Sequential Anthracycline Research Articles

The Impact of Age on Quality of Life in Breast Cancer Patients Receiving Adjuvant Chemotherapy: A Comparative Analysis From the Prospective Multicenter Randomized ADEBAR trial

BackgroundElderly breast cancer patients are affected by poorer quality of life (QoL) compared to younger patients. Because QoL has a relevant impact on guideline-adherent treatment, elderly breast cancer patients are often undertreated, especially with regard to adjuvant chemotherapy, and overall survival is decreased. Thus, understanding the impact of chemotherapy on QoL in elderly patients is crucial. This study compared QoL in patients aged < 65 years and 65 to 70 years receiving adjuvant chemotherapy as a secondary outcome in the prospective randomized multicenter ADEBAR trial. Patients and MethodsPatients with lymph node–positive breast cancer were prospectively randomized for either sequential anthracycline–taxane or epirubicin/fluorouracil/cyclophosphamid chemotherapy (FEC) therapy. QoL was assessed at baseline (t1), before cycle 4 FEC, and cycle 5 epirubicin/cyclophosphamid–docetaxel (EC-DOC) (t2), 4 weeks after chemotherapy (t3), and 6 weeks after radiation (t4) using the European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) and the Breast Cancer–Specific Module (QLQ-BR23). We compared patients aged < 65 years and 65 to 70 years with respect to QoL and discontinuation of chemotherapy. ResultsA total of 1363 patients were enrolled onto the ADEBAR trial, with 16.7% of the patients aged 65 to 70 years. In elderly patients, Eastern Cooperative Oncology Group performance status was higher and global health status and physical functioning were lower at baseline. Global health status decreased between t1 and t3 by 7 points in patients < 65 years and by 11 points in patients 65 to 70 years, and physical functioning decreased in the same period by 13.4 points in patients aged < 65 years and by 15.9 points in patients 65 to 70 years. In both groups, at t4 global health status exceeded baseline by 6 points, and physical functioning was 1.3 points under baseline in patients < 65 years old and 3 points under baseline in patients 65 to 70 years. There was a trend to more fatigue in elderly patients and to more nausea and vomiting while receiving chemotherapy in younger patients at t3. There was a higher dropout rate in patients aged 65 to 70 years (25.7%) than in patients aged < 65 years (16.2%). ConclusionThere were only small or trivial differences in QoL in patients aged < 65 years versus 65 to 70 years who were receiving adjuvant chemotherapy, although the dropout rate from chemotherapy was notably higher in elderly breast cancer patients.

Obesity As a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis.

Patients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer. We performed a random-effects analysis and a network meta-analysis and assessed publication bias. We included 15 studies and 8,745 patients with breast cancers who were treated with anthracyclines and sequential anthracyclines and trastuzumab. Combination of obesity and being overweight was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and a sequential anthracyclines and trastuzumab regimen in patients with breast cancer. Pooled odds ratio for cardiotoxicity was 1.38 (95% CI, 1.06 to 1.80; I(2) = 43%; N = 8,745) for overweight or obesity (body mass index > 25 kg/m(2)), 1.47 (95% CI, 0.95 to 2.28; I(2) = 47%; n = 2,615) for obesity, and 1.15 (95% CI, 0.83 to 1.58; I(2) = 27%; n = 2,708) for overweight. Associations were independent of study design, year of publication, drug regimen (anthracyclines alone v sequential anthracyclines and trastuzumab), or definitions of cardiotoxicity and of overweight or obesity. There was no evidence of publication bias; however, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis. Our findings in a largely unadjusted analysis suggest that overweight and obesity are risk factors for cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab.

Progesterone Receptors, Pathological Complete Response and Early Outcome for Locally Advanced Breast Cancer - a Single Centre Study. (PPLB - 01).

Neoadjuvant chemotherapy (NACT) for locally advanced breast cancer (LABC), apart from increasing breast conservation rates, also provides an opportunity to assess tumour response to chemotherapy, with Pathological Complete Response (pCR) described as an independent prognostic factor and a surrogate marker for better outcome and survival. Our primary aim was to identify clinical and pathological factors associated with pCR following NACT in patients with LABC treated at our institution. Our secondary aim was to analyze the impact of pCR and associated factors on disease free survival (DFS) and overall survival (OS). A retrospective analysis of LABC patients treated with NACT between Jun 2011 and Dec 2013. Clinical and histological variables were analyzed for association with pCR (no invasive or in situ carcinoma in breast or axillary lymph nodes). Kaplan-Meier curves and Cox regression model was used for survival analysis. All values were twosided, and statistical significance was defined as p<0.05. 240 patients were included. The median tumor size was 6cm, with T4 disease in 49.8%. 45% of tumors were of low grade (G1+G2) and 53.8% of high grade (G3). Estrogen Receptor (ER) was positive in 70.8%, progesterone receptor (PR) in 53.3% and Her2 in 38.8%. The preferred NACT regimen was sequential anthracycline and taxane and 88.8% of patients received this regimen. Of 93 potential Her2 Positive patients, only 23 received trastuzumab. Overall 23.2% patients had pCR. At median follow up of 21months (range, 3-42), 16.3% of patients had recurrent disease, and 6.7% had died. High tumor grade (p=0.04), PR negative status (p<0.01) and trastuzumab treatment (p=0.01) were significant predictors of pCR in univariate analysis. On multivariate analysis PR negativity (OR 3.2, 95% CI=1.6 to 6.04, p=0.001) and Trastuzumab use (OR 0.24, 95% CI=0.1 to 0.6, p=0.004) were significant. Patients with pCR had positive associations with survival (p<.02,OS& .02,DFS) and interestingly PR positivity had positive association with DFS (p=0.02) in Kaplan-Meier curves. On Cox regression, PR positivity (HR=0.3, p<0.01) and pCR (HR=0.2, p<0.01) correlated with DFS, though not with early OS. for the PR positive patients were paradoxical. Though less likely to have pCR (15%, vs 32% if PR negative), they had better DFS (p=0.02), and achieving pCR had no survival benefit in this group. In contrast, PR negative patients, irrespective of ER status, had a high pCR rate, and achieving pCR had survival advantage (p<0.05,DFS& p<0.02,OS). PR negative patients without pCR had the worst DFS (p<0.01) among all. High grade and Trastuzumab treatment as predictors of pCR, and pCR as a surrogate marker for survival are well recognized, and are supported by our findings. In present cohort, PR negativity showed prognostic importance independent of ER status. However these results were derived from sub-group, post-hoc analysis of data from a pre-existing cohort, without 'a-priori' hypothesis for survival analysis in relation to PR. These "hypothesis generating" results need confirmation by a well-designed prospective cohort or a randomized trial.

