Chemotherapy For Early Breast Cancer Research Articles

F08 - Dose-dence adjuvant chemotherapy in early breast cancer: the results of 15 years of follow-up

F08 - Dose-dence adjuvant chemotherapy in early breast cancer: the results of 15 years of follow-up

Rates of major complications during neoadjuvant and adjuvant chemotherapy for early breast cancer: An off study population

ObjectivesTo determine the incidence and risk factors for thromboembolic events (TE) and febrile neutropenia (FN) in patients receiving systemic chemotherapy for early breast cancer (EBC). Methods325 patients received FEC75, FEC100-T or ECaP for EBC in 2013. ResultsTE occurred in 7.4% and FN in 19.1% of patients. Risk factors for TE were: central venous catheter (p = 0.011). Risk factors for FN were: FEC100-T treatment versus FEC75 and ECaP (p ≤ 0.001); lower pre-treatment neutrophil count (p = 0.009) and poorer performance status (p = 0.012). Two patients died from treatment-related toxicities. ConclusionIn real-world experience, the majority of patients completed adequate treatment, despite significant complications.

Abstract 1437: Relationship of G-CSF related bone pain (BP) with Bv8/PK2 expression in breast cancer (BC) patients (pts) treated with FEC100 adjuvant chemotherapy (CT)

Abstract The Bv8/Prokineticins (PKs) are a new family of peptides identified in frog, fish, reptiles and mammals that signal through two highly homologous G-protein coupled receptors, PKR1 and PKR2. Over the past few years, several biological functions of Bv8/PK proteins have been elucidated. The high expression level of human Bv8/PK2 in bone marrow, lymphoid organs and leukocytes suggested an involvement of these peptides in hematopoiesis and in inflammatory and immunomodulatory processes. Neutrophils are the main endogenous source of Bv8/PK2, while G-CSF is the the only cytokine able to activate PK2 expression in neutrophiles. Moreover G-CSF derived pain seems to be stronlgly related to blood levels of Bv8/PK. According to these results, we started a clinical experimental trial in order to explore role and expression of Bv8/PK proteins in patients treated with chemotherapy for early breast cancer and receiving G-CSF (filgrastim vs peg-filgrastim), investigating also the relationship with G-CSF related pain. Methods: 20 BC pts were submitted to adjuvant FEC100. G-CSF was given as primary prophylaxis. 12 pts received Lenograstim (L: 5 doses, beginning 96 hours after CT) while 8 pts received Pegfilgrastim (P: 1 dose 24 hours after CT). Real-Time PCR and Elisa test were used to analyze Bv8/PK2 expression both in pts receiving L and P. Blood samples for Bv8/PK2 analysis were taken in different steps and days, in order to evaluate Bv8/PK2 expression according to CT time and G-CSF administration. Incidence of neutropenia (N), febrile-N and BP (NRS) were evaluated in all CT cycles. 6 healthy women were recruited as controls to evaluate their Bv8/PK2 basal level. Results: An impressive increase of Bv8/PK2 expression was observed both in L and P group. N occurred in 41.6% of pts treated with L (G3: 8.3%; G4: 16.7%) and in 75% of pts with P (G3: 12.5%; G4: 62.5%; 1 FN). In pts receiving L an incidence of BP occurred in 59.3% (NRS 7-8: 41%) with a mean duration of 6 days; in P group incidence was 37.5% (NRS 7-8: 37.5%), BP lasting 4 days. In all pts BP started within 24-48 hours after G-CSF administration, concurrently with Bv8/PK2 overexpression. Conclusions: Our preliminary results suggest an emerging role of Bv8/prokineticin system in occurrence of G-CSF related BP in primary prevention of CT induced N. Therefore, inhibition of Bv8/PK2 activity should constitute a promising therapeutic strategy to prevent inflammatory pain and perhaps other cancer characteristics. Citation Format: Luigi Rossi, Anselmo Papa, Federica Tomao, Lucia Negri, Silverio Tomao. Relationship of G-CSF related bone pain (BP) with Bv8/PK2 expression in breast cancer (BC) patients (pts) treated with FEC100 adjuvant chemotherapy (CT). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1437.

