Cyclophosphamide, Methotrexate, 5-fluorouracil Research Articles

Abstract PO1-03-06: Older patients with Early Stage Triple Negative Breast Cancer: The Memorial Sloan Kettering Cancer Center experience

Abstract INTRODUCTION Approximately 15% cases of TNBC are diagnosed in individuals over the age of 70. Older patients remain under-represented in clinical trials. We conducted a retrospective review of patients 70 years of age and older with stage I-III TNBC who were treated at Memorial Sloan Kettering Cancer Center (MSKCC), with the goal of describing the clinical practice patterns and outcomes. MATERIAL AND METHODS A retrospective record review of patients 70 years of age and older with a diagnosis of stage I-III TNBC between January 2015-December 2019 was performed. We report the data on the utilization of systemic chemotherapy and survival analyses. We compared patient characteristics by chemotherapy type using Wilcoxon rank sum test, Pearson’s Chi-squared test, and Fisher’s exact test. Overall Survival (OS), Breast Cancer Specific Survival (BCSS), and Recurrence Free BCSS (RF-BCSS) were examined using Cox proportional hazards models. All statistical analyses were conducted using R. RESULTS A total of 147 patients were included. The median age was 75 years (range 70-96). The number of patients with stage I, II, and III disease was 64 (44%), 66 (45%), 17 (12%), respectively. Twenty-five (18%) patients underwent comprehensive geriatric assessment. Out of total patients, 93 (63%) patients received systemic Chemotherapy (C) while 54 (37%) received no chemotherapy (NC). Patients receiving C were younger (median age 74 years with C vs. 78 years with NC, p< 0.001) and had a higher disease stage (Stage II-III: 66% (C) vs. 41% (NC), p=0.005). There were no significant differences in Activities of Daily Living (ADL) difficulty between both arms. Amongst, Instrumental ADL (IADL) assessment, patients in the NC group reported statistically significant greater difficulty with meal preparation (17% in NC and 4.3% in C, p=0.016). The most common reasons for not receiving chemotherapy were low-risk disease i.e. pT1aN0 or microinvasive (33%), patient preference (29%), and frailty per the treating oncologist (19%). Rate of mastectomy was higher in the NC group (35% in NC vs. 20% in C, p=0.029). Among the 32 patients who had radiation data, breast irradiation rates were higher in the C group (70% in C and 17% in NC, p=0.003). Thirty patients (20%) received neoadjuvant chemotherapy (NAC) and 65 (44%) received adjuvant chemotherapy. Anthracycline-based chemotherapy was the most common NAC (n=17, 57%). Patients who received Cyclophosphamide-Methotrexate-5-Fluorouracil (CMF) were older (age ≥75 years: 51% (CMF) vs. 17% (ACT),p=0.010), more likely treated in an adjuvant setting (87% CMF vs. 61% ACT, p=0.017), had earlier-stage disease (Stage 1: 54% (CMF) vs. 26% (ACT), p=0.028), and reported more ADL (31% in CMF vs. 0% in ACT, p=0.002) and IADL difficulties (31% CMF vs 4.3% in ACT, p=0.021). The use of Docetaxel/Cyclophosphamide (TC) and platinum-based regimens was low (8% and 5%, respectively). In the univariate analysis between the C and NC groups, there was no difference in OS (Hazard Ratio (HR) 0.78, 95% Confidence Interval (CI) 0.42-1.43; p=0.4), BCSS (HR 1.39, 95% CI 0.57-3.39; p=0.5), and RF-BCSS (HR 1.60, 95% CI 0.67-3.83; p=0.3). There was no difference in OS (HR 0.60, 95% CI 0.23-1.55; p=0.3), BCSS (HR 0.48, 95% CI 0.17-1.32; p=0.2), and RF-BCSS (HR 0.71, 95% CI 0.30-1.73; p=0.5) in patients receiving CMF vs. ACT. CONCLUSIONS In our single institutional experience, we observed that two-thirds of older patients with early-stage TNBC received systemic polychemotherapy. A third of patients with NC were very low risk (pT1a or microinvasive disease) which could explain lack of chemotherapy benefit in our study population. Use of CMF was more prevalent in patients aged ≥75, stage I disease, ADL/IADL difficulties, and in the adjuvant setting. We observed no difference in survival outcomes between the two chemotherapy regimens. CMF remains an efficacious option and a potentially viable alternative to ACT in TNBC, especially in the setting of early stage and advanced age. Citation Format: Jasmeet Singh, Diana Lake, West Dente-Ferguson, Yuan Chen, Fiona Erlich, Beatriz Korc-Grodzicki, Mark Robson, Larry Norton, W. Iris Zhi. Older patients with Early Stage Triple Negative Breast Cancer: The Memorial Sloan Kettering Cancer Center experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-03-06.

Older patients with early-stage triple-negative breast cancer: The Memorial Sloan Kettering Cancer Center experience.

