bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiotoxicity risks of adjuvant trastuzumab in Asian breast cancer patients
Authors: Shih V. , Chan A. , Chiang J. , Teo C. , Chen J. , Wong Z. 
Published: August 2020

561 Background: Adjuvant trastuzumab (T)-based chemotherapy has been shown to reduce relapse and improve survival in breast cancer patients but has been associated with increased risks of cardiotoxicity. Our study aims to define the incidence and severity of cardiotoxicity amongst Asian breast cancer patients. Methods: This is a retrospective review of patients who have received adjuvant T from June 2005 to 2007. Cardiotoxicity was defined as a drop in left ventricular ejection fraction (LVEF) to less than 50% and/or reduction of > 10% of baseline. Cardiovascular (CVS) risk factors were defined as having a family history or presence of CAD, hypertension, diabetes mellitus, hyperlipidemia and smoking. We used pair sampled t-test to evaluate the mean LVEF change and Chi-square test to evaluate the association of cardiotoxicity and demographics. Results: There were 179 female patients. Cardiotoxicity was reported in 70 (39.1%), of whom 59 had asymptomatic decline in LVEF and 11 experienced CHF. Mean LVEF, comparing various time points (3, 6, 9 and 12 months) against baseline showed statistically significant decline (p<0.05). T was withheld (n=33) due to asymptomatic decline in LVEF (n=24), symptomatic heart failure (n=4) and both (n=5). Twenty-one with resolution of CHF (n=7) or LVEF recovery (n=14) were rechallenged. Cardiotoxicity recurred in 9 - asymptomatic decline in LVEF (n=8) and recurrent CHF (n=1). There were no cardiac-related deaths. Neither patient demographics nor CVS risk factors predicted for cardiotoxicity. Conclusions: This is one of the largest series reported in Asians receiving T. As previously reported, T-induced cardiotoxicity resulted in mostly asymptomatic reversible decline in LVEF. Our incidence of cardiotoxicity appeared higher (39.1%) in Asians and more importantly, almost half of the patients experienced cardiotoxicity upon rechallenge. It would be prudent to explore whether there is any difference in susceptibility to T-induced cardiotoxicity between the different races. [Table: see text] No significant financial relationships to disclose.
Long-term survival benefits of docetaxel plus cyclophosphamide compared to doxorubicin plus cyclophosphamide in the adjuvant treatment of operable breast cancer
Authors: Thompson M. , Seal B. , Tangirala M. , Asmar L. , Jones S. 
Published: August 2020

563 Background: The U.S. Oncology Adjuvant Trial 9735 recently demonstrated disease-free survival and overall survival (OS) benefits over 7 years for docetaxel plus cyclophosphamide (TC) compared with doxorubicin plus cyclophosphamide (AC) as adjuvant treatment for women with operable stage I-III invasive breast cancer (BC). The life-time benefits of TC vs. AC, however, are unknown. This analysis aimed to project potential life-time survival benefits of TC vs. AC as adjuvant therapy for operable BC. Methods: The 7-year follow-up results of the 9735 study combined with US average life expectancy were used to project the life-time survival benefits of TC vs. AC. In the base case (scenario 1), it was assumed the survival advantage of TC did not persist beyond the 7-year clinical trial period. Rather, all patients alive and disease-free at 7 years (from the starting age of 51 to the age of 58), regardless of treatment, were assumed to be cured and received the average remaining life expectancy of a 58-year old woman in the US general population. As survival benefits from chemotherapy may persist beyond the clinical trial period, two sensitivity analyses were conducted: 1) greater life expectancy in the TC arm of 1.8 months equivalent to the mean difference in OS between TC and AC within the clinical trial period (scenario 2) and 2) greater life expectancy in the TC arm of 22 months equivalent to the difference in survival at the end of 7 years (scenario 3). The total life years gained (LYs) and quality-adjusted life years gained (QALYs) were then calculated. Results: Per patient LYs gained in scenarios 1, 2, and 3 were 0.850, 0.930, and 1.755, respectively; while QALYs gained were slightly lower at 0.674, 0.736 and 1.383, respectively. Applying this benefit to a cohort of 167,133 women in the US with newly diagnosed stage I-III invasive BC in 2008, the gains were 142,063 LYs and 112,648 QALYS in scenario 1. Conclusions: In addition to survival benefit observed within the clinical trial period, the use of TC is associated with long-term survival benefits compared to AC in patients with stage I-III invasive BC. The results provide additional support of the value of TC in the management of early stage BC. [Table: see text]
Risk stratification by hormonal receptor (ER, PgR) and HER2 status in small (≤1cm) invasive breast cancer: Who might be a possible candidate for adjuvant treatment?