Zoledronate for patients with invasive residual disease after anthracyclines-taxane-based chemotherapy for early breast cancer – The Phase III NeoAdjuvant Trial Add-oN (NaTaN) study (GBG 36/ABCSG 29)

BackgroundPatients with invasive residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemo-resistant breast cancer. Bisphosphonates are an established treatment for bone metastases and are of potential benefit as adjuvant treatment in early breast cancer. Patients and methodsPatients who had invasive tumour residuals (ypT1-4 and/or ypN+) after a minimum of four cycles of anthracycline-taxane-containing NACT were eligible for the NeoAdjuvant Trial Add-oN study. Patients were randomised within 3 years after surgery to receive zoledronate 4 mg i.v. for 5 years versus observation. Zoledronate was given every 4 weeks for the first 6 months, every 3 months for the following 2 years, and every 6 months for the last 2.5 years. Primary objective was disease-free survival. ResultsAfter a median time of 54.7 months no difference in disease-free survival was observed between the zoledronate and observation groups (hazard ratio [HR] 0.960, 95% confidence interval [CI] 0.709–1.30, log rank P=0.789). Various subgroups were examined without identifying a treatment effect of zoledronate. Patients over 55 years of age showed a HR of 0.832 in favour of zoledronate, but the result was not significant (P=0.480). A similar result was obtained for overall survival with a HR of 1.19 (95% CI 0.79–1.79; log rank P=0.408). Zoledronate was well tolerated and no new toxicity signal was identified. ConclusionPostneoadjuvant treatment with zoledronate does not improve outcome in patients without pathological complete response after neoadjuvant anthracycline-taxane-based chemotherapy for early breast cancer.

Audit on use of Oncotype DX to guide multidisciplinary team regarding chemotherapy in early breast cancer

Background: Oncotype DX assay can help a breast multidisciplinary team (MDT) decide if patients with early breast cancer will benefit from chemotherapy. The test costs around £2,500. National Institute for Health and Care Excellence (NICE) has issued guidance for use of Oncotype DX as an option to help MDTs decide whether to offer chemotherapy to patients. On average six chemotherapy sessions are needed for breast cancer (£4,000 per session). In our department this test is only offered to early breast cancer patients and our aim was to assess how it guided our MDT regarding chemotherapy.

High Proliferation Predicts Pathological Complete Response to Neoadjuvant Chemotherapy in Early Breast Cancer.

The Oncologist 2016;21: 150–155; first published on January 19, 2016; http://dx.doi:10.1634/theoncologist.2015-0312 The online version of this article has been amended to correct errors that appear in Table 1 on page 152. A row was added to the “Treatment” section to provide missing MDH treatment data. In the “Histologic grade” section, the percentage noted for “GX” in the “pCR = no” column was incorrect; the correct percentage is 73.3. An errant comma in the “G3” heading was removed. For clarity, the heading of the last row of the table was changed to read “Ki67, median (range), %”.

Febrile Neutropenia Rates According to Body Mass Index and Dose Capping in Women Receiving Chemotherapy for Early Breast Cancer

AimsStudies suggest worse outcomes in obese women with breast cancer than in non-obese women. One potential reason may be that oncologists ‘dose cap’ adjuvant chemotherapy in obese patients in order to avoid excessive toxicity. Reductions from standard dosing may compromise survival outcomes in the curative setting. Here we describe the body mass index (BMI) distribution of patients in a non-trial population, the frequency with which oncologists dose cap and its effect on febrile neutropenia chemotherapy toxicity. Materials and methodsIn this non-randomised study, electronic patient records retrospectively identified patients with early breast cancer who initiated neoadjuvant or adjuvant chemotherapy at the Royal Marsden Hospital between 1 January and 31 December 2013. Baseline data included age, BMI, performance status, tumour characteristics, granulocyte colony-stimulating factor and comorbidities. Chemotherapy doses, rates of dose capping across BMI groups and rates of febrile neutropenia were reported. ResultsIn total, 325 patients were eligible: 79 (24.5%) were obese (BMI ≥ 30), 109 (33.5%) were overweight (BMI ≥25 – <30) and 137 (42%) were normal bodyweight (BMI < 25). Sixteen patients (20.5%) in the obese group received dose-capped chemotherapy. Overall, 62 patients (19%) had an episode of febrile neutropenia. Obese patients receiving uncapped chemotherapy did not experience a significant difference in febrile neutropenia rates when compared with overweight or normal bodyweight groups (P = 0.5798). The febrile neutropenia rate in obese patients receiving capped chemotherapy was 6.5%, compared with 24% in obese patients receiving uncapped chemotherapy (P = 0.1216). ConclusionIn a non-trial population of obese patients, dose capping is frequently used. Obese patients receiving uncapped chemotherapy do not experience increased febrile neutropenia rates when compared with uncapped overweight or normal bodyweight patients. Furthermore, dose capping was associated with a trend towards lower rates of febrile neutropenia than in other groups and may indicate relative under-dosing of chemotherapy. This supports international guidelines that state that obese patients should not be dose capped.