12063 Background: Approximately 15% of cases of early-stage triple-negative breast cancer (TNBC) are diagnosed in individuals over the age of 70. Despite studies indicating that older patients derive similar benefits from polychemotherapy as younger patients, breast cancer specific mortality among older patients remains disproportionately high. Use of the comprehensive geriatric assessment (CGA) and individualized risk tools can help tailor treatment and minimize negative side effects while preserving quality of life. We performed a retrospective analysis of patients ≥ 70 years of age diagnosed with stage I-III TNBC at Memorial Sloan Kettering Cancer Center between 2015 and 2019 to describe clinical practices for managing this population. Methods: Demographics, CGA, systemic therapy data were collected from electronic medical records. A multivariable logistic regression model was used to identify factors that were independently associated with the probability of receiving chemotherapy. Results: We included 159 women, with a median age of 74.5 years (range 70-96). 67 (42%) had stage I disease, 71 (45%) had stage II, and 21 (13%) had stage III. 29 (18%) reported difficulty in Activities of Daily Living (ADL), 34 (21%) reported difficulties in Instrumental Activities of Daily Living (iADL), and 40 (26%) were identified as having a high risk for falls. 25 (17%) patients underwent CGA per physician’s choice. The prevalence of cardiac risk factors was as follows: hypertension in 80 patients (50%), diabetes in 25 (16%), obesity in 7 (4.4%), heart failure in 1 (0.6%). 147 underwent breast surgery, with 106 (67%) receiving lumpectomy and 41 (26%) mastectomy. 97 (61%) patients received chemotherapy: 35 (22%) neoadjuvant and 62 (40%) adjuvant. Anthracycline, Cyclophosphamide, Paclitaxel (AC-T) and Cyclophosphamide, Methotrexate, Fluorouracil (CMF) were the most common regimens. In multivariable logistic regression analysis, use of chemotherapy was associated with younger age (odds ratio [OR] 0.84 for one year increase in age, 95% confidence interval [CI] 0.75-0.93, p = 0.001) and higher disease stage (stage II vs. I OR 4.97, 95% CI 1.66-16.4, p = 0.006; stage III vs. I OR 22.0, 95% CI 3.3-312, p = 0.006). No significant difference was found in geriatric referrals, cardiovascular risk factors, or difficulties with ADL or iADL between those receiving or not receiving chemotherapy. Conclusions: In our single center experience, 61% of older patients with early-stage TNBC received chemotherapy, with AC-T and CMF being the most common regimens. The referral rate for CGA was low. Age < 75 years and higher disease stage were significantly associated with receiving chemotherapy. Overcoming barriers to incorporating CGA and toxicity prediction into routine clinical practice is crucial for personalized treatment in this population.

Detailed Sub-study Analysis of the SECRAB Trial: Quality of Life, Cosmesis and Chemotherapy Dose Intensity

AimsSECRAB was a prospective, open-label, multicentre, randomised phase III trial comparing synchronous to sequential chemoradiotherapy (CRT). Conducted in 48 UK centres, it recruited 2297 patients (1150 synchronous and 1146 sequential) between 2 July 1998 and 25 March 2004. SECRAB reported a positive therapeutic benefit of using adjuvant synchronous CRT in the management of breast cancer; 10-year local recurrence rates reduced from 7.1% to 4.6% (P = 0.012). The greatest benefit was seen in patients treated with anthracycline–cyclophosphamide, methotrexate, 5-fluorouracil (CMF) rather than CMF. The aim of its sub-studies reported here was to assess whether quality of life (QoL), cosmesis or chemotherapy dose intensity differed between the two CRT regimens. Materials and methodsThe QoL sub-study used EORTC QLQ-C30, EORTC QLQ-BR23 and the Women's Health Questionnaire. Cosmesis was assessed: (i) by the treating clinician, (ii) by a validated independent consensus scoring method and (iii) from the patients' perspective by analysing four cosmesis-related QoL questions within the QLQ-BR23. Chemotherapy doses were captured from pharmacy records. The sub-studies were not formally powered; rather, the aim was that at least 300 patients (150 in each arm) were recruited and differences in QoL, cosmesis and dose intensity of chemotherapy assessed. The analysis, therefore, is exploratory in nature. ResultsNo differences were observed in the change from baseline in QoL between the two arms assessed up to 2 years post-surgery (Global Health Status: –0.05; 95% confidence interval –2.16, 2.06; P = 0.963). No differences in cosmesis were observed (via independent and patient assessment) up to 5 years post-surgery. The percentage of patients receiving the optimal course-delivered dose intensity (≥85%) was not significantly different between the arms (synchronous 88% versus sequential 90%; P = 0.503). ConclusionsSynchronous CRT is tolerable, deliverable and significantly more effective than sequential, with no serious disadvantages identified when assessing 2-year QoL or 5-year cosmetic differences.

Abstract 12035: Cardiotoxicity-Based Model for Assessment of Drug Value in Breast Cancer

Introduction: Cardiovascular toxicity mediated by chemotherapy drugs has important implications on the clinical outcomes of patients with breast cancer. We created a multi-component drug value framework incorporating efficacy, safety, cost, and cardiovascular toxicity data to define the overall value of standard regimens. The impact of heart failure incidence on the value score of each regimen was evaluated. Methods: The NCCN guidelines were reviewed, and four standard chemotherapy regimens used in non-metastatic HER-2 negative breast cancer were selected. PubMed was reviewed for randomized clinical trials establishing the role of each regimen. Data on the efficacy (defined as 5-year survival) and toxicity (defined as incidence of the most frequent grade 3 toxicity) profile of each regimen were extracted. Data on regimen-specific heart failure incidence at follow up were collected from prospective studies. Regimen-specific costs were derived from a recent observational cohort study. Total drug value scores (range 2.2-8.6, traditional, 2.9-11.7 upgraded) were computed and the effect of cardiotoxicity data on drug value scores was evaluated. Results: Anthracycline-containing regimens had lower mean drug value scores than anthracycline-free regimens (5.3, 61.6% versus 7.4, 86.0%) using a traditional value system based on efficacy, safety, and cost. When data on heart failure incidence were incorporated into the value assessment, anthracycline-containing regimens had lower relative value scores (mean decrease 10.7%) while anthracycline-free combinations had higher relative scores (mean increase 4.3%), compared with a traditional model. Regimen-specific value scores were modified by the addition of heart failure data. Drug value assessments that included efficacy, safety and cost showed superiority of docetaxel, adriamycin, cyclophosphamide (TAC) relative to cyclophosphamide, methotrexate, fluorouracil (CMF) (7.1, 82.6%, 6.6, 76.7%) and the addition of heart failure incidence data reversed that trend (8.6, 73.5%, 9.6, 82.0%). Conclusions: Inclusion of cardiovascular toxicity data modifies the value scores of standard chemotherapy regimens used in breast cancer and likely provides a more patient-centric value assessment.

