Dose-dense And Cyclophosphamide Research Articles

Real life comparison between doxorubicin and cyclophosphamide (AC) dose-dense (dd) and conventional dose AC in patients with triple negative breast cancer (TNBC) under neoadjuvant treatment.

e12662 Background: High-risk early triple-negative breast cancer (TNBC) is frequently associated with early recurrence and high mortality. Studies suggest a sustained clinical benefit in patients with TNBC who have a pathological complete response (PCR) after neoadjuvant chemotherapy (NACT). The dose-dense (dd) regimen demonstrated improved survival regardless of hormone receptor expression or HER2 status. The doxorubicin and cyclophosphamide (AC) regimen can be performed in (dd), therefore it must include granulocyte growth factors, which may increase costs and toxicities. The object of the study was to evaluate their clinical characteristics and treatment, patients with TNBC, stage I-III who received ACdd in neoadjuvant treatment versus patients who received AC dose conventional (dc). Methods: We performed a retrospective observational cohort study of patients with early TNBC, stage I-III who received neoadjuvant treatment with chemotherapy based on doxorubicin, cyclophosphamide, paclitaxel and carboplatin associated with pembrolizumab. Results: All 82 patients were women 57.3% received ACdd, 30.4% received AC dc. In group ACdd 59.5% had intercurrence related with chemotherapy, in which 17.8% were neutropenic fever and 21.4% had developed different types of infections (ex: diarrhea, pneumonia and others). In these 2 groups all of them had received antibiotic. About 50% of the patients had developed intercurrence because of treatment toxicity and just 3.5% had disease progression. The other group that we evaluated is composed by patients who ACdc, dose Regarding to these group 48% developed any intercurrence during the neoadjuvant treatment, in which 8.3% had neutropenic fever and 25% had different types of infections. All of them earned antibiotic. About clinical and pathological response, the group that earned ACdd 61.7% got complete clinical response and 8.5% had a disease progression during the treatment. In the other arm 68% got complete clinical response and 4% had a progression. Conclusions: AC dd was more prevalent in our series, despite the additional use of granulocyte growth factor, there were more complications in this group and it did not demonstrate better results than those who received conventional dose AC.

Local dose-dense chemotherapy for triple-negative breast cancer via minimally invasive implantation of 3D printed devices

Dose-dense chemotherapy is the preferred first-line therapy for triple-negative breast cancer (TNBC), a highly aggressive disease with a poor prognosis. This treatment uses the same drug doses as conventional chemotherapy but with shorter dosing intervals, allowing for promising clinical outcomes with intensive treatment. However, the frequent systemic administration used for this treatment results in systemic toxicity and low patient compliance, limiting therapeutic efficacy and clinical benefit. Here, we report local dose-dense chemotherapy to treat TNBC by implanting 3D printed devices with time-programmed pulsatile release profiles. The implantable device can control the time between drug releases based on its internal microstructure design, which can be used to control dose density. The device is made of biodegradable materials for clinical convenience and designed for minimally invasive implantation via a trocar. Dose density variation of local chemotherapy using programmable release enhances anti-cancer effects in vitro and in vivo. Under the same dose density conditions, device-based chemotherapy shows a higher anti-cancer effect and less toxic response than intratumoral injection. We demonstrate local chemotherapy utilizing the implantable device that simulates the drug dose, number of releases, and treatment duration of the dose-dense AC (doxorubicin and cyclophosphamide) regimen preferred for TNBC treatment. Dose density modulation inhibits tumor growth, metastasis, and the expression of drug resistance-related proteins, including p-glycoprotein and breast cancer resistance protein. To the best of our knowledge, local dose-dense chemotherapy has not been reported, and our strategy can be expected to be utilized as a novel alternative to conventional therapies and improve anti-cancer efficiency.