Abstract P2-02-16: The proliferation index of circulating tumor cells (CTCs) is not influenced by the administration of adjuvant chemotherapy in early breast cancer (BC) and seems to reflect Ki67 expression of the primary tumor

Abstract Background: The assessment of Ki67 in the primary tumor represents a prognostic marker with potential predictive implications in early BC. We evaluated Ki67 expression in CTCs from patients with early BC and assessed the effect of adjuvant chemotherapy as well as Ki67 expression in the primary tumor. Methods: Ki67 was evaluated in CTCs of 97 patients with early BC pre- and post- adjuvant chemotherapy by the use of immunofluorescence analysis. Cytospins of peripheral blood mononuclear cells were double stained with A45-B/B3 cytokeratin mouse antibody and a Ki67 rabbit antibody. Ki67 staining of the primary tumor was also performed for 13 CTC-positive patients. A proliferation index (PI) in CTCs was considered as the ratio of Ki67-positive CTCs/total CTCs. A PI of up to 14% was defined as 'low' whereas a PI above 14% was defined as 'high'. Results: CTCs were detected in 26 (26.8%) patients before and/or after chemotherapy. Seven (27%) of 26 CTC-positive and 8 (11%) of 74 CTC-negative patients relapsed (p = 0.047). Ki67-positive CTCs were identified in 20 (76.9%) of 26 patients, whereas in 1 (3.9%) and 5 (19.2%) patients, exclusively Ki67-positive and Ki67-negative CTCs, respectively, were detected. Seven (33%) of 21 Ki67-positive patients relapsed in contrast to none among the exclusively Ki67-negative patients (p = 0.13). A total of 154 and 161 CTCs were detected pre- and post-chemotherapy, respectively; the PI in CTCs was 56% and 55%, respectively. In 8 patients with detectable CTCs at both time points, the PI was 65% and 49% pre- and post-chemotherapy, respectively. In 5 (62.5%) out of 8 patients, the PI remained high, in 2 (25%) increased and in 1 patient no Ki67–positive CTCs were detected post-chemotherapy. Seventeen patients were CTC-positive at baseline [HER2 positive, n=5; triple negative, n=1; hormone receptor positive, n=11]. A concordance in Ki67 staining between the primary tumor and CTCs was recorded in 10 (77%) out of 13 patients. Moreover, in 2 (67%) of 3 patients with exclusively Ki67-negative CTCs, low Ki67 expression was also observed in the primary tumor. Interestingly, 2 out of 5 patients with HER2 positive primary relapsed and both had high PI in their CTCs, whereas 2 out the 3 HER2 positive patients that did not relapse had low CTC proliferation index. Similarly, the triple negative patient had low PI in her CTCs and has not relapsed after 4 years of follow up. Conclusions: Adjuvant chemotherapy fails to decrease the proliferation index in CTCs. Ki67 expression in CTCs seems to reflect Ki67 expression in the primary tumor and could be predictive of patient outcome. Citation Format: Agelaki S, Spiliotaki M, Spanaki A, Kassiou L, Tzardi M, Koinis F, Kafousi M, Georgoulias V, Mavroudis D. The proliferation index of circulating tumor cells (CTCs) is not influenced by the administration of adjuvant chemotherapy in early breast cancer (BC) and seems to reflect Ki67 expression of the primary tumor. [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 P2-02-16.

Abstract P3-07-62: Association of overexpression of hypoxia inducible factor 1α with response to neoadjuvant chemotherapy in early stage breast cancer