Neuroprotective effect of Mulmina Mango against chemotherapy-induced cognitive decline in mouse model of mammary carcinoma

The post-treatment status of breast cancer survivors has become a concern because of the toxicity induced by chemotherapeutic agents in the brain tissues resulting in cognitive deficits, which is generally referred as chemobrain. The aim of this study was to assess the effect of a proprietary ayurvedic formulation Mulmina Mango against chemotherapy-induced cognitive impairment (CICI). Mammary carcinoma was induced by subcutaneously inoculating 4T1 cells into the mammary fat pad of the animals. Intraperitoneal administration of Cyclophosphamide, Methotrexate, 5-Fluorouracil (CMF) regimen was carried out once a week for three weeks. Treatment of Mulmina began one week before chemotherapy and continued till the end of the chemotherapy cycle. After three cycles of chemotherapy, cognitive decline was assessed by Morris water maze task followed by assessment of locomotor activity by open-field test. Tumor progression was evaluated by measurement of tumor volume. Oxidative and neuroinflammatory markers were also evaluated from the isolated brain samples. CMF treatment resulted in a considerable reduction in tumour volume. We found chemotherapy negatively affected behavioral and biochemical parameters in animals and Mulmina treatment ameliorated these cognitive impairments by restoring antioxidant and maintaining cytokine levels. The combination of phytochemicals in Mulmina proved its possible ability to alleviate CICI without affecting chemotherapeutic efficiency and could pave the way for identifying treatment strategies to combat chemobrain.

Chemotherapy-related subjective cognitive impairment in breast cancer patients in semi-rural South Africa

BackgroundBreast cancer is the most commonly diagnosed cancer amongst women worldwide. Whilst current evidence indicates the therapeutic benefits from the use of chemotherapy, self-perceived cognitive difficulties emerged as a frequent occurrence during and after chemotherapy treatment in breast cancer patients.AimThe current study sought to investigate self-perceived cognitive impairment in a group of breast cancer patients in semi-rural South Africa.SettingThe patients were recruited from an outpatient oncology clinic at a semi-rural, tertiary academic hospital in Gauteng, South Africa.MethodsIn a randomised, quantitative, time-based series study, 30 female patients aged 21–60 years (mean age = 50 years) diagnosed with stages II and III breast cancer on CMF (cyclophosphamide, methotrexate, fluorouracil) (n = 10) and FAC (fluorouracil, adriamycin, cyclophosphamide) (n = 20) chemotherapy regimens, completed the self-reported Functional Assessment of Cancer Therapy-Cognition (Fact-Cog) test as a measure of subjective cognitive functioning at three points during the course of treatment (T0, T1, T2).ResultsThe results of the paired sample t-tests showed the scores on the Fact-Cog test confirmed significant cognitive decline for both treatment groups from baseline (T0) to completion (T2) of chemotherapy; CMF group, t (9) = 2.91, p = 0.017 and the FAC group t (19) = 4.66, p < 0.001.ConclusionThis study confirms that self-reported subjective cognitive impairment is common in breast cancer patients who received chemotherapy in a sample of South African patients. The results have implications for the overall care of cancer patients.ContributionThe context-based knowledge engendered by the current study is expected to augment the continuum of care for breast cancer patients.

Abstract GS4-05: Neoadjuvant chemotherapy (NCT) response in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) resistant to endocrine therapy (ET) in the ALTERNATE trial (Alliance A011106)

