (Ex) and 4) Ex + Dox. Daily distance run was measured. One week after randomization (acclimatization period), the intervention was commenced. Body composition was measured at randomization and at end point. Tumors were harvested after 5 weeks of intervention or at ethical endpoint. Tumor immune infiltrates were analyzed, and transcriptomic analysis performed. Results In the TNBC PDX model, there was no difference in tumor volume at randomization (p=0.96), or cumulative distance run after 1 week of acclimatization to the running wheel (p=0.47). At 5 weeks, Ex alone significantly reduced tumor growth rate compared with controls (relative reduction 10%, p=0.025). There was no difference between the other interventions. Mice randomized to Ex + Dox ran a shorter cumulative distance over 5 weeks compared with Ex alone (103.6 ± 16.2km vs 168.8 ±23km, p=0.028). There was no correlation between distance run and tumor volume in either of the treatment cohorts involving exercise (p=0.39). PyMT, transcriptomic and immune cell infiltration analysis will be reported. At baseline, there was no significant difference in mean total body mass (TBM), lean mass (LM) or fat mass (FM) between the intervention groups (p&amp;gt;0.05). At 5 weeks, the mean TBM and LM in both groups treated with Dox was significantly lower than Ex only and controls. The Ex and the control mice gained weight (11%), compared with Dox only and Ex + Dox mice which did not gain weight (0% and -6% respectively). Therefore exercise had no significant impact on TBM or LM at 5 weeks, but Dox resulted in loss of TBM and LM compared with mice not treated with Dox. Conclusion Exercise significantly reduced tumor growth compared with sedentary controls in our preclinical TNBC PDX model, however there was not synergistic effect seen with Dox. Cumulative doses of Dox resulted in weight loss and loss of lean mass, and reduced the cumulative running distance, compared with mice not treated with Dox. Citation Format: Wahlroos S, Wilkinson A, Gallego-Ortega D, Febbraio M, Lim E. Concurrent exercise and chemotherapy in preclinical breast cancer models [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 P6-21-05.

The NeST (neoadjuvant systemic therapy in breast cancer) study – Protocol for a prospective multi-centre cohort study to assess the current utilization and short-term outcomes of neoadjuvant systemic therapies in breast cancer

IntroductionNeoadjuvant systemic therapy (NST) has several potential advantages in the treatment of breast cancer. However, there is currently considerable variation in NST use across the UK. The NeST study is a national, prospective, multicentre cohort study that will investigate current patterns of care with respect to NST in the UK. Methods and analysisPhase 1 – a national practice questionnaire (NPQ) to survey current practice.Phase 2 – a multi-centre prospective cohort study of breast cancer patients, undergoing NST.Women undergoing NST as their MDT recommended primary breast cancer treatment between December 2017 and May 2018 will be included. The breast surgery and oncological professional associations and the trainee research collaborative networks will encourage participation by all breast cancer centres.Patient demographics, radiological, oncological, surgical and pathological data will be collected, including complications and the need for further intervention/treatment. Data will be collated to establish current practice in the UK, regarding NST usage and variability of access and provision of these therapies. Prospective data on 600 patients from ~50 centres are anticipated.Trial registration: ISRCTN11160072. Ethics and disseminationResearch ethics approval is not required for this study, as per the online Health Research Authority decision tool. The information obtained will provide valuable insights to help patients make informed decisions about their treatment. These data should establish current practice in the UK concerning NST, inform future service delivery as well as identifying further research questions.This protocol will be disseminated through the Mammary Fold Academic Research Collaborative (MFAC), the Reconstructive Surgery Trials Network and the Association of Breast Surgery. Participating units will have access to their own data and collective results will be presented at relevant conferences and published in appropriate peer-reviewed journals, as well as being made accessible to relevant patient groups.

Internal Mammary Node Irradiation (IMNI) Improves Survival Outcome for Patients With Clinical Stage II-III Breast Cancer After Preoperative Systemic Therapy

The indication for internal mammary node irradiation (IMNI) after preoperative systemic therapy in breast cancer remains vague. This study was designed to evaluate the effect of IMNI in patients with clinical stage II-III breast cancer after preoperative systemic therapy and surgery. Between August 2005 and December 2013, 497 patients with clinical stage II-III breast cancer underwent anthracycline- or taxane-based preoperative systemic therapy, surgery, and postoperative radiation therapy. A median dose of 50Gy (range, 46-60Gy) in 25 fractions was delivered to the chest wall or breast with IMNI (n=236) or without IMNI (n=261). Disease-free survival (DFS) and overall survival (OS) rates with or without IMNI were evaluated using the Kaplan-Meier method and compared with the log-rank test. Propensity score matching was performed to adjust for the unbalanced characteristics between the 2 groups. Prognostic factors associated with survival were evaluated by univariate and multivariate analysis. The median follow-up time was 64months. Patients with IMNI presented with more advanced clinical T stage, pathologic N stage, positive lymph-vascular invasion, and medically or centrally located disease (P<.05). The 5-year DFS and OS rates were 73.7% and 86.3% in the IMNI group and 71.5% and 86.7% in the non-IMNI group, respectively (P>.05). Multivariate analysis demonstrated that IMNI was an independent prognostic factor for DFS (P=.018) and resulted in a borderline improvement in OS (P=.067). After propensity score matching, characteristics were well balanced. The 5-year DFS rates of IMNI and non-IMNI group were 76.8% and 63.4%, respectively (P=.030), and the 5-year OS rates were 88.9% and 84.1%, respectively (P=.083). IMNI was independently prognostic for DFS (P=.014) and OS (P=.047) in matched patients. IMNI improves survival outcomes in patients with clinical stage II-III breast cancer after preoperative systemic therapy. Further prospective studies are warranted to identify the role of IMNI in the preoperative systemic therapy setting.