Selection of Optimal Adjuvant Chemotherapy Regimens for Human Epidermal Growth Factor Receptor 2 (HER2) -Negative and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline.

A Cancer Care Ontario (CCO) guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer including adjuvant targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancers was identified for adaptation. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for adapting clinical practice guidelines developed by other organizations. The CCO guideline was reviewed for developmental rigor and content applicability. On the basis of the content review of the CCO guideline, the ASCO Panel agreed that, in general, the recommendations were clear and thorough and were based on the most relevant scientific evidence, and they presented options that will be acceptable to patients. However, for some topics addressed in the CCO guideline, the ASCO Panel formulated a set of adapted recommendations on the basis of local context and practice beliefs of the Panel members. Decisions regarding adjuvant chemotherapy regimens should take into account baseline recurrence risk, toxicities, likelihood of benefit, and host factors such as comorbidities. In high-risk HER2-negative populations with excellent performance status, anthracycline- and taxane-containing regimens are the standard of care. Docetaxel and cyclophosphamide for four cycles is an acceptable non-anthracycline regimen. In high-risk HER2-positive disease, sequential anthracycline and taxanes administered concurrently with trastuzumab or docetaxel, carboplatin, and trastuzumab for six cycles are recommended. An alternative regimen in a lower-risk, node-negative, HER2-positive population is paclitaxel and trastuzumab once per week for 12 cycles. Trastuzumab should be given for 1 year. Platinum salts should not be routinely administered in the adjuvant triple-negative population until survival efficacy data become available.

Cost-effectiveness of strain-targeted cardioprotection for prevention of chemotherapy-induced cardiotoxicity

BackgroundCancer chemotherapy increases the risk of heart failure. This cost-effectiveness model compared strain-guided cardioprotection with other protective strategies using a health care payer perspective and five-year time horizon. MethodsThree cardioprotection strategies were assessed: 1) usual care (EF-guided cardioprotection, EFGCP) with cardioprotection initiated on diagnosis of LVEF-defined cardiotoxicity (EF-CTX), 2) universal cardioprotection (UCP) for all such patients, and 3) strain-guided cardioprotection (SGCP — treatment of patients with subclinical cardiotoxicity [S-CTX]). A Markov model, informed by the published literature on transitional probabilities, costs and quality-adjusted life years (QALYs) was developed to assess the incremental cost-effectiveness ratio (ICER). Costs, effects and ICER of each specified cardioprotective strategy were assessed over a 5-year range, with sensitivity analyses for significant variables. ResultsIn the reference case of a 49year old woman with stage IIb breast cancer treated with sequential anthracyclines and trastuzumab, strain-guided cardioprotection (3.79 QALYS and $4159 cost over 5years) dominated both UCP (3.64 QALYs and $5967 cost over 5years) and EFGCP (3.53 QALYs and $7033 cost over five years). Model results were dependent on the probabilities of patients developing subclinical LV dysfunction, with UCP dominating alternative strategies at probabilities ≥51%. Variations in the cost of cardioprotective medications and probabilities of cardioprotection side-effects had no effect on model conclusions. ConclusionsIn patients at risk of chemotherapy-related cardiotoxicity, strain-guided cardioprotection provides more QALYs at lower cost than standard care or uniform cardioprotection.

Abstract SS1-2: Guidelines and management of advanced breast in limited resource settings

Abstract Advanced Breast Cancer Burden and Guidelines: GLOBOCAN 2012 data estimated a total of 1.67 million breast cancer cases worldwide. Advanced Breast Cancer (ABC) represents only 5-10% of cases in High Income Countries (HIC) but still represents about 60% of cases in Low and Middle Income Countries (LMIC). Improvements in breast cancer outcomes seen in HIC have not yet been seen in low-resource settings. We will discuss Breast Health Global Initiative (BHGI)1 and ABC Consensus Guidelines2. Locally Advanced Breast Cancer: Diagnosis: Clinical evaluation, biopsy, staging, then systemic therapy followed by surgery and radiation therapy.2,3 Pathology and receptor evaluations are important in order to choose the type and duration of systemic therapy. Pathology: Pathology services remain scarce in many LMIC. BHGI considers ER should be made available in LMIC. Systemic Therapy: pre-operative chemotherapy, with anthracyclines, or sequential anthracyclines &amp; taxanes, with or without trastuzumab. 2,3,4 Anthracyclines are widely available. Generic taxanes have become recently available. Chemotherapy administration requires training and setup. For patients with ER positive tumors hormonal therapy can be considered. Tamoxifen is widely available. Aromatase inhibitors have become generic, but at a higher cost. Surgery: Surgery remains essential for LABC, usually after initial Neoadjuvant therapy. Infrastructure and human resource capabilities need further development in most LMIC5. Radiation Therapy: it is either not available or not accessible for millions of cancer patients worldwide. Investment in RT not only enables treatment of cancer cases to save lives and provide palliative care, but also brings positive economic benefits.6 Targeted Therapy: Trastuzumab was recently added to the “Essential Medications List” of the WHO for early breast cancer.7 It is essential for LABC. It requires determination of HER2 receptors. Shorter durations of trastuzumab therapy, or reducing its price are discussed. Metastatic Breast Cancer: Hormonal Therapy: is the mainstay of management for hormone receptor-positive MBC, unless patients have so-called visceral crisis requiring chemotherapy for rapid response2. Tamoxifen, with OFS by LHRHa, radiation, or oophorectomies. In post-menopausal women, aromatase inhibitors (AI) have a slight advantage, but more expensive. Fulvestrant, everolimus, and palbociclib are prohibitively expensive. Chemotherapy: it is generally palliative. Options of hormonal therapy or less toxic chemotherapy should be offered where appropriate. Targeted therapy: Trastuzumab, pertuzumab and t-DM1 prohibitive costs do not allow use in most LMIC. Supportive Care and Survivorship: Support, palliative care and access to pain medication is variable and limited in many LMIC8. Conclusions: Resource-stratified guidelines, multidisciplinary management, more access to modern therapy, improved resources are all needed to improve access to care and to reduce disparities in patients' outcome.