Abstract Background: Ki67 values &amp;gt;10% 2-4 weeks (wks) after starting neoadjuvant ET (NET) indicates persistent cell proliferation, resistance to ET, and is associated with increased risk of recurrence. The ACOSOG Z1031 trial suggested that these tumors are also relatively chemotherapy (chemo) resistant with a low pathologic complete response (pCR) rate to NCT. The ALTERNATE trial (NCT01953588) is a randomized study of neoadjuvant anastrozole (ANA), fulvestrant (FUL), or ANA + FUL in postmenopausal patients (pt) with newly diagnosed clinical stage II or III ER+ (Allred score 6-8)/HER2- BC. Ki67 &amp;gt;10% at wk 4 or 12 after starting NET triggered triage to NCT of physician choice or weekly paclitaxel. Pts who refused protocol-directed therapy, were not candidates for NCT, or decided to undergo immediate surgery are being followed per protocol. Here we report the rates of pCR and residual cancer burden (RCB) following NCT for pts triaged to NCT due to Ki67 &amp;gt;10% at wk 4 or 12. Results: Of the 1,299 eligible pts randomized to receive ANA, FUL, or ANA + FUL, 286 (22%) had Ki67 &amp;gt;10% at wk 4 or 12. 168 of these 286 pts (58.7%) chose to switch to NCT, 32 went to surgery (11.2%), and 86 discontinued further protocol-directed therapy (30.1%). Among the 168 pts who underwent NCT, the presenting clinical T stages were cT2 (n=113; 67.26%), cT3 (n=47; 27.98%) and cT4 (n=8; 4.76%) and N stages were cN0 (n=82; 48.8%), cN1 (n=75; 44.6%), cN2/3 (n=9; 5.4%) and cNx (n=2; 1.2%). Central ER testing was performed on pre-treatment biopsies and confirmed ER Allred score 6-8 in 155 of 168 (92.2%) pts, with the rest being ER Allred score 4-5 (n=5; 3%), ER- (Allred score 0) (n=2; 1.2%), or not tested (n=6; 3.6%). Most (n=139; 82.7%) were ER+/PR+, while 17.3% (n=29) were ER+/PR-, and tumor grades were G1 (n=10; 6%), G2 (n=99; 58.9%), G3 (n=54; 32.1%), not reported (n=5; 3%). Baseline Ki67 levels prior to NET were &amp;gt;10% in 94% (n=158), ≤10% in 3% (n=5), and not done in 3% (n=5). NCT regimens administered included doxorubicin/cyclophosphamide (AC) followed by paclitaxel (T) (n=60; 35.71%); weekly paclitaxel (n=56; 33.33%), docetaxel/cyclophosphamide (TC) (n=33; 19.65%), other doxorubicin and/or taxane containing regimen (n=17; 10.12%), and cyclophosphamide/methotrexate/fluorouracil (CMF) (n=2; 1.19%). 35 (20.8%) pts did not complete planned course of NCT due to toxicity (n=27) or refusal (n=8). 154 NCT pts underwent surgery (mastectomy in 40.3%, and breast conserving surgery in 59.7%). The path ypT stages were Tis/0 (n=10; 6.5%), T1 (n=62; 40.3%), T2 (n=61; 39.6%), and T3/4 (n=21; 13.6%), and the ypN stages were N0 (n=66; 42.9%), N1 (n=57; 37%), N2/3 (n=30; 19.5%), and Nx (n=1; 0.6%). Among the 168 pts who started on NCT (intent to treat population), there were 8 pCRs (no invasive disease in the breast or lymph nodes) (4.8%; 95% CI: 2.1% to 9.2%). Residual Cancer Burden (RCB) categories include RCB 0 (n=8; 4.8%), RCB 1 (n=15; 8.9%), RCB 2 (n=82; 48.8%), RCB 3 (n=42; 25.0%), and not determined (n=21; 12.5%). Correlations of baseline pt and tumor characteristics with pathology response to NCT will also be presented. Conclusion: In pts with NET-resistant ER+/HER2- BC, salvage NCT is not likely to induce a complete or near complete response. More effective treatments are needed for this high-risk ER+/HER2- pt population. Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG); NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. Clinical Trials.gov Identifier: NCT01953588 Citation Format: Cynthia X Ma, Vera Suman, A. Marilyn Leitch, Souzan Sanati, Kiran Vij, Gary W Unzeitig, Jeremy Hoog, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Horacio Maluf, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, Travis Dockter, Jo Anne Zujewski, Anna Weiss, Kelly Hunt, Clifford Hudis, Eric P Winer, Matthew J Ellis, Lisa A Carey, Ann H Partridge. Neoadjuvant chemotherapy (NCT) response in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) resistant to endocrine therapy (ET) in the ALTERNATE trial (Alliance A011106) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-05.

Impact of adjuvant chemotherapy or tamoxifen-alone on the ovarian reserve of young women with breast cancer.

To determine the longitudinal impact of adjuvant chemotherapy and tamoxifen-only treatments on the reproductive potential of women with breast cancer by using a sensitive ovarian reserve marker anti-Mullerian hormone (AMH) as a surrogate. One-hundred-and-forty-two women with a primary diagnosis of breast cancer were prospectively followed with serum AMH assessments before the initiation, and 12, 18 and 24months after the completion of adjuvant chemotherapy or the start of tamoxifen-only treatment. The chemotherapy regimens were classified into Anthracycline-Cyclophosphamide-based (AC-based) and Cyclophosphamide-Methotrexate + 5-Fluorouracil (CMF). Longitudinal data were analyzed by mixed effects model for treatment effects over time, adjusting for baseline age and BMI. Both chemotherapy regimens resulted in significant decline in ovarian reserve compared to the tamoxifen-only treatment (p < 0.0001 either regimen vs. tamoxifen for overall trend). AMH levels sharply declined at 12months but did not show a significant recovery from 12 to 18 and 18 to 24months after the completion of AC-based or CMF regimens. The degree of decline did not differ between the two chemotherapy groups (p = 0.53). In contrast, tamoxifen-only treatment did not significantly alter the age-adjusted serum AMH levels over the 24-month follow up. Likewise, the use of adjuvant tamoxifen following AC-based regimens did not affect AMH recovery. Both AC-based regimens and CMF significantly compromise ovarian reserve, without a recovery beyond 12months post-chemotherapy. In contrast, tamoxifen-only treatment does not seem to alter ovarian reserve. These data indicate that the commonly used chemotherapy regimens but not the hormonal therapy compromise future reproductive potential.

Response of a chemo-resistant triple-negative breast cancer patient to a combination of p62-encoding plasmid, Elenagen, and CMF chemotherapy.