A case of squamous cell carcinoma of the breast achieved a pathological complete response after dose-dense AC + dose-dense PTX

BackgroundSquamous cell carcinoma (SCC) of the breast is a rare form of breast cancer, accounting for approximately 0.1% of all breast cancers. It is known for its rapid tumor growth and poor prognosis with no established treatment.Case presentationA 56-year-old woman was diagnosed with breast SCC with axillary, supraclavicular and internal thoracic lymph node metastases. She received neoadjuvant chemotherapy (NAC) with dose-dense doxorubicin and cyclophosphamide (AC) followed by dose-dense paclitaxel (PTX). This treatment resulted in a pathological complete response (pCR) after breast-conserving surgery. The patient was then treated with radiotherapy. She remained free of recurrence for three years postoperatively.ConclusionsWe report a rare case of breast SCC treated with preoperative dose-dense chemotherapy, resulting in pCR and allowing breast-conserving surgery.

Comparison of Treatment Completion Rate Between Conventional and Dose-dense Doxorubicin and Cyclophosphamide (AC) Followed by a Taxane in Patients With Breast Cancer: A Propensity Score-matched Analysis.

To maximize the effect of perioperative chemotherapy in breast cancer, it is critical to keep the relative dose intensity (RDI) high. While bi-weekly doxorubicin and cyclophosphamide, dose-dense AC (ddAC), instead of tri-weekly conventional AC (cAC) followed by a taxane has been adopted as standard perioperative chemotherapy, postponement or discontinuation are sometimes experienced during ddAC or subsequent taxane phase. This study aimed at evaluating whether ddAC, compared to cAC, was associated with reduced RDI. We compared ddAC and cAC, both followed by a taxane, for perioperative breast cancer regarding the proportion of completion of planned treatment (%completion), defined as an RDI ≥85% for both AC and taxane phases. There was no remarkable difference between the groups in patient characteristics after propensity score matching (n=46 in ddAC, and n=86 in cAC). The %completion was similar between the groups (67.4% vs. 65.1%). Most other endpoints related to RDI were similar between groups. The incidence of pneumonia was higher in the ddAC group (13% vs. 3%) including one Pneumocystis jiroveci pneumonia. ddAC followed by a taxane can be considered with sufficient supportive measures and precautions for pneumonia.

Abstract PS6-41: Mammaprint and blueprint as prognostic indicators for elderly patients with early stage breast cancer