Response and survival of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy.

BackgroundPredicting treatment benefit and/or outcome before any therapeutic intervention has taken place would be clinically very useful. Herein, we evaluate the ability of the intrinsic subtypes and the risk of relapse score at diagnosis to predict survival and response following neoadjuvant chemotherapy. In addition, we evaluated the ability of the Claudin-low and 7-TNBCtype classifications to predict response within triple-negative breast cancer (TNBC).MethodsGene expression and clinical-pathological data were evaluated in a combined dataset of 957 breast cancer patients, including 350 with TNBC, treated with sequential anthracycline and anti-microtubule-based neoadjuvant regimens. Intrinsic subtype, risk of relapse score based on subtype and proliferation (ROR-P), the Claudin-low subtype and the 7-TNBCtype subtype classification were evaluated. Logistic regression models for pathological complete response (pCR) and Cox models for distant relapse-free survival (DRFS) were used.ResultsBasal-like, Luminal A, Luminal B, and HER2-enriched subtypes represented 32.7 %, 30.6 %, 18.2 %, and 10.3 % of cases, respectively. Intrinsic subtype was independently associated with pCR in all patients, in hormone receptor-positive/HER2-negative disease, in HER2-positive disease, and in TNBC. The pCR rate of Basal-like disease was >35 % across all clinical cohorts. Neither the Claudin-low nor the 7-TNBCtype subtype classifications predicted pCR within TNBCs after accounting for intrinsic subtype. Finally, intrinsic subtype and ROR-P provided independent prognostic information beyond clinicopathological variables and type of pathological response. A 5-year DRFS of 97.5 % (92.8–100.0 %) was observed in these neoadjuvant-treated and clinically node-negative patients predicted to be low risk by ROR-P (i.e. 57.4 % of Luminal A tumors with clinically node-negative disease).ConclusionsIntrinsic subtyping at diagnosis provides prognostic and predictive information for patients receiving neoadjuvant chemotherapy. Although we could not exclude a survival benefit of neoadjuvant chemotherapy in patients with early breast cancer with clinically node-negative and ROR-low disease at diagnosis, the absolute benefit of cytotoxic therapy in this group might be rather small (if any).Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0540-z) contains supplementary material, which is available to authorized users.

High accuracy gene signature for chemosensitivity prediction in breast cancer

Neoadjuvant chemotherapy is usually offered to breast cancer patients to shrink the tumor and any involved lymph nodes. Pathologic complete response is a way of measuring response to this treatment, which is normally defined as the absence of residual invasive disease in the breast and in the axillary lymph nodes at the completion of the treatment. Clinically patients who achieve pCR tend to have a very good prognosis. As a standard treatment for breast cancer, neoadjuvant chemotherapy offers several benefits to patients. But not all patients benefit equally from this treatment. Therefore it is of great value to investigate what molecular information obtained from a patient’s tumor could be used to determine if the patient would benefit from a particular chemotherapy. In practice the estrogen receptor status could be used to guide the decisions on hormonal therapy. Further, the gene expression data that reflect subtle differences in tumors could be utilized to build a predictor of response to cancer drugs. In this study we sought to use gene expression data to predict who might achieve pCR to sequential anthracycline paclitaxel preoperative chemotherapy. Our aim was to uncover one gene signature for developing predictors of pCR to neoadjuvant chemotherapy that have a much higher accuracy than DLDA-30, so it might have the potential for clinical applications. With the ability to account for multiple gene interactions, the multivariable techniques, such as genetic algorithm and SLR, have demonstrated their utility in identifying robust gene signatures of clinical relevance.

Abstract CT127: Can potential curability be reached in high risk/metastatic breast cancer patients with a treatment optimization strategy that includes a novel GNT (gemcitabine, vinorelbine, docetaxel) in front line combination chemotherapy