Triple-negative breast cancers are often characterized by aggressive behavior and short clinical course once they become chemotherapy-resistant. We describe below a patient who has shown a response to combination of chemotherapy with Elenagen, a plasmid encoding p62. Elenagen was tested in a previous phase I/II study in patients with refractory solid tumors and shown to be safe. Also, plasmid ability to halt tumor progression and restore sensitivity to chemotherapy was found. Preclinical data supports effects on tumor grade and change the tumor’s microenvironment in spontaneous canine breast cancers. We describe here a 48-year old female with triple-negative and BRCA1/2-negative breast cancer who had a primary resistance to chemotherapy and negative dynamics despite the use of multiple lines of treatments. Elenagen was applied intramuscularly at a dose of 1 mg weekly in combination with standard chemotherapy scheme CMF (cyclophosphamide, methotrexate, fluorouracil). In this patient we observed partial tumor regression (by 33%) and 19 weeks of progression-free survival. This first observed objective response to a combination of Elenagen with chemotherapy demonstrates that even in heavily pretreated chemo-resistant triple-negative tumor, the addition of Elenagen to a chemotherapy regimen can cause an objective response and increase in progression-free survival. Such a regimen is worthy of further study in a larger number of patients.

Antitumor activity and efficacy of shorter versus longer duration of anthracycline-taxane neoadjuvant chemotherapy in stage II-III HER2-negative breast cancer: a 10-year, retrospective analysis.

Background:Neoadjuvant anthracycline-taxane-based chemotherapy (ChT) is a standard of care treatment option for stage II–III breast cancer (BC) patients. However, the optimal duration of neoadjuvant ChT has been poorly investigated so far.Material and methods:We retrospectively retrieved clinical data of patients with stage II–III human epidermal growth factor receptor 2-negative (HER2–) BC who were treated between October 2007 and January 2018 with neoadjuvant AT (doxorubicin-paclitaxel) for three cycles followed by CMF (cyclophosphamide-methotrexate-5-fluorouracil) for three cycles (cohort A) or with four AT cycles followed by four CMF cycles (cohort B). The aim of our study was to investigate the impact of neoadjuvant ChT duration (cohort A versus cohort B) on pathological complete response (pCR) rates, disease-free survival (DFS) and overall survival (OS).Results:Of 209 HER2– BC patients included, 62 had triple-negative breast cancer (TNBC) and 147 had hormone receptor-positive (HR+) BC. Median age was 48 years (range 30–74 years). A total of 111 patients belonged to cohort A and 98 patients belonged to cohort B. pCR was detected in 29 (13.9%) patients, 25 (40.3%) of whom had TNBC and four (2.7%) had HR+ HER2– BC. Patients achieving pCR had significantly longer DFS and OS, with statistical significance reached only in patients with TNBC. We found no differences between cohort A and cohort B in terms of pCR rates (15.3% versus 12.2%; p = 0.55), DFS (p = 0.49) or OS (p = 0.94). The incidence of grade 3/4 adverse events was similar in cohort A versus cohort B as well (22.5% versus 19.4%; p = 0.54).Conclusion:Shorter duration of neoadjuvant anthracycline-taxane ChT was not associated with worse clinical outcomes in patients with stage II–III BC. Prospective studies are needed to evaluate whether the duration of neoadjuvant anthracycline-taxane-based ChT can be reduced in specific patient subgroups without negatively affecting clinical outcomes.

196P - The clinical impact of adjuvant dose-dense sequential chemotherapy (dds-CT) in patients with high-risk operable breast cancer (BC): Pooled analysis of 6 clinical trials

196P - The clinical impact of adjuvant dose-dense sequential chemotherapy (dds-CT) in patients with high-risk operable breast cancer (BC): Pooled analysis of 6 clinical trials

The Role of CXCL13 and CXCL9 in Early Breast Cancer

BackgroundChemokines, cytokines in the immune microenvironment of tumors, may be associated with patient outcome. We assessed the impact of CXCL13 and CXCL9 on disease-free (DFS) and overall survival (OS), in an attempt to retrospectively evaluate both T and B cell function in the microenvironment of primary tumors from patients with breast cancer. Materials and MethodsFormalin-fixed paraffin-embedded tissue blocks from patients with intermediate/high-risk, early breast cancer, treated with sequential adjuvant epirubicin, paclitaxel, and cyclophosphamide methotrexate fluorouracil within a randomized trial, were tested for CXCL13 and CXCL9 messenger RNA expression; 557 patients with adequate tissue were eligible for the analysis. ResultsCXCL13 was correlated with CXCL9 (rho = 0.52; P < .001). High-expressing CXL13 and CXCL9 tumors had higher Ki67 and tumor infiltrating lymphocyte density (P-values < .001). High CXCL9 expression was an unfavorable prognosticator for OS among all patients (hazard ratio [HR], 1.73; P = .021), whereas it showed favorable significance for both DFS and OS in patients with triple negative disease (HR, 0.29; P = .027 and HR, 0.32; P = .045). High CXCL13 conferred longer DFS and OS among patients with luminal-human epidermal growth factor receptor 2 disease (HR, 0.31; P = .013 and HR, 0.25; P = .005). Patients with low CXCL13 and high CXCL9 expression had shorter DFS and OS compared with those with high expression of both chemokines (HR, 1.63; P = .006 and HR, 1.61; P = .016). ConclusionsBoth biomarkers were associated with poor prognosis characteristics and with tumor infiltrating lymphocyte density. High CXCL9 conferred an improved prognosis in the triple negative subtype, whereas high CXCL13 was associated with improved outcome in the luminal-human epidermal growth factor receptor 2 subtype. Chemokines can be associated with breast cancer subtype and outcome. These data should be evaluated prospectively.