Abstract Background: Hypoxia inducible factor 1 alpha (HIF-1α) is a master transcription factor involved in multiple oncogenic processes. In breast cancer, HIF-1α overexpression is associated with increased resistance to radiation therapy, chemotherapy, and inferior disease-free and overall survival. Patients who achieve a pathologic complete response (pCR) following neoadjuvant therapy have improved survival outcomes. Limited data are available regarding the association between HIF-1α expression and rates of pCR. We investigated the relationship between HIF-1α overexpression and pCR rates following neoadjuvant chemotherapy for early breast cancer. Methods: Eligible women were those with HER2-negative, stage II-III breast cancer, who received anthracycline- and taxane-based neoadjuvant chemotherapy from 2002 to 2012, and were included in an institutional review board-approved Integrated Breast Cancer Research Database at Johns Hopkins. The database includes patient age, sex, menopausal status, breast cancer diagnosis, tumor histopathology, treatment history, laboratory data, and outcomes. Both diagnostic and surgical tissue blocks were retrieved from pathology archives. Whole section slides were prepared and analyzed by immunohistochemical staining with appropriate negative and positive controls. The intensity of cells positive for HIF-1α was estimated visually by a pathologist blinded to clinical data. A semi-quantitative scoring of nucleus expression was used to score HIF-1α expression: score 0 is defined as less than 1%, 1 is defined as 1-5%, 2 as 5-20% and 3 as &amp;gt;20% tumor cells positive for HIF-1α. Overall tumor HIF-1α negativity was defined as (0, 1) and positivity as (2, 3). We compared baseline HIF-1α status among responders (pCR defined as no invasive tumor in the breast or lymph nodes) and non-responders (no pCR) using Fisher's exact test, and evaluate the association between baseline and surgical specimens in those who did not achieve pCR using NcNemar's test. Results: A total of 122 women meeting the eligibility criteria underwent a definitive surgical procedure following neoadjuvant chemotherapy. Of those, 50 patients had no tissue blocks available at baseline and additional 16 patients' blocks did not contain sufficient tissue for analysis. Thus, tumors from 56 women were available for analysis. Median age was 50 (range 33-78), 54% were White and 35% Black; 41% and 59% of women had triple negative and hormone receptor-positive tumors, respectively; 71% women had Ki67&amp;gt;30%, and 80% were node-positive. Overall pCR was observed in 12 women (21%). We did not detect a significant association between HIF-1α score on the diagnostic specimen with pCR status (p=0.627). However, a positive HIF-1α score was significantly associated with positive lymph nodes (p=0.01). We observed a significant decrease in HIF-1α score following chemotherapy (p&amp;lt;0.001). Conclusions: We did not observe a clear association between HIF-1α expression and response to neoadjuvant chemotherapy. However, HIF-1α expression on a diagnostic specimen was statistically higher than following chemotherapy and was associated with lymph node positivity. Our study is limited by its retrospective nature and a small sample size. Citation Format: Zhi WI, Huang C-Y, Gabrielson E, Tully E, Cimino-Mathews A, Santa-Maria C, Jeter S, Kai C, Semenza G, Stearns V. Association of overexpression of hypoxia inducible factor 1α with response to neoadjuvant chemotherapy in early stage breast cancer. [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 P3-07-62.

Neoadjuvant De-Escalation/No Systemic Chemotherapy in Early Breast Cancer with 12-Week T-DM1

Neoadjuvant De-Escalation/No Systemic Chemotherapy in Early Breast Cancer with 12-Week T-DM1

High Proliferation Predicts Pathological Complete Response to Neoadjuvant Chemotherapy in Early Breast Cancer.

In the neoadjuvant setting, changes in the proliferation marker Ki67 are associated with primary endocrine treatment efficacy, but its value as a predictor of response to chemotherapy is still controversial. We analyzed 262 patients with centralized basal Ki67 immunohistochemical evaluation derived from 4 GEICAM (Spanish Breast Cancer Group) clinical trials of neoadjuvant chemotherapy for breast cancer. The objective was to identify the optimal threshold for Ki67 using the receiver-operating characteristic curve method to maximize its predictive value for chemotherapy benefit. We also evaluated the predictive role of the defined Ki67 cutoffs for molecular subtypes defined by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). A basal Ki67 cutpoint of 50% predicted pathological complete response (pCR). Patients with Ki67 >50% achieved a pCR rate of 40% (36 of 91) versus a pCR rate of 19% in patients with Ki67 ≤ 50% (33 of 171) (p = .0004). Ki67 predictive value was especially relevant in ER-HER2- and ER-HER2+ patients (pCR rates of 42% and 64%, respectively, in patients with Ki67 >50% versus 15% and 45%, respectively, in patients with Ki67 ≤ 50%; p = .0337 and .3238, respectively). Both multivariate analyses confirmed the independent predictive value of the Ki67 cutpoint of 50%. Basal Ki67 proliferation index >50% should be considered an independent predictive factor for pCR reached after neoadjuvant chemotherapy, suggesting that cell proliferation is a phenomenon closely related to chemosensitivity. These findings could help to identify a group of patients with a potentially favorable long-term prognosis. The use of basal Ki67 status as a predictive factor of chemotherapy benefit could facilitate the identification of a patient subpopulation with high probability of achieving pathological complete response when treated with primary chemotherapy, and thus with a potentially favorable long-term prognosis.

Port catheter versus peripherally inserted central catheter for postoperative chemotherapy in early breast cancer: a retrospective analysis of 448 patients.