Abstract Aiming at improving the therapeutic outcome of sequential taxane and anthracycline front line chemotherapy in breast cancer, G and N were incorporated into the taxane arm; GNT x 4 courses (G 1800-2500mg/m2, N 20-30mg/m2, T 100mg/m2, I.V. on day 1. GNT was administered sequentially with L-FAC x 4 courses; 72hr infusion of 400mg/m2/d 5-fluorouracil modulated by I.V. bolus 200mg/m2/d x 3 leucovorin. This was given concomitantly with 24hr d1 I.V. infusion 600mg/m2 cyclophosphamide, followed by 48hr I.V. infusion d2 + d3 60mg/m2 doxorubicin (ASCO 2006# 10741). Chemotherapy was given in a dose dense pattern with filgrastim support. As data became available, transtuzumab (for 1≤ year) was incorporated in HER2+ subset (15 patients) as of 11/2004, cis-platin (P) 70mg/m2/d1; GNTP in HER2+ and Triple negative (TN) subsets (20 patients) as of 5/2007 and bevacizumab 5mg/kg/wk I.V. in inflammatory and Stage IV HER2- subsets (6 patients) as of 10/2007. Hormone receptor positive (HOR+) subset (18 patients) received post chemotherapy hormone maintenance. Ten patients also received additional therapies. From 3/2001 to 2/2012, 52 patients (Median age 48) participated including the following stages: I; 3 (6%), II; 24 (46%), III; 17 (33%), IV; 8 (15%). The following subsets were represented; Triple negative 22 (42%), HER2+ 19 (37%), HER2-/HOR+ 11 (21%). Modified Blacks nuclear grade 3 was noted in 71% and Ki67 &amp;gt; 14% in 91%. 83% had breast conservation and 23 (44%) neoadjuvant chemotherapy; 87% achieved major pathologic response (14 PCR, 2 RCB1, 4 PET/CR/negative biopsy) at a median follow up of 75 months (m). Adjuvant chemotherapy follow up was longer at 116 m. At 81 m, 8/8 Stage IV patients achieved complete remission, though 1 patient (HER2+) had successfully treated intracranial relapse and another developed a second breast primary. At an overall follow up of 85 m (29-154), 4 relapses were observed; 2 HER+ (Stage III/without transtuzumab; Stage IV intracranial relapse only), 1 Inflammatory TN without PCR, 1 HOR+ late relapse &amp;gt; 10 year with short hormonal therapy. There were 3 deaths; 2 breast cancer related. Freedom from relapse for TN was 95% at 82 m, HER2+ 89% at 84 m, HER-/HOR+ 91% at 116 m. Dose dense limiting events included thrombocytopenia, muco-cutaneous reactions, and patient desired breaks. Other side effects noted were; decreased cardiac ejection fraction (2), decreased hearing (1), chronic peripheral neuropathy (2), AML (1), and MDS (1). Despite the limited study population number, this treatment approach resulted in high pathologic remission, complete remission in Stage IV and substantial freedom from relapse in high-risk and metastatic breast cancer subsets. This is highly suggestive that the natural history of aggressive breast cancer can be favorably influenced with this treatment approach. Citation Format: Khaled Jabboury, Lena Rogers, Krystal Sexton, Odelia Garcia. Can potential curability be reached in high risk/metastatic breast cancer patients with a treatment optimization strategy that includes a novel GNT (gemcitabine, vinorelbine, docetaxel) in front line combination chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT127. doi:10.1158/1538-7445.AM2015-CT127

Effects of conventional neoadjuvant chemotherapy for breast cancer on tumor angiogenesis.

The effects of breast cancer conventional chemotherapy on tumor angiogenesis need to be further characterized. Neoadjuvant chemotherapy is an ideal model to evaluate the results of chemotherapy, allowing intra-patient direct comparison of antitumor and antiangiogenic effects. We sought to analyze the effect of neoadjuvant chemotherapy on tumor angiogenesis and its clinical significance in breast cancer. Breast cancer patients (n=108) treated with neoadjuvant sequential anthracyclines and taxanes were studied. Pre- and post-chemotherapy microvessel density (MVD) and mean vessel size (MVS) were analyzed after CD34 immunohistochemistry and correlated with tumor expression of pro- and antiangiogenic factors (VEGFA, THBS1, HIF1A, CTGF, and PDGFA) by qRT-PCR. Angiogenic measures at diagnosis varied among breast cancer subtypes. Pre-treatment higher MVS was associated with triple-negative subtype and more advanced disease. Higher MVS was correlated with higher VEGFA (p=0.003), while higher MVD was correlated with lower antiangiogenic factors expression (THBS1, p<0.0001; CTGF, p=0.001). Increased angiogenesis at diagnosis (high MVS and glomeruloid microvascular proliferation) and higher VEGFA expression were associated with tumor recurrence (p=0.048 and 0.009, respectively). Chemotherapy-induced angiogenic response (defined as decreased MVD) was present in 35.2% of patients. This response correlated with an increase in antiangiogenic factors (THBS1) without changes in VEGFA expression, and it was associated with tumor downstaging, but not with clinical response, pathologic complete response, or prognosis. Global effects of chemotherapy mainly consisted in an increased expression of antiangiogenic factors (THBS1, CTGF), with significant changes neither of tumor VEGFA nor of MVS. Conventionally scheduled neoadjuvant chemotherapy exerts antiangiogenic effects, through an increase in antiangiogenic factors, THBS1 and CTGF, but the expression of VEGFA is maintained after treatment. Better markers of angiogenic response and a better understanding of the cooperation of chemotherapy and antiangiogenic therapy in the neoadjuvant clinical scenario are needed.