Predictive value of in vitro methyl thiazolyl tetrazolium assay chemosensitivity test of cytotoxic drug activity in breast cancer

Objective To investigate the value of methyl thiazolyl tetrazolium assay (MTT) in predicting drug sensitivity of breast cancer cells in vitro. Methods From January 2010 to July 2016, one hundred and ninety-two patients with breast cancer who underwent modified radical mastectomy or breast conserving surgery (no preoperative radiotherapy or chemotherapy) in the Shanghai Fengxian District Central Hospital were selected.MTT method was used to determine the inhibitory level and sensitivity of 12 drugs and 3 chemotherapy regimens to primary cultured cancer cells of 192 patients with breast cancer. Results (1)The sensitivity of breast cancer cells to 12 drugs were in sequence from high to low as follows: Paclitaxel (PTX) > Epirubicin (EPI) > Cisplatin (DDP) > 5-Fluorouracil (5-FU) > Mitoxantrone (MIT) >Vincristine (VCR) > Pirarubicin (THP) > Isosophosphamide (IFO) > Carboplatin (CBP) >Cyclophosphamide (CTX) > Methotrexate (MTX) > Changchun Rui bin (NVB). The sensitivity of chemotherapy regimens in the three groups from high to low was docetaxel/doxorubicin/cyclophosphamide (TAC)>cyclophosphamide/epirubicin/fluorouracil (CEF)>cyclophosphamide/methotrexate/fluorouracil (CMF). The sensitivity rates of PTX, EPI and DDP were 54% (104/192), 42% (81/192) and 37% (71/192) respectively.(2) The average inhibitory rates of DDP, CBP and MIT in stage III breast cancer was higher than those in stage I and II breast cancer, and the differences were statistically significant (F=11.14, 4.303, 3.182, P<0.05). (3) HR-breast cancer is more sensitive than HR+ breast cancer, PTX, EPI, THP, MIT in HER-2(+ ) breast cancer is more sensitive than in HER-2(-)breast cancer. Conclusion As a widely used drug sensitivity test method, MTT assay has a certain reference value for screening sensitive drugs and selecting clinical chemotherapy regimens in neoadjuvant chemotherapy of breast cancer.PTX, EPI and DDP are more sensitive to other breast cancer cells than other drugs.Chemotherapy based on in vitro susceptibility results improves the efficiency of chemotherapy and decreases the proportion of changes in chemotherapy schemes due to inefficiency. Key words: MTT assay; Breast cancer; Cell; Chemosensitivity test

National Planning and Policy Improvement for ABC Patients in Kyrgyzstan

Background and context: Breast cancer takes the first place among the cancer diseases in the Kyrgyz Republic. Almost 40% of breast cancer cases are detected in the advanced III and IV stages. Specialized oncology services for cancer patients are available in two oncology centers in the Kyrgyz Republic. One is in Bishkek (capital of the country), and another is in Osh (the second large city). However, medical services provided by the government are limited to the surgery, particularly, with mastectomy. Radiotherapy is not available because of deterioration and breakdown of equipment. Mandatory Health Insurance Fund does not cover chemotherapy cost for cancer patients, and patients pay out of pocket. Kyrgyz National Essential Drug List does not include many vital antineoplastic agents recommended by WHO. The absence of essential antineoplastic agents in National Essential Drug List negatively affects medicine registration and procurement, makes them unavailable, inaccessible and unaffordable in Kyrgyzstan. Advanced breast cancer patients cannot plan their upcoming expenses. Many patients can´t finish the full course of treatment. Ergene is the only organization in Kyrgyzstan that advocates and provides technical assistance to the Oncology Institute and the Ministry of Health to improve access to oncological drugs for the treatment of breast cancer. Aim: Improve access to oncology medicines and treatment of patients with advanced breast cancer. Strategy/Tactics: Ergene team accessed National Essential Drug List (EDL) and selected available oncology drugs. Then the experts compared available oncological drugs from the National EDL and oncology drugs from the WHO list. Together with oncologists, experts analyzed the availability of essential drugs for advanced breast cancer and identified missing drugs to be included in National EDL. These drugs are trastuzumab, anastrozole, paclitaxel, and gemcitabine. Program/Policy process: The team of experts calculated the cost of treatment of breast cancer regimens including therapy with trastuzumab and started negotiations with Mandatory Health Insurance Fund (MHIF) for chemotherapy treatment coverage. The policy makers agreed that the cost of basic chemotherapy regimens is affordable for insurance coverage (adriamycin cyclophosphamide-245 USD, cyclophosphamide methotrexate fluorouracil - 390USD, fluorouracil adriamycin cyclophosphamide -426 USD). However, the cost of monotherapy regimen is more expensive (capecitabine, docetaxel -2400 dollars) and requires additional financial resources. Outcomes: MHIF will include coverage of essential AC, FAC, and CMF regimens for women with breast cancer and will consider partial coverage of trastuzumab and several monotherapy regimens. What was learned: Chemotherapy regimens cost calculation is an integral part of advocacy and policy work. It helped to negotiate chemotherapy treatment insurance coverage for women with breast cancer.

Dynamic relationship between cycling kinetics of triple-negative breast cancer and tumor infiltrating immune cells.