Abstract Background: Elderly breast cancer (BC) patients are an understudied population, with limited evidence regarding treatment options and outcomes and a lack of research involving prognostic multigene assays for this group. One study in patients 65-89 years old with an Oncotype DX Recurrence Score ≥ 26 concluded that gene expression profiling tests have limited utility in elderly patients, and should only be used for patients aged 65-74 with no/low to moderate comorbidities and not for patients ≥ 75. In this study, the 70-gene risk of distant recurrence signature, MammaPrint (MP), and 80-gene molecular subtyping signature, BluePrint (BP), were evaluated in both the neoadjuvant and adjuvant settings in elderly patients with early stage BC. Methods: This analysis included 211 BC patients classified as cT2-4N0-3M0 (T2 > 3.5 cm if N0) who received neoadjuvant chemotherapy and enrolled in the Multi-Institutional Neoadjuvant Therapy MammaPrint Project (MINT) study from 2011-2016. Lymph node (LN) involvement was established following neoadjuvant treatment. The second analysis included 517 early stage BC patients with 0-3 positive LNs who enrolled in the community based cohort study (COPPER) from 2009-2016. Patients were given adjuvant treatment following standard of care. Patients from both cohorts were divided into age at diagnosis groups: < 65, 65-74, and > 74. MP stratified patients into either Low Risk (LR) or High Risk (HR) groups. BP classified patient samples into Luminal, HER2, or Basal subtype. Kaplan Meier analysis and log-rank test were used to assess differences in overall survival (OS) and distant metastasis free survival (DMFS). Clinical risk assessment based on the MINDACT trial algorithm was performed. Results: From MINT, 35 patients were ≥ 65 years old; 80% were HR and 20% were LR. Pathological complete response (pCR) was achieved in 36% (10/28) of elderly HR patients, of whom 70% were HER2 and 30% were Basal by BP. Nodal downstaging occurred in 55% (11/20) of LN positive elderly HR patients, of whom 64% (7/11) achieved pCR. BP classified patients with nodal downstaging as HER2 (55%), Basal (36%), or Luminal (9%). Importantly, pCR and nodal downstaging were more likely to be achieved in HR tumors and correlated with BP subtype in both young and elderly patients. From the COPPER cohort, 77% of HR patients 65-74 years old received chemotherapy (CT), whereas 74% of LR patients omitted CT. Of patients > 74, 49% of HR patients received CT, whereas 75% of LR patients omitted CT. OS and DMFS probabilities indicated good survival outcomes in LR patients that omitted CT and HR patients that received CT, with no significant difference between age groups. A majority of HR patients treated with CT and over 1/3 of LR patients that omitted CT had high clinical risk. Interestingly, among all patients that had a metastasis event, mortality was less likely to occur in patients that received dose dense AC (doxorubicin and cyclophosphamide). Conclusion: MP and BP may identify HR elderly patients who are likely to achieve nodal downstaging and pCR. Elderly patients were safely spared or assigned adjuvant CT based on MP results independent of clinical risk. Furthermore, these data are in line with previous studies that suggest similar survival benefits between older and younger patients who are candidates for aggressive CT regimens. MP and BP elucidate information about tumor biology and provide prognostic value, which may help inform treatment decisions, independent of patient age. MINTAge group< 6565-74> 74MP resultHRLRHRLRHR# of patients152242177% of patients with pCR35% (53/152)033% (7/21)043% (3/7)# of LN+ patients103181456% of LN+ patients with nodal downstaging49.5% (51/103)22% (4/18)50% (7/14)067% (4/6)% of LN+ patients with pCR & nodal downstaging65% (33/51)071%(5/7)050%(2/4)COPPERAge group< 6565-74> 74MP resultHRLRHRLRHRLR# of patients1409988665569# of patients received CT121256813278# of patients omitted CT116717492052# of patients with unknown treatment873489Groups treated based on MPHR treated with CTLR omitted CTAge group< 6565-74> 74< 6565-74> 745-yr DMFS probability (95% CI)91% (80.2-96.7)87% (60.2-91.4)87% (55.2-96.6)100%98% (84.3-99.7)94% (75.9-98.5)5-yr OS probability (95% CI)94% (80.2-98.2)96% (83.4-98.9)86% (54.7-96.5)100%98% (84.3-99.7)97% (80.4-99.6)% Clinical high risk83% (100/121)76% (52/68)63% (17/27)34% (23/67)37% (18/49)35% (18/52) Citation Format: Peter W. Blumencranz, Mehran Habibi, Lisa Blumencranz, Andrea Menicucci, Shiyu Wang, Amy Truitt, William Audeh, Jolanta L. Baginski, Steven Shivers, Geza Acs, Charles E. Cox, MINT Investigators Group. Mammaprint and blueprint as prognostic indicators for elderly patients with early stage breast cancer [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 PS6-41.

Abstract P4-21-38: Cardiac safety of dual anti-HER2 therapy in the neoadjuvant setting for treatment of HER2-positive breast cancer