Abstract P3-06-49: Prognostic impact of discordance in hormone receptor status after the neoadjuvant chemotherapy in primary breast cancer

Abstract Background: Hormone receptor (Estrogen receptor (ER), Progesterone receptor (PgR)) is an important biological marker for predicting prognosis and making effective treatment decisions. Discordance in these biomarkers between the primary tumor and recurrent lesions is reported frequently. However, it is not well known whether these biomarkers are affected by neoadjuvant chemotherapy and their impacts on outcomes still remain to be elucidated. The aim of the present study is to evaluate the changes in HR status after neoadjuvant chemotherapy in patients with operable breast cancer and their relationship with response to treatment and prognosis. Patients and Methods: Of 162 patients with stage II/III breast cancer patients receiving neoadjuvant chemotherapy from January 2005 to September 2012 at Keio University Hospital, 140 patients with non-pCR were analyzed. Patients were treated with sequential anthracycline and taxane. ER and PgR were assessed in both CNB performed prior to neoadjuvant chemotherapy and surgical samples. HR status was assessed by immunohistochemistry (IHC). ER/PgR status was determined using the Allred score and defined as positive when score was 3 and more. HR status was considered positive in cases of ER and/or PgR positivity. Pathological response criteria were classified as grade 0, 1, 2, or 3: grade 0 includes almost no change in cancer cells; grade 1 includes slight or marked changes in less than two thirds of area; grade 2 includes marked changes in more than two thirds of area; grade3 includes necrosis or disappearance of all tumor cells. Results: ER, PgR and HR positive rates before neoadjuvant chemotherapy were 72.9%, 67.1% and 76.4%, respectively. Changes in ER, PgR and HR status between CNB and surgical samples were 12.1% (4.3% gain; 7.8% loss), 17.1% (2.1% gain; 15.0% loss) and 9.3% (2.9% gain; 6.4% loss), respectively. In ER-discordant group, grade 2 rate of pathological response was significantly higher than ER- concordant group (61.1% vs. 30%, p=0.033), whereas there were no significant differences of pathological response between discordant and concordant group in PgR status. In the disease free survival (DFS), there were no significant difference between concordance and discordance group for ER, PgR and HR (p=0.216, 0.859, 0.233) after a median follow-up of 40.4 months. But patients with a loss in ER and/or HR status had a trend to a shorter DFS compared with the concordant ER and/or HR-positive group (p=0.169 and 0.154) Conclusions: After neoadjuvant chemotherapy, discordance of biomarkers was seen in 5-20%. The pathological response was significantly associated with the change in ER status. A loss in ER and/or HR status may affect a prognosis of breast cancer after neoadjuvant chemotherapy, but still need further investigation. Citation Format: Toshiaki Kurihara, Hanako Ueno, Masaru Takemae, Aiko Nagayama, Maiko Takahashi, Tetsu Hayashida, Hiromitsu Jinno, Yuko Kitagawa. Prognostic impact of discordance in hormone receptor status after the neoadjuvant chemotherapy in primary breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-49.

Should trastuzumab be administered concomitantly with anthracycline in women with early, HER2-positive breast cancer?

Clinical targeting of the human epidermal growth factor receptor 2 (HER2) has dramatically improved the outlook of a subset of about 15% of breast cancers carrying HER2 gene amplification and/ or HER2 protein overexpression. Since the initial experiences with the anti-HER2 monoclonal antibody trastuzumab, it was clear that combination with conventional chemotherapy was required to exploit the full potential of HER2-targeting. However, prohibitive rates of cardiac toxicity were observed when trastuzumab was given concurrently with anthracyclines, which are compounds that have played a pivotal role in the treatment of breast cancer for decades. While most of the anti-HER2 programs have been designed as to avoid concomitance with anthracyclines, high rates of pathological complete remission were obtained in carefully selected patients with operable breasts cancer receiving concomitant trastuzumab and anthracycline in the preoperative setting. A recently published randomized study compared directly the current standard of sequential anthracycline followed by concomitant taxane and trastuzumab with a reversed sequence of taxanes followed by anthracyclines with trastuzumab administered concurrently with the whole program as neoadjuvant treatment for patients with early, operable breast cancer. The practical question asked by this study was whether a potential increase in the efficacy of trastuzumab based regimens could be worth the risk of giving it in concomitance with anthracyclines. This editorial will review the background of this study and discuss the impact of its results on the current clinical practice and on future research in the field.

Neoadjuvant chemotherapy with sequential anthracycline–docetaxel with gemcitabine for large operable or locally advanced breast cancer: ANZ 0502 (NeoGem)

BackgroundNeoadjuvant chemotherapy has a sound rationale for use in women with large operable breast cancer, and achievement of pathological complete response (pCR) is prognostic. Epirubicin and cyclophosphamide followed by docetaxel is a standard chemotherapy regimen for early breast cancer. In metastatic breast cancer the combination of gemcitabine and a taxane has shown promising results. This phase II study investigated the efficacy and safety of incorporating gemcitabine into neoadjuvant therapy. MethodsFemale patients with operable breast cancer that was clinically T2 (≥3 cm) or T3-4, N0-1, M0 were enrolled to receive 24 weeks of neoadjuvant chemotherapy using epirubicin and cyclophosphamide followed by docetaxel and gemcitabine, plus trastuzumab if HER2-positive. The primary endpoint was the pathological complete response (pCR) rate in the breast in separate HER2-negative and HER2-positive cohorts. Secondary endpoints included pCR in both the breast and axillary lymph nodes, clinical and radiological response rates, disease free survival and safety. Results81 patients were enrolled: 63 HER2-negative and 18 HER2-positive. 67 (84%) completed all cycles of chemotherapy, and 78 (96%) proceeded to surgery. pCR was achieved by 12 (20%) patients with HER2-negative, and 9 (53%) with HER2-positive disease. At the first interim analysis, addition of prophylactic G-CSF was recommended due to excess neutropenia. The HER2-negative cohort was closed to accrual because it did not meet the pre-specified target for pCR, and the HER2-positive cohort was closed due to slow accrual. At a median follow-up of 24 months, 12 of 81 (15%) patients had experienced a relapse of their breast cancer. ConclusionNeoadjuvant gemcitabine, when added to docetaxel, after epirubicin and cyclophosphamide, did not reach the pre-specified expectations for pCR rate in HER2-negative tumours. Excess neutropenia was observed, requiring growth factor support. Addition of gemcitabine to docetaxel in this schedule cannot be recommended.Australia and New Zealand Clinical Trials Registry (www.anzctr.org.au) registration number ACTRN12606000191594.