1100 Background: Recent studies show strong correlation between tumor infiltrating lymphocytes (TILs) and triple-negative breast cancer (TNBC) patient survival. CD8+ T cells serve as a favorable prognostic marker for TNBC. In addition, other cells such as CD4+ T cells, macrophages, B cells, and Tregs also infiltrate tumors. In this study, we delineate a strong relationship between the cycling kinetics of proliferating cells in TNBCs and antitumor immune response. Methods: A multi-institutional study performed by our group has previously shown that KAMS (Ki67-Adjusted Mitotic Score) provides a measure of the cycling kinetics of proliferating tumor cells and robustly stratifies TNBC patients into slow cycling (low KAMS) cyclophosphamide-methotrexate-fluorouracil (CMF)-responsive and fast cycling (high KAMS) CMF-resistant subgroups. In this study, we reviewed clinical data from 124 CMF-treated TNBC patients from Nottingham Hospital and sought correlations between cycling kinetics (High/Low KAMS) and tumor infiltrating immune cells. Results: We found that slow cycling TNBCs had higher mean expression of tumor infiltrating immune cells than fast cycling TNBCs. Intratumoral CD68 (p = 0.003), CD3 (p = 0.006), CD20 (p = 0.01), FOXP3 (p = 0.01), and total numbers of intratumoral and stromal CD68 (p = 0.01) and CD3 (p = 0.03) expressing cells were found to be significantly higher in low KAMS tumors than in high KAMS tumors. Of these biomarkers, CD68 was significantly associated with patients’ breast cancer-specific survival (BCSS): (a) low KAMS, high CD68 TNBCs had better BCSS than low KAMS, low CD68 (p = 0.01) TNBCs, and (b) high KAMS, low CD68 cases had better BCSS than high KAMS, high CD68 cases. Conclusions: Our observation that there are more TILs in slow cycling TNBCs suggests that there may be a dynamic cross-regulation between cycling kinetics and antitumor immune response. From our surprising observation that CD68 exerts polar roles in low/high KAMS subgroups, we propose that distinctions in M1 and M2 macrophage subsets in slow and fast cycling TNBCs may correlate with distinct outcomes. In addition, metabolic competition between tumor and immune cells may determine the level and function of TILs.

Postmastectomy Radiation Therapy

Postmastectomy Radiation Therapy

A network meta-analysis for toxicity of eight chemotherapy regimens in the treatment of metastatic/advanced breast cancer.

ObjectiveTo compare the incidence of toxicity of 8 different chemotherapy regimens, including doxorubicin + paclitaxel, doxorubicin, capecitabine, CMF (cyclophosphamide + methotrexate + 5-fluorouracil), FAC (fluorouracil + doxorubicin + cyclophosphamide), doxorubicin + docetaxel, doxorubicin + cyclophosphamide and paclitaxel in the treatment of metastatic/advanced breast cancer.ResultsThis network meta-analysis included 8 randomized controlled trials (RCTs). The findings revealed that, with regard to capecitabine alone regimen exhibited higher incidence of nausea/vomiting than doxorubicin + paclitaxel regimen, doxorubicin alone regimen and paclitaxel alone regimen in the treatment of patients with metastatic/advanced breast cancer (OR = 32.48, 95% CI = 1.65~2340.57; OR = 22.75, 95% CI = 1.03~1923.52; OR = 59.63, 95% CI = 2.22~5664.88, respectively). Furthermore, doxorubicin + cyclophosphamide regimen had lower incidence of febrile neutropenia than doxorubicin + docetaxel (OR = 0.17, 95% CI = 0.03~0.96). No significant difference in the incidence of stomatitis was observed among eight chemotherapy regimens.Materials and MethodsWe initially searched PubMed, Cochrane Library and Embase databases from the founding of these databases to January 2016. Eligible studies investigating the 8 different chemotherapy regimens for treatment of metastatic/advanced breast cancer were included for direct and indirect comparison. The odds ratio (OR) and surface under the cumulative ranking curves (SUCRA) value of the incidence of toxicity among eight chemotherapy regimens were analyzed.ConclusionsCapecitabine alone regimen and doxorubicin + docetaxel regimen may have a more frequent toxicity in the treatment of metastatic/advanced breast cancer.

Osteopontin splice variants are differential predictors of breast cancer treatment responses.

BackgroundOsteopontin is a marker for breast cancer progression, which in previous studies has also been associated with resistance to certain anti-cancer therapies. It is not known which splice variants may mediate treatment resistance.MethodsHere we analyze the association of osteopontin variant expression before treatment, differentiated according to immunohistochemistry with antibodies to exon 4 and to the osteopontin-c splice junction respectively, with the ensuing therapy responses in 119 Polish breast cancer patients who presented between 1995 and 2008.ResultsWe found from Cox hazard models, logrank test and Wilcoxon test that osteopontin exon 4 was associated with a favorable response to tamoxifen, but a poor response to chemotherapy with CMF (cyclophosphamide, methotrexate, fluorouracil). Osteopontin-c is prognostic, but falls short of being a significant predictor for sensitivity to treatment.ConclusionsThe addition of osteopontin splice variant immunohistochemistry to standard pathology work-ups has the potential to aid decision making in breast cancer treatment.