Cardioprotective Approaches to the Management of Patients with Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Do We Need Increased Surveillance in Elderly Women on Trastuzumab?

Cardiotoxic effects in patients with breast cancer may present as asymptomatic left ventricular (LV) dysfunction or symptomatic LV decline, which can progress to overt heart failure (HF). Trastuzumab is a monoclonal antibody against human epidermal growth factor receptor (HER)2 and is a recommended targeted treatment for patients with overexpression of this receptor. However, the use of trastuzumab is associated with cardiotoxicity, manifested as LV dysfunction or HF. This review addresses the key issues related to individualised cardioprotection and surveillance, especially in elderly patients with HER2-positive breast cancer, based on the current cardio-oncology literature. Cardiac imaging techniques (e.g., echocardiography or multiple-gated acquisition scan) and biomarkers (e.g., cardiac troponins) that play a crucial role in the detection and monitoring of cardiotoxicity related to systemic therapies for breast cancer are briefly described. This review presents cardioprotective approaches, including interruption or termination of trastuzumab therapy, and treatment with an angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, or beta-blocker, which have been recommended for the reduction of cardiac adverse effects. Since the data relevant to cardiotoxicity of trastuzumab among real-world older women with breast cancer and cardiovascular diseases are still limited, this article focusses on improvements to the cardiac safety of trastuzumab-based regimens. In particular, this review emphasises the importance of intense surveillance in the elderly female population.

Neoadjuvant Therapy for Breast Cancer: Updates and Proceedings From the Seventh Annual Meeting of the Canadian Consortium for Locally Advanced Breast Cancer

Therapy for breast cancer involves a complex interplay of three main treatment modalities: surgery, systemic therapy, and radiation therapy. The Canadian Consortium for Locally Advanced Breast Cancer (LABC) was established with the goal to convene a strong multidisciplinary team of breast oncology clinicians and scientists who are dedicated to the advancement of LABC research and treatment, with a vision to drive progress through increased collaboration across disciplines and throughout Canada. The most recent meeting in May 2017 highlighted the latest evidence and literature about the optimal use of neoadjuvant systemic therapy in breast cancer. There is a need for increased clinical and scientific collaboration and the development of guidelines for the use of emerging treatment strategies. The interactive meeting sessions fostered unique opportunities for academic debate and nurtured collaboration between the attendees.

Validation of CPS+EG, Neo-Bioscore, and modified Neo-Bioscore staging systems after preoperative systemic therapy of breast cancer: Protocol of a retrospective multicenter cohort study in China.

Prognostic assessment after preoperative systemic therapy (PST) is critical to develop a therapeutic strategy for breast cancer management. Currently, a clinical–pathologic staging system that incorporates ER status and nuclear grading (CPS + EG), and the Neo‐Bioscore system that includes HER2 status into CPS + EG, are used to predict outcomes in patients with breast cancer after PST. While HER2‐positive is recognized as a favorable factor in the Neo‐Bioscore system based on results in patients administered one year of trastuzumab as anti‐HER2 therapy, most HER2‐positive cases have difficulty accessing anti‐HER2 treatment in China. Therefore, it is crucial that a modified Neo‐Bioscore staging system is developed that incorporates an additional factor of poor prognosis, HER2‐positive status without trastuzumab treatment, to determine accurate prognosis. We propose a retrospective multicenter cohort study in China to validate CPS + EG, Neo‐Bioscore, and the modified Neo‐Bioscore system and determine the accuracy of prediction. Primary breast cancer patients without metastasis treated with PST and surgery in academic institutions or hospitals of provincial level in China will be included. Disease‐free, disease specific, and overall survival will be calculated using the Kaplan–Meier Method, stratified by CPS + EG, Neo‐Bioscore, and the modified Neo‐Bioscore staging system. Areas under the curve of each staging system will be calculated. Multivariate analysis using Wald testing and maximum likelihood estimates in a Cox proportional hazards model will be conducted.

Progress in adjuvant systemic therapy for breast cancer.

The prognosis of patients with early stage breast cancer has greatly improved in the past three decades. Following the first adjuvant endocrine therapy and chemotherapy trials, continuous improvements of clinical outcomes have been achieved through intense therapeutic escalation, albeit with increased health-care costs and treatment-related toxicities. In contrast to the advances achieved in surgery or radiotherapy, the identification of the patient subgroups that will derive clinical benefit from therapeutic escalation has proved to be a daunting process hindered by a lack of collaboration between scientific groups and by the pace of drug development. In the past few decades, initiatives towards de-escalation of systemic adjuvant treatment have achieved success. Herein, we summarize attempts to escalate and de-escalate adjuvant systemic treatment for patients with breast cancer and argue that new, creative trial designs focused on patients' actual needs rather than on maximizing drug market size are needed. Ultimately, the adoption of effective treatments that do not needlessly expose patients and health-care systems to harm demands extensive international collaboration between academic groups, governments, and pharmaceutical companies.