Regional myocardial edema detected by T2 mapping is a feature of cardiotoxicity in breast cancer patients receiving sequential therapy with anthracyclines and trastuzumab

Background Cardiotoxicity from cancer chemotherapy is an important cause of morbidity and mortality in breast cancer survivors. Left ventricular (LV) systolic dysfunction due to sequential use of anthracyclines and trastuzumab has been reported in up to 20-25% of patients. The pathophysiological changes associated with LV dysfunction have not been described non-invasively. We performed cardiac MRI (cardiac MR) with T2 mapping to assess whether myocardial edema is a feature of acute cardiotoxicity in women with breast cancer receiving sequential anthracyclines and trastuzumab.

The Tolerability of in the Adjuvant Treatment of Breast Cancer Comprising Sequential Anthracycline and Taxane Treatment: Single Center Experience

OBJECTIVE: We studied the side effects associated with the adjuvant therapy combinations containing anthracycline-taxane which is the most frequently used recently in the breast cancer. Our goal is to demonstrate these side effects affecting patient quality of life and treatment success and to emphasize the importance of patient awareness.METHODS: In the study, the files of one hundred patients with diagnosis of breast cancer were investigated retrospectively.RESULTS: Sixty of the patients (60%) were premenopausal and 40 of them (40%) were postmenopausal (40%). One (%1) patient was stage I, 52 (52%) patients were stage II, 47 (47%) patients were stage III. While 31 of the patients received intensive therapy [paclitaxel (n=26, 80.7%), docetaxel (n=5,19.3%)], 69 of them received 3 weekly therapy [paclitaxel (n=10, 14.4%), docetaxel (n=59, 85.6%)]. Neuropathy, neutropenia and nail changes were found to be more frequent (32.3%, p

Abstract P3-14-16: A phase 2 trial of myocet®, cyclophosphamide +/- trastuzumab followed by weekly paclitaxel +/- trastuzumab as primary systemic therapy in operable and locally advanced breast cancer

Abstract BACKGROUND: Anthracycline- and taxane-based chemotherapies are highly effective in primary systemic treatment of breast cancer (BC). Myocet® (M) is a non-pegylated liposomal doxorubicin exhibiting reduced cardiotoxicity as compared to doxorubicin. Combination of M and cyclophosphamide (C) has demonstrated efficacy in first line treatment of metastatic BC, however few data are available in neoadjuvant setting, especially in combination with trastuzumab (T). The aims of the study were activity, in terms of pathological complete response (pCR; ie, no remaining invasive tumor in breast and lymphnodes) and safety of a sequential schedule of M and C +/- T followed by weekly paclitaxel (P) +/- T. METHODS: Estrogen receptor (ER), progesterone receptor (PgR), HER2 positivity (defined as 3+ overexpression by immunoistochemical testing or HER2 amplification by fluorescent in situ hybridisation) and Ki67 index were assessed in core needle biopsies at baseline and in residual tumour after chemotherapy. Patients with stage II/III BC received 4 cycles of MC (myocet 60 mg/m2, cyclophosphamide 600 mg/m2 on day 1 every 3 weeks), followed by 12 weekly doses of P (paclitaxel 80 mg/m2); all patients with HER2+ disease received T in combination with chemotherapy (trastuzumab loading dose of 8 mg/kg followed by 3 cycles of 6 mg/kg alongside MC; 2 mg/kg per week with the following 12 P administrations). RESULTS: 49 patients were enrolled, with 44 patients having completed chemotherapy and undergoing surgery to date. Median age was 56 years (range, 34 to 72). Tumour characteristics were as follows: stage IIA 10 patients, IIB 16, IIIA 13, IIIB 5, IIIC 1, and 4 patients with inflammatory BC; ER+/PgR+ 21 patients, ER+/PgR- 13, triple negative 8, HER2+ 16; Ki67&amp;gt; 15% in 41 patients. Forty-four patients were evaluable for pathological response. pCR was obtained in 12 patients (27.3%). The rate of pCR in HER2+ and HER2- BC was 57.1% and 13.3%, respectively. Clinical response was obtained in 36 out of 41 clinically evaluable patients (87.8%): CR in 20 (48.8%) and PR in 16 (39%). Conservative surgery was performed in 16 patients (36.4%) and mastectomy in 28 (63.6%). The most frequently observed grade 3-4 AEs were: alopecia 47 patients (95.9%), grade 3 neutropenia 2 (4.1%), febrile neutropenia 2 (4,1%), grade 3 paresthesia 2 (4.1%), grade 3 vomiting 1 (2%), grade 3 cutaneous erythema 1 (2%). Only 1 patient experienced an asymptomatic decrease of ejection fraction lower than 50%. Five patients (10.2%) discontinued treatment with M+C because of: allergic reaction to M in 3 patients, grade 2 liver toxicity in 1 and grade 3 vomiting in 1. All of them completed the following treatment with P. Three patients (6.1%) discontinued P because of: allergic reaction in 1 patient, infectious pneumonia in 1 and grade 3 cutaneous erythema in 1. CONCLUSIONS: The use of M in this sequential anthracycline- and taxane-based regimen resulted tolerable even in combination with T and active despite of the high rate of patients with ER+ disease and with locally advanced cancer. Consistently with previous data, pCR was higher in patients with HER2+ BC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-16.