Abstract S1-08: High risk premenopausal luminal A breast cancer patients derive no benefit from adjuvant chemotherapy: Results from DBCG77B randomized trial

Abstract Aim: To determine the predictive value of intrinsic subtypes for response to adjuvant chemotherapy using specimens from a randomized clinical trial. Background: Several studies have shown distinct clinical profiles of intrinsic breast cancer subtypes. The Luminal A subtype has a favorable prognosis with higher survival rate and lower recurrence in comparison to other breast cancer subtypes (luminal B, HER2 and basal-like). In addition, there is mounting evidence suggesting that intrinsic breast cancer subtypes differ in their responsiveness to adjuvant chemotherapy. Based on these data, we hypothesized that Luminal A breast cancer patients derive no benefit from adjuvant chemotherapy whereas other intrinsic subtypes do. Randomized breast cancer trials with a no chemotherapy arm and available tissues are rare, but represent the best materials to test for markers predicting chemotherapy benefit. The 77B clinical trial from the Danish Breast Cancer Cooperative Group (DBCG) offers a unique opportunity to test such hypotheses as it randomized 1146 premenopausal women, who had positive axillary lymph nodes or tumors &amp;gt;5 cm, to two chemotherapy arms (single-agent oral cyclophosphamide, or cyclophosphamide-methotrexate-fluorouracil (CMF)), and two no chemotherapy arms (levamisole, or no agent). All arms included radiotherapy but no endocrine therapy. Methods: We performed a full intrinsic subtype analysis on the 709 breast cancers available from DBCG77B on tissue microarrays using previously published, locked-down immunohistochemical (IHC) methods and intrinsic subtype definitions based on ER, PR, HER2, Ki67 and basal markers (Prat et al. JCO 2014). Biomarker scoring was performed in Vancouver by researchers with no access to the clinical database. A full statistical plan was prespecified in the Material Transfer Agreement and executed accordingly by the DBCG Statistical Office. 10-year invasive disease-free survival (IDFS) was the primary end point in DBCG77B; overall survival was also a predefined endpoint. The primary hypothesis was to assess interaction between benefit of chemotherapy (chemotherapy yes vs no) and subtype (Luminal A vs non-luminal A). This was analyzed in multivariate Cox proportional hazards models using the Wald test for interaction. Results: 709 patients had tissue available and completed IHC intrinsic subtyping. The effect of chemotherapy in this subset of patients was similar to the original trial: hazard ratio 0.56, favoring chemotherapy for 10-yr IDFS. IHC classified 165 as luminal A, 319 luminal B, 58 HER2E and 91 as triple negative (including 82 core basal). Patients with luminal A breast tumors did not benefit from chemotherapy (HR = 1.07, 95% CI = 0.53-2.14, p = 0.86), whereas patients with non-luminal A subtypes did (HR = 0.50, 95% CI = 0.38-0.66, p &amp;lt; 0.001). This heterogeneity was statistically significant (p=0.048). A similar trend for 25-yr OS was seen, although not significant. Conclusions: In a formal prospective-retrospective analysis of the DBCG 77B study randomizing women to adjuvant cyclophosphamide-based chemotherapy vs. no chemotherapy arms, patients with non-luminal A breast tumors (defined by IHC), but not luminal A tumors, benefit from adjuvant chemotherapy. Citation Format: Nielsen TO, Jensen [lrm] M-B, Gao D, Leung S, Burugu S, Liu S, Tykjær Jørgensen CL, Balslev E, Ejlertsen B. High risk premenopausal luminal A breast cancer patients derive no benefit from adjuvant chemotherapy: Results from DBCG77B randomized trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S1-08.

Cardiac assessment of early breast cancer patients 18 years after treatment with cyclophosphamide-, methotrexate-, fluorouracil- or epirubicin-based chemotherapy

BackgroundEpirubicin-based chemotherapy improves the outcome of early breast cancer (BC) patients. However, cardiotoxicity remains an important side effect. MethodsWe re-consented node-positive BC patients enrolled in a phase III trial between 1988 and 1996 which compared six cycles of oral cyclophosphamide, methotrexate, fluorouracil (CMF) versus two epirubicin–cyclophosphamide regimens differing by the anthracycline cumulative dose [standard-dose epirubicin and cyclophosphamide (SDE) (8×60mg/m2) and higher-dose epirubicin and cyclophosphamide (HDE) (8×100mg/m2)]. Eligible patients were those who were alive and free of disease and had no contra-indications to the proposed tests (cardiac evaluation). Cardiotoxicity was defined as asymptomatic systolic dysfunction (left ventricular ejection fraction (LVEF)<50%, New York Heart Association (NYHA) Class I) or symptomatic heart failure (NYHA Class II–IV).Differences in cardiotoxicity between CMF and SDE/HDE were assessed using chi-square and Fisher Exact tests for binary variables and t-test and Wilcoxon test for continuous variables. ResultsAmong the 777 patients, 20 cases of CHF were reported (CMF=1, SDE=5, HDE=14; p<0.001). Between September 2010 and June 2013, 82 patients (30%) out of 269 eligible patients accepted to participate in this substudy. Median follow-up was 18years (range 15–24). Epirubicin-treated patients had significantly higher heart rate, more abnormal echocardiograms and LVEF by magnetic resonance imaging (MRI) compared to CMF-treated ones. A trend towards higher BNP was also observed in the SDE/HDE group (P=0.08). No differences were observed in LVEF assessed by echocardiogram or troponin T levels. ConclusionsParticipation rate in this substudy was lower than expected highlighting the complexity of re-calling patients several years after the initial BC diagnosis. After 18years, epirubicin-treated patients had a lower LVEF by MRI, more abnormal echocardiograms, higher heart rates compared to patients treated with CMF. However, no major delayed cardiotoxicity was observed.