Authors: Park Y. , Kim S. , Ok O. , Baek H. , Lee J. , Nam S. , Yang J. , Cho E. , Ahn J. , Im Y. 
Published: August 2020

564 Background: With the increasing use of screening mammography, the proportion of ≤ 1 cm invasive breast cancer is increasing. Identification of breast cancer molecular subtypes has resulted in a better appreciation of the biologic heterogeneity, which is not fully explained by clinicopathologic features including staging system. The aims of this study were: 1) to identify the risk factors of systemic metastases in patients with ≤ 1 cm invasive breast cancer and 2) to investigate the patients group at greatest risk of such failure even in these small tumors. Method: Data were collected retrospectively in the breast cancer registry of our institution for patients with invasive breast cancer from October 1994 to December 2004. Results: Of 4,036 patients who received curative breast cancer surgery, 466 patients who had T1a or T1b breast cancer were identified. 39 patients who received neoadjuvant chemotherapy were excluded in this study. Ipsilateral axillary lymph node involvement was found in 13% (57/427) at the time of surgery. Axillary lymph node involvement was much more common in HER-2 positive group (33% vs 11%, p < 0.0001) and triple negative (TN) group (24% vs 11%, p = 0.002) than in hormone receptor positive group. During median 61 months of follow-up, overall 10 year estimated distant relapse-free survival (DRFS) and overall survival (OS) were 95% and 92%, respectively. Multivariate analysis was conducted in 370 (T1aN0, T1bN0) patients, who had no lymph node involvement. In Cox-regression model, HER-2 positivity and triple negativity were identified as independent prognostic factors to predict DRFS [Hazard ratio (HR) 8.8, p = 0.003 for HER-2 positive group; HR 5.1, p = 0.026 for TN group] and OS (HR 5.0, p = 0.067 for HER-2 positive group; HR 11.1, p = 0.017 for TN group) in T1bN0 tumors. Limiting to T1aN0 tumors, statistical significance was not maintained. Conclusions: Even though T1aN0 and T1bN0 tumors have been known to have a relative low risk of systemic failure, anti-HER-2 directed therapy for HER-2 positive group and new innovative adjuvant systemic treatment for TN group in patients with T1bN0 tumor should be considered. Prospective adjuvant trials should be warranted in these subgroups of patients. No significant financial relationships to disclose.
Preplanned first-step analysis of LET-LOB neoadjuvant study: A double-blind randomized phase IIb trial of letrozole (L) plus lapatinib (Lp) or placebo (P) in postmenopausal HER2-ve, HR+ve operable breast cancer
Authors: Frassoldati A. , Guarneri V. , Bottini A. , Cagossi K. , Cavanna L. , Bisagni G. , D'Amico R. , Piacentini F. , Oliva C. , Conte P. 