Abstract P6-12-13: Synchronous metastases are highly prevalent in HER2 positive inflammatory breast carcinomas evaluated by 18F-FDG PET/CT

Abstract Background: Inflammatory breast carcinomas have poor prognosis even in the absence of evident synchronous metastases. 18F-FDG PET/CT is not recommended in initial staging but could improve the sensibility of synchronous metastases detection and the management of the patients. Objective: To assess factors associated with synchronous metastases in inflammatory breast carcinomas when evaluated by 18F-FDG PET/CT. Methods: Since 2006, initial staging of locally advanced breast carcinomas in our center consisted of 18F-FDG PET/CT in addition to standard laboratory and radiological tests. We reviewed data of patients with inflammatory breast carcinomas treated from 2006 to 2013 who had an initial evaluable18F-FDG PET/CT. Fisher's exact test and logistic model were used to assess factors associated with synchronous metastases. Overall survival was estimated with the method of Kaplan-Meier. Results: Among 353 locally advanced breast carcinomas seen at the breast disease unit, hospital Saint Louis from 04/2006 to 04/2013, we identified 40 inflammatory breast carcinomas. Initial 18F-FDG PET/CT was available for review in 32 inflammatory breast carcinomas. Median age was 57 years (range 38-78), 39% had pre-menopausal status (n = 12), clinical node involvement was found in 87.5% (n = 28). Histological features on biopsy were: ductal invasive carcinoma 91% (n = 29), SBR grade III 72% (n = 23), negative hormonal receptor 75% (n = 24), positive HER2 37.5% (n = 12), triple negative 44% (n = 14). Synchronous metastases were found in 41% of inflammatory breast carcinomas (n = 13), bone (n = 7), liver (n = 6) and mediastinum (n = 4). Synchronous metastases seemed more common in HER2 positive than in HER2 negative inflammatory breast carcinomas (58% vs 30%, p = 0.15). In multivariate analysis, no factor was associated with synchronous metastases. All patients with inflammatory breast carcinomas received neoadjuvant chemotherapy with sequential anthracycline and taxane (16 patients), dose-dense anthracycline and alkylating agent (8 patients), taxane with or without bevacizumab (7 patients) and anthracycline in 1 patient. Trastuzumab was given in all HER2 positive inflammatory breast carcinomas. Clinical response to neoadjuvant chemotherapy was complete in 16.5% (n = 5), partial in 67% (n = 20), stable or progressive in 16.5% (n = 5) and missing for 1 patient. One patient died before response assessment. Thirty patients (94%) underwent radical mastectomy with axillary node dissection. Pathologic complete response in breast and nodes was found in 27.5% (n = 8). Axillary node invasion was found in 45% (n = 13). All positive hormonal receptors patients received endocrine therapy after surgery. With a median follow-up of 33 months, 10 patients died. Median overall survival was 38.8 months (95%CI: 30.3-NA) with no difference between HER2 positive and HER2 negative patients. Conclusion: Synchronous metastases are common in inflammatory breast carcinomas especially in case of HER2 positive tumors. Complete initial staging with 18F-FDG PET/CT could be useful to detect synchronous metastases mainly in bone and liver and thus allowed to adapt further treatment. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-13.

Abstract P5-01-08: Changes induced by neoadjuvant chemotherapy (NCT) in breast cancer tumor infiltrating lymphocytes (TIL) subpopulations are associated with chemo-sensitivity and prognosis

Abstract Background: Recent data support the modulation of immune response in breast cancer microenvironment by neoadjuvant chemotherapy. This immune modulation might favor treatment response and modify post-treatment tumor immunosurveillance. The association of TIL with outcome after breast cancer (BC) NCT has also been suggested by several studies. Thereby, the differences in NCT-induced immune changes could reflect different profiles of immune modulation and translate into diverse prognosis. The objective of our study was to evaluate the predictive and prognostic value of NCT-induced TIL changes in patients with BC. Methods: We analyzed a series of consecutive breast cancer patients treated with sequential anthracyclines and taxanes NCT (80.4% sequential AC-docetaxel). Pre- and post-chemotherapy biopsies were included in a tissue microarray and immunohistochemical (IHC) staining was performed for CD3, CD4, CD8, CD20, FOXP3 and CD68. After slide scanning and acquisition of digital images, computerized morphometric analysis (TIL count/mm2) was performed with ImageJ (NIH) software. Variations on pre- and post-NCT TIL infiltration were quantified and expressed as the absolute difference in number of cells/mm2 (postNCT TIL – preNCT TIL); median values were used as cut-point. Association of TIL changes with pCR was evaluated by logistic regression models. Kaplan-Meier analysis and Cox proportional hazard models were used for survival Results: 121 patients with a diagnosis of invasive BC were included. Stages: IIB (28%), IIIA-C (56.4%). Phenotype was determined by immunohistochemistry: 50.4% Her2- hormone-sensitive (HS), 13.2% Her2+ HS, 10.7% Her2+ non-HS, and 21.5% triple negative. Pathologic complete response (pCR) rate was 17.4%. NCT produced a decrease in tumor infiltration by CD4 (p = 0.01), CD20 (p = 0.04) and CD68 (p = 0.03) and an increase in CD8 infiltrating lymphocytes (p = 0.0001). NCT-induced decreases of TIL infiltration above the median level of change were associated with pCR: CD3 (p = 0.01; odds ratio [OR]: 0.12, 95% confidence interval [95%CI] 0.02-0.63), CD4 (p = 0.02; OR 0.2; 95%CI 0.05-0.85) and CD20 (p = 0.01; OR 0.15; 95%CI 0.03-0.64). With a median follow-up of 60 months, median overall survival (OS) and disease free survival (DFS) has not been reached. A NCT-induced CD3 decrease higher than the median cut-off independently predicted higher DFS (hazard ratio [HR]:6.56; 95%CI 1.3-33.2; p = 0,02) and OS (HR:9.85; 95%CI 1.03-93.7, p = 0.04). Conclusions: TIL variations induced by chemotherapy are related to pRC and prognosis in patients with invasive BC receiving anthracyclines and taxanes. These results suggest that the degree of immune modulation by NCT has an impact on survival and might be useful for prognostic classification in the setting of BC treated with NCT [Supported by GEICAM-Beca Ana Balil]. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-01-08.