We aimed to compare the complication rate between port catheters (PC) and peripherally inserted central catheters (PICC) for the administration of postoperative chemotherapy for breast cancer. All patients treated from January 2010 to August 2012 at the Centre Henri Becquerel for early breast cancer requiring postoperative chemotherapy were retrospectively screened. The primary endpoint was the occurrence of a major complication related to the central venous catheter. Major complications were defined as any grade 3 event according to CTCAE 4.0, delay in chemotherapy >7 days, change of the device, life-threatening event, event requiring a hospitalization, or a prolongation of hospitalization. A total of 448 patients were included; 290 had a PC and 158 a PICC. Overall, 31 major complications related to the central venous catheter were observed: 13 for patients with a PC (4.5%) and 18 for patients with a PICC (11.4%). In univariate analysis, having a PICC was the only factor significantly associated with a higher risk of major complications (HR = 2.83, p = 0.0027). We observed a trend for a higher risk of major complications for patients older than 60 years or with BMI >25 (p = 0.06). In multivariate analysis, having a PICC was the only predictive factor of major complications (HR = 2.89, p = 0.004). In univariate and multivariate analysis, having a PICC instead of a PC was the only predictive factor of device-related major complication. If confirmed prospectively by the NCT02095743 ongoing trial, this result might modify the management of adjuvant chemotherapy administration.

Time to initiation of adjuvant chemotherapy in patients with rapidly proliferating early breast cancer

AimTo evaluate the optimal time interval from definitive surgery to commencing chemotherapy in early breast cancer (EBC). Patients and methodsThe relationship between time to initiation of adjuvant chemotherapy (TTC), calculated in weeks, and disease-free (DFS) or overall survival (OS), was assessed in 921 EBC patients with rapidly proliferating tumours (thymidine labelling index >3% or G3 or Ki67 >20%), randomised in a phase III clinical trial (NCT01031030) to receive chemotherapy with or without anthracyclines (epirubicin→cyclophosphamide, methotrexate and fluorouracil (CMF) versus CMF→epirubicin versus CMF). DFS, OS and 95% confidence intervals (95% confidence interval (CI)) were calculated by the Kaplan–Meier method. Multivariate Cox analysis was performed in relation with nodal involvement, oestrogen receptor and human epidermal growth factor receptor 2 (HER2) status, Ki67 value, type of adjuvant chemotherapy, menopausal status and tumour size. ResultsAt a median follow-up of 105months (range 2–188), a prolonged TTC resulted in a significant increase in the risk of relapse: hazard ratio (HR) 1.15 (95% CI 1.02–1.30, p=0.019). Using a backward elimination procedure, TTC, tumour size and nodal involvement remained significantly associated with DFS. A time-dependent receiver-operating characteristic (ROC) curve analysis was subsequently utilised to evaluate the best cut-off for TTC, identifying 7weeks as the best threshold for longer OS (p=0.043): 8-year OS 88% (95% CI 85–90) for patients with a TTC <7weeks and 78% (95% CI 68–87) for the other group. ConclusionsOur results confirm that a shorter TTC may reduce relapses and possibly also improve clinical outcome in patients with highly proliferating EBC.

Abstract P5-21-05: ERALOP study: Post adjuvant FEC - docetaxel chemotherapy for early breast cancer: Hair regrowth in the real life