Abstract Background: Trastuzumab and pertuzumab are approved for the treatment of HER2-postiive breast cancer in the neoadjuvant setting. However, limited cardiac safety data is available when used in combination with doxorubicin-based chemotherapy. At a single center we retrospectively report the cardiac safety of dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel, trastuzumab, and pertuzumab (THP) in the neoadjuvant setting followed by adjuvant trastuzumab-based therapy. Methods: Patients treated with neoadjuvant dose dense AC followed by THP from September 1, 2014 to March 1, 2015 were retrospectively identified. Patients then had breast surgery and completion of anti-HER2 therapy for 1 year. The primary outcome was cardiac event rate, defined by New York Heart Association (NYHA) class III/IV or cardiac death. The secondary outcome was significant asymptomatic decline in left ventricular ejection fraction (LVEF) of 10%-15% from baseline to below the lower limit of normal, or > 16% from baseline. Patients underwent LVEF monitoring at baseline prior to AC, prior to initiation of THP, and serially during 1 year of anti-HER2 therapy (neoadjuvant to adjuvant phases). Results: Fifty-seven patients were included in the study. The median age was 46 years (range 26-68 years). The median number of cycles of trastuzumab and pertuzumab in the neoadjvuvant setting was 6 (range 3-8) and 6 (range 2-8), respectively. In the adjuvant setting, 56 (98%) patients received trastuzumab with pertuzumab with a median cycle number of 12 (range 1-13). Two of 57 (3.5%) patients developed NYHA class III/IV heart failure after 5 and 9 months of trastuzumab, leading to permanent discontinuation of anti-HER2 treatment. Additionally, 7 (12.3%) patients developed a significant LVEF decline (without severe HF symptoms). The median LVEF was 65% (range 55-75%) at baseline and 64% (range 53-72%) after AC. There was a reduction in median LVEF to 60% (range 35-70%), 60% (range 23- 73%), 61% (range 25-73%), and 58% (range 28-66%) at 3, 6, 9, and 12 months (+/- 6 weeks) of trastuzumab-based therapy. Conclusion: In patients with HER2-positive breast cancer treated with neoadjuvant dose-dense AC and THP followed by completion of anti-HER2 therapy in adjuvant setting, the overall rate of NYHA Class III/IV heart failure was comparable to rates reported in trials of sequential doxorubicin and trastuzumab. Our findings do not suggest an increased risk of cardiotoxicity when pertuzumab is added to trastuzumab following a doxorubicin-based regimen. Citation Format: Yu AF, Wang R, Singh J, Liu JE, Eaton A, Jones L, Oeffinger K, Steingart RM, Hudis CA, Dang CT. Cardiac safety of dual anti-HER2 therapy in the neoadjuvant setting for treatment of HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-38.

Enhancing accrual to chemotherapy trials for patients with early stage triple-negative breast cancer: a survey of physicians and patients.

The optimal chemotherapy regimen for patients with early stage triple-negative breast cancer (TNBC) remains unknown. The purpose of the study is to survey physicians and breast cancer patients about preferred chemotherapy regimens for early stage TNBC and clinical trial strategies. A standardised online questionnaire was developed and circulated to medical oncologists known to treat breast cancer. A separate questionnaire was given to patients who had received chemotherapy for breast cancer. The questionnaire was completed by 41/84 medical oncologists (48.8% response rate) and 74 patients. The most commonly used neoadjuvant and adjuvant chemotherapy regimens for TNBC were dose-dense doxorubicin and cyclophosphamide (AC)-paclitaxel (P), dose-dense AC followed by weekly P and fluorouracil, epirubicin, cyclophosphamide-docetaxel (FEC-D). The majority of medical oncologists (80%) would be willing to enrol patients in trials evaluating the most effective chemotherapy regimen for TNBC. Oncologists favoured a three arm trial design comparing currently available standard of care treatments (36%) and trials of novel or non-standard of care agents 22% (9/41). Sixty percent (41/74) of patients indicated that they would be willing to be enrolled in trials evaluating various adjuvant regimens for TNBC. Both oncologists and patients were interested in novel consent approaches such as using the integrated consent model. Optimisation of chemotherapy for TNBC is an important and unmet clinical need. It is apparent that various chemotherapy regimens are used for patients with early stage TNBC. The majority of medical oncologists and patients are interested in entering trials to optimise chemotherapy choices.

Abstract P1-14-17: Pathologic complete response rate with doxorubicin and cyclophosphamide followed by weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-positive early stage breast cancer: A single institution experience