Published: August 2020

570 Background: In HR+ve BC, the simultaneous blockade of ER and HER-related pathways could prevent the hormone-resistance due to activation of EGFR-family signalling, as shows the high activity of the combination of letrozole and lapatinib in HR+ve/HER2+ve advanced BC. The LET-LOB trial evaluates the clinical and biological effects of the combined inhibitory strategy with letrozole + lapatinib in untreated ER+ve/HER2-ve BC patients suitable for hormonal neoadjuvant therapy. Methods: Postmenopausal women with stage II-IIIa, HR+ve/HER2-ve BC are randomized to L (2.5 mg/d) + Lp (1500 mg/d) or L + P, given continuously for 24 weeks before surgery. Primary end point is the clinical RR (with ultrasonography, US); secondary endpoints are the pathological RR, the safety, and HR/EGFR-related biomarker evaluation. According to the “two step Simon's design” of the study, at least 20 cORs (8 in L+P and 12 in L+Lp) must be observed in the first 43 patients; then, additional 48 patients will be recruited to demonstrate a 40% increase in cOR with L+Lp, assuming a cOR of 50% with L+P. Results: Since April 2007, 39/55 randomized patients completed the preoperative treatment. Median age was 68 yrs. At diagnosis, mean US tumor size was 3 cm. All patients were HER2-ve, and either ER+ve or PR+ve (both +ve: 76%). After 3 and 6 months of therapy, a 29% and 41% reduction from baseline mean US longest tumor diameter was observed. No change in mean LVEF has been reported at the 3- and 6-month evaluations. 5 episodes of G3 toxicity have occured (skin rash, 1; liver function parameters, 4). So far 31 women underwent surgery (conservative in 65 %). The efficacy results according to the first step Simon's analysis will be performed by the IDMC on march 2009, and will be presented at the meeting along with updated clinical and safety data. Conclusions: Preliminary blinded results suggest that the combination of L+Lp in ER+ve/HER2-ve operable BC is feasible, without early cardiac events or other severe toxicities, and associated with clear tumor downstaging. Biological correlative studies will clarify the relationship between the double inhibition strategy and the clinical response. Supported by GlaxoSmithKline. [Table: see text]
Anthracycline-based preoperative chemotherapy plus lapatinib and trastuzumab or both in HER2-positive breast cancer: Preliminary cardiac safety report of the CHER LOB trial
Authors: Guarneri V. , Frassoldati A. , Bottini A. , Cagossi K. , Cavanna L. , Ravaioli A. , Amadori D. , Giardina G. , Oliva C. , Conte P. 
Published: August 2020

573 Background: The combination of anthracyclines and anti-HER-2 agents is highly active in HER-2 positive breast cancer, but its use is limited by an enhanced risk of cardiac toxicity. We are running a randomized phase II trial of combined preoperative chemotherapy (CT) with anthracycline plus trastuzumab, lapatinib, or both in HER-2 positive stage II-IIIA breast cancer patients. Aims of the study are the percentage of pathological complete response (pCR = breast + axillary nodes) and cardiac safety. We report the updated cardiac safety and activity data following the IDMC recommendation to continue study accrual. Methods: CT consists of sequential paclitaxel (P) 80 mg/m2 weekly for 12 weeks followed by 4 courses of FE75C administered every 3 weeks. Arm A is CT + trastuzumab 2 mg/kg weekly; arm B is CT + lapatinib 1500 mg po daily; arm C is CT + trastuzumab 2 mg/kg weekly + lapatinib 1,000 mg po daily. Both trastuzumab and lapatinib are started concomitantly with the first P administration, and are administered throughout the duration of CT. Left ventricular ejection fraction (LVEF) is evaluated at baseline, before the start of FE75C, and at the completion of treatment. The planned sample size is 120 patients, and has been calculated according to the two steps Simon's design. Results: 53 out of the 120 planned patients have been randomized: 16 in arm A, 17 in arm B, and 20 in arm C. Median age is 48 years (range 27–66). The mean LVEF was 63% (range 54–77%) at baseline, 61% (50–78%) at the completion of weekly P + trastuzumab, lapatinib, or trastuzumab + lapatinib, and 60.3% (54–74%) at the completion of the whole treatment plan. Thirty patients underwent surgery: 19 patients (63%) received breast conserving surgery; 13 patients (43%) achieved a pCR. Conclusions Following the updated interim analysis, the combination of T, L or both with an anthracycline-containing regimen is feasible, with very interesting level of activity. The next planned analysis will be performed when 60 patients will be evaluable and will be presented at the Meeting. [Table: see text]
Improved clinical response from neoadjuvant taxane chemotherapy across breast cancer subtypes
Authors: Jenkins E. O. , Deal A. M. , Burrows E. , Drobish A. , Carey L. A. 