Abstract Background : during 2008 we have collected one hundred observations of persistent significant alopecia (PSA). FEC 100-docetaxel 100 mg/msq regimen was mostly concerned. We therefore decided to evaluate exact incidence of this relevant side effect through women points of view. Methods : ERALOP is a retrospective study using a self-questionnaire targeting patients (pts) treated with this sequential regimen from 2008 to 2009. The primary objective was to estimate the incidence of a PSA at 6 months after last course of docetaxel with CTCAE 4.0 classification : grade 1 : hair loss of up to 50% not obvious from a distance, a different hair style may be required to cover the hair loss, grade 2 : hair loss &amp;gt; 50% with a psychosocial impact. The sample size calculation of 635 patients took into account : PSA incidence of 3.2% (TAC regimen), precision of 0.015, α risk at 0.05, 20% patients lost for follow up. ERALOP study was approved by local ethic comitee. Results: from July 2012 to October 2012, 829 pts received a self-questionnaire. 176 pts (21%) did not answer and were considered as without PSA. 653 (79%) answers with medical data fully documented were collected. Median age of patients was 56 years. Six months after last docetaxel course, PSA incidence grade 2 : 8.6% (71 pts), grade 1 : 32.6% (271 pts), grade 0 : 56% (466 pts), NA : 2.5% (21 pts). 73% of pts with PSA received hormonotherapy. At the time of the inquiry (median follow up of 3.7 years), PSA incidence grade 2 was 3.5% (29 pts), grade 1 : 30% (248 pts), grade 0 : 63,8% (529 pts), for a global PSA incidence of 33.4%. Between 6 months after last course of docetaxel and time of the inquiry, it appears slight or total regrowth for 40 pts with PSA grade 2 and 187 with PSA grade 1.Three pts still wore a wig, and many pts had suboptimal regrowth of eyelash (31%), eyebrow (47%), pubic hair (27%), and nail disorders (27%). A multivariate analysis was performed to look for PSA risk factors. All the oral treatments, including dexpanthenol, biotin, methionine cysteine and cystin-vitamin B6 proved to have no efficacy. Treatment by topical minoxidil could have a little efficacy. Impairment of health-related quality of life will be assesed by Dermatology Life Quality Index (DLQI) and alopecia grade will be evaluated at the end of hormonotherapy. Conclusions: Physicians and patients should be aware of this new distressing side-effect. This high level of PSA lead us to conduct ALOPREV trial to investigate, in spite of FEC induced alopecia, the properties of cooling cap prevention trial during docetaxel infusion. Preliminary results are encouraging and this option could be considered. Citation Format: Hugues Pierre Bourgeois, Aurélie Jamet, Françoise Grudé, Carole Adounkpe, Pierre Kerbrat, Remy Delva, Hélène Simon, Philippe Deguiral, Bertrand Diquet, Pascale Lainé, Anne-Lise Septans. ERALOP study: Post adjuvant FEC - docetaxel chemotherapy for early breast cancer: Hair regrowth in the real life [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 P5-21-05.

Abstract P3-09-04: AML and MDS after adjuvant chemotherapy: A population based study among older breast cancer patients

Abstract Background: Adjuvant chemotherapy for early breast cancer is associated with a small risk of developing MDS and AML. The aim of this study is to determine the risk of developing AML or MDS after modern adjuvant chemotherapy in older breast cancer patients and to further define the risk of individual chemotherapy regimens. Methods: Patients diagnosed with stage I-III breast cancer from 2003 to 2009 were identified in the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database. Development of AML or MDS, chemotherapy use, and comorbidities were identified using ICD-9 and HCPCS codes. A single inpatient or 2 outpatient codes 30 days apart were required for identification of AML or MDS. Analyses included descriptive statistics, Kaplan-Meier method for 5-year AML/MDS rates and Cox proportional hazards models to estimate the hazard of AML and MDS after adjusting for clinically relevant covariates. Results: 68,702 patients were included, of them 166 (0.24%) developed AML and 385 (0.56%) developed MDS. The median time from breast cancer diagnosis to AML or MDS was 924 and 943 days respectively. The 5-year AML rates were 0.23% for the no chemotherapy group, 0.53% for anthracycline (A)-based regimens, 0.48% for anthracycline and taxane (AT)-based regimens, 0.39% for other (O) regimens and 0.09% for those who received docetaxel and cyclophosphamide (TC). 5-year MDS estimates were 0.62%, 1.07%, 0.72%, 1.08 and 0.38% respectively. In the multivariable model using no chemotherapy as the reference category, A (HR 3.03; 95%CI 1.75-5.24) and AT (HR 3.06; 95%CI 1.70-5.52) were the chemotherapy regimens associated with the highest risk for developing AML, followed by O (HR 2.05; 95%CI, 1.13-3.69). No significant increase in risk was observed in patients who received TC (HR 0.91; 95%CI 0.26-4.60). Similar results were observed when evaluating risk of MDS among patients treated with A (HR 2.25; 95%CI, 1.50-3.37), AT (HR 1.67; 95%CI 1.06-2.65), O (HR 2.30; 95%CI 1.61-3.29) and TC (HR 1.22; 95%CI 0.60-2.66). Conclusion: In this large cohort of patients we observed a small but significant increase in risk for AML and MDS with adjuvant chemotherapy. The highest risk was associated with A and AT-based chemotherapy. TC was the only regimen that was not significantly associated with an increased risk. Because of relative recent adoption of TC, longer follow-up is needed to better estimate the risk of MDS and AML in this group of patients. Citation Format: Aron S Rosenstock, Sharon H Giordano, Jiangong Niu, Hui Zhao, Antonio C Wolff, Thomas A Buchholz, Mariana Chavez-MacGregor. AML and MDS after adjuvant chemotherapy: A population based study among older breast cancer patients [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 P3-09-04.