Abstract Background: Trastuzumab and pertuzumab (HP) with standard chemotherapy is approved for use in the neoadjuvant setting. We performed a retrospective analysis of patients (pts) treated with dose-dense doxorubicin and cyclophosphamide (AC) → paclitaxel, trastuzumab, pertuzumab (THP) in the neoadjuvant setting. Here we report the pathologic complete response (pCR) rate. Methods: We abstracted medical records of patients who were treated with pertuzumab-based therapy in the neoadjuvant setting from September 1, 2013 to March 1, 2015. Charts were analyzed for pt demographics, stage of breast cancer, pathology reports, surgical data, and information on systemic therapy. Results: Charts from 66 pts were reviewed; 60 pts were evaluable for pCR defined as absence of invasive disease in the breast, and 6 were not (3-no anthracycline, 1-incomplete chart, 1-no surgery yet, 1-metastatic). Median age was 47 years (range 28-68 years). Of 60 pts, 52 (86%) had operable breast cancer (T1-3, N0-1, M0) of which 7 had clinical stage I disease (T1N0)]; 7 (12%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 1 (2%) had inflammatory breast cancer (T4d, any N, M0). 49 (82%) and 11 (18%) had hormone receptor (HR)-positive and negative diseases, respectively. All patients had HER2-positive breast cancer defined as immunohistochemistry (IHC) 3+ and/or fluorescent in-situ hybridization (FISH) of > 2.0. 30 pts (50%) underwent mastectomy and lumpectomy, respectively. Out of 60 evaluable pts, 41 (68%) had pCR; 32/49 (65%) with HR-positive and 9/11 (82%) with HR-negative diseases had pCR, respectively. Overall 58/60 (97%) pts completed neoadjuvant therapy; 2 did not (1 developed Steven Johnson Syndrome after one cycle of AC and 1 developed pneumonitis after third weekly dose of T with HP). Conclusions: At our single center experience the pCR rate of dose dense AC→THP is high at 68 %. These data are similar to results seen in the TRYPHAENA study, and we await the results from the BERENICE trial evaluating pCR as a secondary endpoint. Patient Demographics Age, years <4525 (42%)45-5419 (32%)>5516 (26%) ECOG Performace Status 031 (52%)129 (48%) Hormone receptor (HR) status HR+ Her2+49 (82%)HR- Her2+11 (18%) Status of Her-2 Positivity IHC positive52 (86%)FISH positive8 (14%) Median tumor size2.6cm (range: 1-8.4cm) Stage Operable (T1-2, N0-1, M0)52 (86%)Operable Stage I7 (12%)Operable Stage II/III45 (74%)Locally advanced (T2-3, N2-3, M0 or T4a-c, any N, M0))7 (12%)Inflammatory (T4d, any N, M0)1 (2%) Type of surgery Lumpectomy30 (50%)Mastectomy30 (50%) Citation Format: Singh JC, Sugarman S, Jones L, Boafo C, Patil S, Schweber S, Yu A, Argolo D, Modi S, Iyengar N, Smyth L, Norton L, Baselga J, Hudis C, Dang C. Pathologic complete response rate with doxorubicin and cyclophosphamide followed by weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-positive early stage breast cancer: A single institution experience. [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 P1-14-17.

Abstract P1-12-05: Phase 2 study of dose-dense doxorubicin and cyclophosphamide followed by eribulin mesylate with or without prophylactic growth factor for adjuvant treatment of early-stage breast cancer