Abstract P4-07-15: Prognostic impact of miR-18a expression in residual tumor after neoadjuvant chemotherapy for locally advanced breast cancer

Abstract Background: microRNAs (miRNAs) are small ribonucleic acids that regulate protein expression through gene silencing mechanisms and show differential expression between cancer subtypes. Several studies have demonstrated that over- or under-expression of miRNA levels in tumors can modulate the expression levels of their gene/protein targets and thus their behavior. In breast cancer, the members of cluster miR-17-92 increase their expression levels as the histological grade increases, behaving like an oncogene, and are preferentially expressed in basal-like carcinomas. Moreover, mature components of this cluster are involved in estrogen receptor pathways and epithelial-mesenchymal transition, which suggest their implication in resistance to chemotherapy. The aim of this study was to determine the prognostic impact of miR-18a expression in the residual (resistant-to-treatment) tumor after neoadjuvant chemotherapy (nQT) in patients with locally advanced breast cancer (BC). Methods: Small RNA was isolated from FFPE samples of post-chemotherapy residual tumor in patients without pathological complete response (pCR). Quantification of miR-18a was performed by RT-qPCR. Expression levels were determined by 2-DDCt method using snRNAU6 as endogenous control. We used the quartiles of expression as cutoff point. Association of miR-18a levels with clinical and pathological characteristics was evaluated with non-parametric tests. Kaplan-Meier curves, log-rank test and Cox proportional hazard regression multivariate models were used for disease free (DFS) and overall (OS) survival analysis. Statistical analysis was performed with SPSS 18.0 software. Results: 121 consecutive women with invasive BC were included, mostly with stages IIB (28%) or IIIA-C (56.4%). Patients were immunohistochemically (IHC) classified as Her2- hormone-sensitive (HS) in 50.4% of cases; other phenotypes: Her2+ HS, 13.2%; Her2+ non-HS, 10.7%; triple negative, 21.5%. Treatment included sequential anthracyclines and taxanes (80.4% docetaxel) and a pCR was obtained in 17.4% of patients. Median overall survival (OS) and disease free survival (DFS) were not reached after a median follow-up of 60 months. High (above the median) expression levels of miR-18a in post-chemotherapy residual tumor were associated with pre-treatment grade 3 (p = 0.008), cN2-3 (p = 0.004), non-HS (p = 0.006) and triple negative phenotype (p = 0.01). No other associations with clinical or pathologic tumor characteristics (stage, HER2NEU overexpression) were found. High expression levels of miR-18a in residual tumors were also associated with reduced DFS and OS (log-rank test; p = 0.004 and p = 0.041 respectively). This negative prognostic impact was also confirmed for DFS in a multivariate analysis that included IHC phenotype and ypN+ (Table 1). Table 1 OR95%CIPPhenotype1.571.11-2.230.010ypN+7.291.67-31.800.008miR-18a high3.091.01-9.410.047 Conclusion: High expression levels of miR-18a in chemotherapy-resistant residual breast cancer associates with pre-treatment aggressive biological characteristics and independently predicts disease recurrence. Our results suggest that post-treatment miR-18a might serve as a marker of treatment resistance and as a new target for BC treatment. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-07-15.

Abstract P1-01-23: Increased Diagnostic Performance of Sentinel Lymph Node Biopsy Combined with Radiologic-pathologic Factors After Neoadjuvant Chemotherapy in Breast Cancer Patients with Cytologically Proven Node Metastasis at Diagnosis

Abstract Background: It is undetermined whether sentinel lymph node biopsy (SLNB) is feasible and accurate for predicting final nodal status after neoadjuvant chemotherapy (NCT) in breast cancer patients with cytologically proven node metastasis at the time of diagnosis, although currently completion node dissection is a standard surgical procedure for the management of axilla. The aim of this study was to investigate diagnostic performance of SLNB after NCT in this subgroup. Methods: Of 374 patients with T1-T3 breast cancer who received NCT, 178 had initially biopsy proven axillary/supraclavicular metastasis and subsequently underwent SLNB using radioisotope alone followed by completion node dissection between 2008 and 2011. Detection rate, sensitivity, false negative rate (FNR), negative predictive value (NPV), and accuracy of SLNB were retrospectively analyzed and it was explored using regression analysis whether combination with clinicopathologic factors improved performance. Results: At initial presentation, 60.7% of patients were cT2 stage and 88.2% treated with concurrent or sequential anthracycline plus taxane preoperatively. SLNB was successfully performed in 169 (94.9%) patients. The mean number of sentinel and regional nodes retrieved was 2.1 ± 1.6 and 12.8 ± 6.3, respectively. Tumoral non-responder and extensive residual nodal disease were significantly associated with detection failure of SLNB. Conversion to node-negative disease was noted in 69 (40.8%) patients. Sensitivity, FNR, NPV, and accuracy of SLNB were 78.0%, 22.0%, 75.8%, and 87.0%, respectively and diagnostic performance increased when ≥ 3 sentinel nodes were evaluated. By logistic regression model, tumoral and nodal responder, absent lymphovascular invasion (LVI), estrogen receptor (ER)-negativity, and HER2-positivity were significantly associated with node-negative disease after NCT. Area under the receiver operating characteristic curve increased from 0.890 to 0.949 when considering radiologic-pathologic factors and FNR was the lowest value of 14.3% in 46 patients with tumoral responder, absent LVI, and ER-negative tumor. Conclusions: SLNB was technically feasible but solely showed higher FNR in this study. Improved diagnostic performance of SLNB combined with radiologic-pathologic characteristics suggests possible clinical value of SLNB after NCT in highly selected patients with node metastasis at diagnosis. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-23.