Predicting Anthracycline Benefit: TOP2A and CEP17—Not Only but Also

Evidence supporting the clinical utility of predictive biomarkers of anthracycline activity is weak, with a recent meta-analysis failing to provide strong evidence for either HER2 or TOP2A. Having previously shown that duplication of chromosome 17 pericentromeric alpha satellite as measured with a centromere enumeration probe (CEP17) predicted sensitivity to anthracyclines, we report here an individual patient-level pooled analysis of data from five trials comparing anthracycline-based chemotherapy with CMF (cyclophosphamide, methotrexate, and fluorouracil) as adjuvant chemotherapy for early breast cancer. Fluorescent in situ hybridization for CEP17, HER2, and TOP2A was performed in three laboratories on samples from 3,846 of 4,864 eligible patients from five trials evaluating anthracycline-containing chemotherapy versus CMF. Methodologic differences did not affect HER2-to-CEP17 ratios but necessitated different definitions for CEP17 duplication: > 1.86 observed copies per cell for BR9601, NEAT, Belgian, and DBCG89D trials and > 2.25 for the MA.5 trial. Fluorescent in situ hybridization data were available in 89.3% (HER2), 83.9% (CEP17), and 80.6% (TOP2A) of 3,846 patient cases with available tissue. Both CEP17and TOP2A treatment-by-marker interactions remained significant in adjusted analyses for recurrence-free and overall survival, whereas HER2 did not. A combined CEP17 and TOP2A-adjusted model predicted anthracycline benefit across all five trials for both recurrence-free (hazard ratio, 0.64; 95% CI, 0.51 to 0.82; P = .001) and overall survival (hazard ratio, 0.66; 95% CI, 0.51 to 0.85; P = .005). This prospectively planned individual-patient pooled analysis of patient cases from five adjuvant trials confirms that patients whose tumors harbor either CEP17 duplication or TOP2A aberrations, but not HER2 amplification, benefit from adjuvant anthracycline chemotherapy.

P103 Subcutaneous trastuzumab plus chemotherapy for early breast cancer: interim safety from SafeHer

P103 Subcutaneous trastuzumab plus chemotherapy for early breast cancer: interim safety from SafeHer

Population-based assessment of emergency room visits and hospitalizations among women receiving adjuvant chemotherapy for early breast cancer.

Adjuvant chemotherapy is considered standard care for patients with lymph node (LN) -positive and high-risk LN-negative early breast cancer (EBC). Although chemotherapy-associated toxicities are documented in clinical trials, the impact of toxicities on emergency room (ER) visits and hospitalizations (ER + Hs) at a population level with contemporary chemotherapy is unknown. We undertook a population-based study of ER + Hs in patients with EBC receiving adjuvant chemotherapy compared with noncancer controls (NCCs). All patients diagnosed with EBC between January 2007 and December 2009 in Ontario, Canada, were identified from the Ontario Cancer Registry. Patient records were linked deterministically to provincial health care databases to provide comprehensive medical follow-up. All patients received ≥ one cycle of adjuvant chemotherapy. Patient cases of EBC (n = 8,359) were matched to NCCs (n = 8,359) on age, comorbidity, and geographic location. ER + Hs within 30 days of chemotherapy were identified. If the primary reason for the visit was a common chemotherapy toxicity, the visit was considered chemotherapy associated. All-cause and chemotherapy-associated visits were compared between patient cases and controls. Logistic regression models were used to identify covariates associated with ER + Hs. The proportion of patients with at least one ER + H was significantly higher in patients with EBC undergoing chemotherapy compared with NCCs (43.4% v 9.4%; P < .001). Patients with EBC were also more likely to have multiple ER + Hs (17.9% v 2.4%; P < .001). On multivariable analysis, comorbidity, receiving a regimen containing docetaxel, and certain geographic regions were associated with increased odds of ER + Hs. ER + Hs are common among patients with EBC receiving chemotherapy and significantly higher than among controls. This represents a potential opportunity for quality improvement.