Abstract Background: Eribulin has demonstrated antitumor activity and significantly improved overall survival (OS) in patients (pts) with heavily pretreated locally advanced/metastatic breast cancer (BC). This trial assessed the feasibility of eribulin as adjuvant therapy following dose-dense doxorubicin and cyclophosphamide (AC) for pts with human epidermal growth factor receptor 2 (HER2)-negative early-stage BC. Methods: Pts with HER2(-), stage I–III, invasive BC were enrolled. Pts received dose-dense AC (doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV) on D1 of each 14-day cycle for 4 cycles with pegfilgrastim, followed by 4 cycles of eribulin (1.4 mg/m2 IV) on D1 and D8 every 21 days. Pts were divided into 2 cohorts: Cohort 1 did not receive any prophylactic growth factor (GF); Cohort 2 received a short course of prophylactic GF (filgrastim) on days 3, 4, 10, and 11 of each eribulin cycle. Primary endpoint of feasibility was determined as %pts who completed eribulin portion of the regimen without a dose delay (>2 days) or reduction due to eribulin-related adverse event (AE). Based on similar previous studies, the target for feasibility was 80%. Relative dose intensity of eribulin and toxicities were also summarized by cohort. Exploratory objectives include efficacy endpoints of 3-yr disease-free survival and OS. Results: We report data from 81 pts (55 Cohort 1; 26 Cohort 2) enrolled in the study, of whom 88% completed study treatment. Pt characteristics include median age 49 yrs (range 26–69), ECOG status 0 (85%), BC stages 1/2/3 (21%/57%/22%). Of 90% (73/81) pts evaluable for feasibility, 27% and 40% of pts in Cohorts 1 and 2, respectively, had dose delay or reduction during eribulin treatment, indicating the primary endpoint was not met. Overall, results were similar between the 2 cohorts (Table). Median duration of treatment with eribulin was 10.14 weeks in both cohorts (vs 10 weeks planned). Most eribulin-related dose delays were due to grade 3 (n=18) or grade 4 (n=7) neutropenia. Non-fatal serious AEs were observed in 11% of pts in Cohort 1 and 15% in Cohort 2. Discontinuations due to AEs occurred in 6% of pts in Cohort 1 and 0 in Cohort 2. Neutropenia (all grades) was reported in 36% of pts in Cohort 1 and 42% in Cohort 2. Most common AEs (all grades) were fatigue (96%), nausea (75%), alopecia (73%), hot flush (63%), and constipation (57%). ACEribulin Cohort 1*Cohort 2*Cohort 1 (without GCSF)Cohort 2 (with GCSF)Relative dose intensity, mean99.5%99.0%92.0%90.9%Completed all planned doses98.2%96.2%87.0%84.0%Dose modification†12.7%15.4%35.2%40.0%GCSF, granulocyte-colony simulating factor. *With pegfilgrastim 6 mg given subcutaneously on D2 of each AC cyle; † including dose delays (>2 days)/reduction/interruptions, missing, and permanent discontinuation due to AE. Conclusions: The primary study endpoint of >80% feasibility of planned dose delivery without any dose delays or reduction was not met. However, adjuvant treatment with dose-dense AC-eribulin was given safely, with two-thirds (67%) of pts achieving full dosing with no dose delay or reduction. Investigation into alternative dosing schedules or GF support is recommended. Citation Format: Cadoo K, Kaufman PA, Hudis C, Chang C, Berrak E, Song J, Seidman AD, Traina TA. Phase 2 study of dose-dense doxorubicin and cyclophosphamide followed by eribulin mesylate with or without prophylactic growth factor for adjuvant treatment of 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 P1-12-05.

Impact of dosing schedule of doxorubicin and cyclophosphamide (AC) chemotherapy on rates of hospitalization and resource utilization.

78 Background: 4 cycles ofAC chemotherapy are given as a component of several important and widely used chemotherapy regimens in the adjuvant treatment of breast cancer. We queried whether the use of dose-dense (every 2 week) AC chemotherapy is associated with a lower rate of hospitalization and resource utilization in clinical practice. Methods: We identified patients with early stage breast cancer treated with 3-weekly AC chemotherapy in a single institution. Cases were matched to controls by year of diagnosis and age. Rates of hospitalization during AC chemotherapy as well as duration of hospitalization, associated costs and use of pegfilgrastim were compared between the two groups. Fisher's exact test was used to compare categorical variables, and paired t-test was used to compare continuous variables. Results: 26 patients were included in the analysis. The mean age was 56 in both groups. As expected, rates of growth factor support with pegfilgrastim were higher in the dose dense versus 3-weekly group (52 versus 23 cycles, 2-tailed p = 0.0003). There was no difference in the likelihood of hospitalization among patients treated with dose dense versus 3-weekly AC (Fisher's exact test, p-value = 1.00). There was no difference in the mean duration of hospitalization between groups (mean 2.31 versus 1.23 days, 2-tailed p = 0.3352).Costs pertaining to pegfilgrastim use and hospitalization will be compared. Conclusions: In this clinical setting, dose dense administration of AC was not associated with lower rates or mean duration of hospitalization.