Published: August 2020

576 Background: Adjuvant trials suggest that taxane (T) after doxorubicin and cyclophosphamide (AC) has little benefit in hormone receptor positive (HR+) patients compared to hormone receptor negative (HR-) patients, particularly if HER2 negative. Primary chemotherapy sensitivity is best determined from the neoadjuvant setting, therefore we sought to determine if HR+ primary tumors are less sensitive to taxane chemotherapy than HR- tumors. Methods: Clinical stage II-III breast cancer patients from the UNC Neoadjuvant Database who received sequential AC and T chemotherapy were evaluated. Clinical and radiographic responses were determined after AC and again after T allowing intrapatient sensitivity comparison, and included RECIST-defined complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Hormone receptor status was determined at diagnosis, and subtypes included ER or PR positive, HER2 negative (HR+), ER and PR negative, HER2 positive (HER2+/ER-), and ER, PR and HER2 negative (TN). The ER or PR+, HER2+ group was too small for analysis. Patients who received neoadjuvant trastuzumab were excluded. Relationships of subtype and clinical response to AC and to T were assessed using Fisher's exact test. Results: 157 patients received neoadjuvant AC sequentially followed by T and were eligible for analysis. The majority of TN patients had PR to AC (56%), while the majority of HR+ patients had SD (54%). Of those with measurable disease after AC (n=127), a higher proportion of TN and HER2+/ER- patients had CR to T (43% and 45%, respectively) than HR+ patients (13%, p = 0.008 and p = 0.0393, respectively). While the majority of HR+ patients again had SD (52%), 42% responded to T. Conclusions: Our data suggests that TN and HER2+/ER- patients benefit more from neoadjuvant taxane chemotherapy than HR+ patients, however HR+ patients clearly derived benefit from T administered after AC. [Table: see text] No significant financial relationships to disclose.
Prognostic significance of PI3K mRNA expression in patients with operable high-risk breast cancer
Authors: Papaxoinis G. , Pectasides D. , Wirtz R. M. , Kotoula V. , Papadimitriou C. , Gogas H. , Aravantinos G. , Skarlos D. , Kalogeras K. T. , Fountzilas G. 