263PD - Time to Initiation of Adjuvant Chemotherapy in Patients with Rapidly Proliferating Early Breast Cancer

ABSTRACT Introduction: The optimal time from surgery to commencing chemotherapy in early breast cancer (EBC) remains unclear. We assessed the influence of time to initiation of adjuvant chemotherapy (TTC) on the outcome of EBC patients enrolled onto a phase III clinical trial (NCT01031030). Methods: The relationship between TTC, calculated as the time (in weeks) from definitive surgery to initiation of adjuvant chemotherapy, and disease-free (DFS) or overall survival (OS) was assessed in 1066 EBC patients with rapidly proliferating tumors (thymidine labeling index > 3% or G3 or Ki67 > 20%), randomized to receive adjuvant chemotherapy with or without anthracyclines (epirubicin → CMF vs CMF → epirubicin vs CMF). DFS, OS and their 95% confidence intervals (95% CI) were calculated by the Kaplan-Meier method. Multivariate Cox analysis was performed in relation to nodal involvement, estrogen receptor and HER2 status, Ki67 value, type of adjuvant chemotherapy, menopausal status and tumor size. Results: Information on TTC was available for 713 women. At a median follow-up of 105 months (range 2-188), a prolonged TTC resulted in a significant increase of 16% in the risk of relapse (95% CI 1.03–1.30, p = 0.016) in a multivariable Cox regression model (Table 1). The impact on OS was not significant. Using a backward elimination procedure, TTC, tumor size and nodal involvement remained significantly associated with DFS (Hazard ratio [HR] = 1.15, 95% CI 1.02-1.29, p = 0.018; HR = 1.44, 95% CI 1.08-1.92, p = 0.012; HR = 1.44, 95% CI 1.08-1.92, p = 0.012, respectively). Again, nodal involvement and Ki67 were associated with OS (HR = 1.66, 95% CI 1.11-2.49, p = 0.014; HR = 1.63, 95% CI 1.03-2.59, p = 0.039, respectively). DFS OS HR (95% CI) p HR (95% CI) p TTC 1.16 (1.03–1.30) 0.016 1.14 (0.97–1.35) 0.121 Age 0.99 (0.97–1.02) 0.829 0.99 (0.96–1.03) 0.615 ER Positive 1.00 1.00 Negative 1.20 (0.89–1.61) 0.242 1.20 (0.78–1.84) 0.397 HER2 Positive 1.00 1.00 Negative 0.99 (0.73–1.33) 0.929 0.92 (0.60–1.42) 0.713 Lymph node status Negative 1.00 1.00 Positive 1.53 (1.14–2.04) 0.004 1.71 (1.13–2.59) 0.011 Menopausal status Premenopausal 1.00 1.00 Postmenopausal 1.32 (0.85–2.04) 0.219 1.56 (0.82–2.97) 0.177 Tumor size 1.00 1.00 ≥2 cm 1.41 (1.05–1.88) 0.020 1.44 (0.95–2.18) 0.085 Ki67 ≤20% 1.00 1.00 >20% 1.06 (0.77–1.44) 0.724 1.54 (0.96–2.48) 0.073 Treatment arm E»CMF 0.72 (0.49–1.04) 0.079 0.69 (0.41–1.16) 0.161 CMF»E 0.79 (0.55–1.14) 0.202 0.75 (0.45–1.25) 0.273 CMF 1.00 1.00 Conclusions: Our results suggest that patients with rapidly proliferating EBC should be treated as soon as possible once their recovery from surgery is complete. Disclosure: All authors have declared no conflicts of interest.

309P - Does Administration Order of Sequential Fec- Docetaxel As Adjuvant Chemotherapy for Breast Cancer Affect on the Toxicities? : a Retrospective Analysis from a Single-Center

ABSTRACT Aim: Anthracyclines and taxanes based regimens have been established as one of standard adjuvant chemotherapy for early breast cancer. For the high-risk patients, sequential rather than the concomitant use of both agents should be considered.Conventionally, Anthracyclines followed by taxanes (AT) are preferred. However, some recent trials reported that preceding taxanes had equivalent efficacy. Since each has different toxic profile, it is important to compare AT with TA in terms of toxicity and relative dose intensity (RDI). The purpose of this retrospective study was to assess the influence of administration order. Methods: We analyzed 88 patients with early breast cancer who were treated with each 4 cycles of FEC (5-fluorouracil, epirubicin and cyclophosphamide) and Doc (docetaxel) as adjuvant chemotherapy. Consecutive 46 and 42 patients received FEC → Doc (AT group) From January to December of 2012 and Doc → FEC (TA group) for the same period of 2013, respectively. The data was collected from medical records, and toxicities were evaluated by CTCAE criteria. Statistical analysis was performed using Fisher's exact test. Results: There was no significant bias in patients' characteristics between both groups. Although the hematological toxicities seen in FEC and Doc phase were equal in both group, schedule delay of FEC were found more frequent in TA (19.0%) than AT (8.6%) because of insufficient recovery of neutropenia (p Conclusions: The administration of Doc before FEC results in reduced HFS by Doc, but RDI of FEC tends to decrease because of altered hematological toxicity. Evaluation of the prospective study is desired. Disclosure: All authors have declared no conflicts of interest.