Published: August 2020

577 Background: The aim of the study was to examine the prognostic and predictive significance of PI3K, AKT-1, mTOR, and PTEN mRNA expression and PIK3CA mutations in patients with operable high-risk breast cancer. Methods: Formalin-fixed paraffin-embedded tumor tissue blocks were available from 279 out of 595 operable high-risk breast cancer patients enrolled in a phase III clinical trial of E-T-CMF vs E-CMF. Updated clinical data were retrospectively used in the present translational research study. RNA was isolated followed by kinetic one-step quantitative RT-PCR for assessment of the expression of PI3K, AKT-1, mTOR, and PTEN. Mutations (E542K, E545K and H1047R) in the helical (exon 9) and the kinase (exon 20) domains of the PIK3CA gene encoding the catalytic p110 subunit of PI3K were investigated with custom Taqman SNP genotyping assays in 223 tumor DNA samples from the patient population enrolled in this study. Results: The two groups were well balanced concerning their basic characteristics except for grade (p = 0.015). The vast majority of hormone receptor positive patients (92%) received tamoxifen for 5 years, with LHRH analogs for premenopausal patients. The distribution of AKT-1 values was bimodal and therefore the 25th percentile was a natural cut-off. The median was used as a cut-off for all other genes. Mutations of the PIK3CA gene were detected in 51 patients (23%) (E542K in 8, E545K in 17 and H1047R in 26 patients). After a median follow-up time of 97 months, 93 patients (33%) had relapsed and 65 (23%) had died. High PI3K mRNA expression was associated with significantly shorter DFS (p = 0.044), irrespectively of the treatment arm. Multivariate analysis showed that high PI3K mRNA expression was an adverse prognostic factor for OS (HR = 2.14, 95% CI = 1.16–3.94, p = 0.015) and DFS (HR = 1.71, 95% CI = 1.09–2.68, p = 0.02), while PIK3CA mutations negatively affected OS (HR = 2.05, 95% CI = 1.07–3.95, p = 0.031). None of the other genes assessed was found to be of prognostic significance. Conclusions: High PI3K mRNA expression and PIK3CA mutations appear to be of adverse prognostic significance in patients with high-risk operable breast cancer. No significant financial relationships to disclose.
Association between HER2/neu overexpression and calcifications in breast cancer
Authors: Christy C. J. , Rishi M. , Schwartz J. , Grube B. J. , Bossuyt V. , Philpotts L. , DiGiovanna M. P. , Tavassoli F. , Lannin D. R. 
Published: August 2020

579 Background: HER-2/neu overexpression is an important parameter that influences prognosis and treatment for breast cancer. The purpose of this study is to explore the relationship between HER-2/neu overexpression and calcifications identified by either mammographic imaging or histologic examination. Methods: A retrospective review of the prospectively collected database was performed to evaluate the mammographic and histologic characteristics of all cases of invasive breast cancers diagnosed between 2003 and 2008. HER-2/neu positivity was defined as either overexpression by FISH analysis or 3+ staining on immunohistochemistry. Results: Of 502 invasive cancers, 165 (33%) had calcifications on mammography and 337 (67%) did not. HER-2/neu positivity was found in 63 (38%) of the calcification cases and 40 (12%) of the non-calcified cases (p < 0.001). This association persisted across all age groups and races and was independent of tumor size, nodal status, or hormone receptor status. Calcifications seen histologically also correlated with HER-2/neu overexpression, but the relationship was more complex. Among 155 cases with histologic calcifications seen within a ductal intraepithelial neoplasia (DIN) component, there were 45 (29%) that were HER-2/neu positive, compared with 67/414 (16%) that did not have calcifications within DIN (p < 0.001). If the calcifications were only within invasive tumor, the rate of HER-2/neu overexpression was less, 9/63 (14%). Univariate analysis demonstrated that tumor grade, necrosis, lymphovascular invasion and hormone receptor negativity were significantly associated with HER-2/neu overexpression (all p < 0.01). Multivariate logistic regression showed only the following factors to be significantly associated with HER-2/neu overexpression: grade of invasive tumor, presence of necrosis, progesterone receptor negativity in either the invasive or the in situ component, and mammographic calcifications. Conclusions: Recognition of the strong association between HER-2/neu overexpression and mammographic calcifications may have clinical usefulness and could lead to a better understanding of the underlying tumor biology of this important tumor marker. [Table: see text]
Cardiac effects when using trial-derived monitoring protocols for adjuvant trastuzumab: Results from a retrospective multicenter UK audit
Authors: Canney P. , Linsday C. , Wardley A. , Jones A. , Verril M. , Todd R. , Barrett-Lee P. , Keni M. , Robb S. , Plummer C. 
Published: August 2020

582 Background: Guidelines for cardiac scanning in adjuvant Trastuzumab (T) trials were developed due to clinical concerns regarding cardiotoxicity, and these same guidelines are now used in clinical practice. This was a retrospective audit to assess adherence to these guidelines and characterise the nature and timescale of problems experienced with adjuvant T in clinical practice. Methods: A retrospective review of MUGA/ECHO results was conducted in patients who received adjuvant T for breast cancer. Data was compiled from five UK cancer centres: Glasgow, Manchester, Cardiff, The Royal Free hospital and Newcastle. Results: A total of 424 patients received at least one dose of adjuvant T between September 2005 and January 2008, using a HERA trial schedule. There were 262 with detailed information regarding treatment delays/withdrawals for cardiac reasons. 12% (32/262 pts) were withdrawn from adjuvant trastuzumab treatment for cardiac reasons, with another 11% (29/262 pts) experiencing at least 1 delay in treatment. Analysis of cardiac scan results for the remaining 162 pts suggested a total cardiac delay/withdrawal percentage of 14.4% (61/424 pts). There was no age effect with 15% (50/338) of <65 year olds experiencing cardiac delays/withdrawals compared to 18% (9/50) of ≥65 year olds. Preherceptin cardiac scan results did appear to be predictive of subsequent problems, with 29% (38/132 pts) who had an ejection fraction (EF) of 40–59% experiencing cardiac delays/withdrawals compared to 10% (19/183 pts) with an EF of 60–69% and 4% (4/98 pts) with an EF ≥ 70%. Pretreatment with Doxorubicin was associated with an approximate doubling of cardiac problems (6/20 pts; 30%) compared to pretreatment with Epirubicin containing chemotherapy regimens. No temporal relationship existed between timing of cardiac delays/withdrawals and stage of T treatment. Conclusions: Significant numbers of patients are experiencing delays/withdrawals during adjuvant T treatment. In routine practice the withdrawal rates are more than twice those reported in the HERA trial population. There is a clear role for a re-assessment of the trial-derived cardiac management guidelines, which should be prospectively audited. [Table: see text]
Adding cisplatin to an anthracycline-based primary chemotherapy in triple-negative (TN) and non-triple negative (non-TN) T4 breast cancer patients (pts): Long-term outcomes
Authors: Ionta M. , Atzori F. , Murgia M. , Frau B. , Barca M. , Coinu A. , Trogu A. , Eltrudis F. , Minerba L. , Massidda B. 
Published: August 2020

583 Background: Clinical data demonstrated that standard anthracycline-based chemotherapy may be less beneficial in TN. Conversely, there is extensive preclinical work showing that TN tumors are highly sensitive to platinum agents. Only a few studies compared cisplatin vs non-cisplatin containing regimens among TN or non-TN homogeneous populations. The aim of this study was to evaluate the efficacy in terms of long-term outcomes of adding cisplatin to an anthracycline-based neoadjuvant regimen (cisplatin, C) compared with a standard anthracycline-based (Non-C) regimen in T4 breast cancer according to TN or non-TN status. Methods: We retrospectively analyzed 125 consecutive T4 breast cancer pts available for ER/PR and HER2 status; 98 pts (80%) were non-TN, of whom 63 treated with Non-C and 35 treated with C regimen; 27 pts (20%) were TN, of whom 10 treated with Non-C and 17 treated with C regimen. All pts received CMF, RT and hormone-therapy if indicated as adjuvant setting. None of the HER2 positive pts received peri-operative trastuzumab. Results: At a median follow-up of 101 months (8–217), estimated 10-year DFS and OS in TN pts treated with C were 47% and 59% versus 10% and 30% in pts treated with Non-C. In non-TN pts DFS and OS were 57% and 70% in pts treated with C versus 37% and 49% in pts treated with Non-C. Conclusions: Our data suggest that both TN and non-TN pts derive a better outcomes from the add of cisplatin over a standard anthracycline-based regimen. Of note, the magnitude of the benefit of cisplatin appears greater in the TN group. In order to validate these findings large prospective randomized trials are warranted. [Table: see text] No significant financial relationships to disclose.