Near-complete pathological response with preoperative chemotherapy in a patient with metaplastic breast carcinoma

Metaplastic breast carcinoma (MBC) is a rare form of breast cancer comprising less than 1% of all invasive breast carcinomas. There are no clinical studies available for the management of this rare disease and MBC is associated with a poor prognosis. We present a case of a 50-year-old female patient with MBC who showed a favorable response with preoperative chemotherapy. The patient presented with a palpable left breast mass, and diagnostic breast imaging showed a 4.4 cm mass in the left breast, which was biopsied. Pathological review led to a diagnosis of MBC. Staging workup for distant metastasis was negative. She received four cycles of dose-dense AC (doxorubicin and cyclophosphamide), followed by 10 weekly doses of carboplatin (area under the curve=2) and paclitaxel (80 mg/m). The patient underwent partial mastectomy and sentinel lymph node sampling, and pathological review indicated a near-complete pathological response, with few scattered malignant cells at the tumor bed. A current review of the literature on MBC is summarized in this report.

A phase II, single-arm, feasibility study of dose-dense doxorubicin and cyclophosphamide (AC) followed by eribulin mesylate for the adjuvant treatment of early-stage breast cancer (EBC).

TPS1145 Background: Randomized trials have confirmed the benefit of the combination of an anthracycline (A) and cyclophosphamide (C) for the adjuvant treatment of EBC. The addition of taxane therapy to AC therapy has further improved survival. Despite the improvement in adjuvant therapies for BC, new approaches for improving outcomes are of significant importance and may involve developing improved combination regimens. Eribulin mesylate has demonstrated antitumor activity and significant improvement in overall survival (OS) in patients with heavily pretreated locally advanced or metastatic breast cancer (MBC) and may improve outcomes in EBC as well. Methods: This study will determine the feasibility of eribulin as adjuvant therapy following dose-dense AC for HER2 normal EBC. A completion rate of >80% was set as a threshold for feasibility as established adjuvant regimens have shown feasibility rates ranging from ~65% for trastuzumab to >80%. This is a phase 2, single-center, feasibility study of dose-dense adjuvant chemotherapy in patients with EBC. Dose-dense AC (Doxorubicin 60 mg/m2 IV plus C 600 mg/m2 IV) on day 1 of every 14-day cycle is given for 4 cycles, followed by 4 cycles of eribulin mesylate at 1.4 mg/m2 over 2-5 minutes IV on days 1 and 8 every 21 days. Growth factors are given on day 2 of AC cycles and only for neutropenia events with eribulin treatment. Feasibility is determined by the ability to complete the eribulin portion of the regimen without a dose delay or reduction. Exploratory objectives include efficacy endpoints of 3-year disease-free survival (DFS) and OS. Patients have histologically confirmed HER2 normal stage I-III invasive disease and adequate bone marrow, liver, and renal function. Thirty two of approximately 80 planned patients are currently enrolled. Feasibility rates will be calculated with growth factor support (ie, the successful use of growth factor support following a neutropenia event is not considered a dose delay)and without growth factor support (ie, where need for growth factors is considered a delay). Secondary endpoints include DFS and OS and will be estimated by Kaplan-Meier method.

Dose-dense adjuvant Doxorubicin and cyclophosphamide is not associated with frequent short-term changes in left ventricular ejection fraction.

Doxorubicin and cyclophosphamide (AC) every 3 weeks has been associated with frequent asymptomatic declines in left ventricular ejection fraction (LVEF). Dose-dense (dd) AC followed by paclitaxel (P) is superior to the same regimen given every third week. Herein, we report the early cardiac safety of three sequential studies of ddAC alone or with bevacizumab (B). Patients with HER2-positive breast cancer were treated on two trials: ddAC followed by P and trastuzumab (T) and ddAC followed by PT and lapatinib. Patients with HER2-normal breast cancer were treated with B and ddAC followed by B and nanoparticle albumin-bound P. Prospective LVEF measurement by multigated radionuclide angiography scan before and after every 2 week AC for 4 cycles and at month 6 from all three trials were aggregated to determine the early risks of cardiac dysfunction. From January 2005 to May 2008, 245 patients were enrolled. The median age was 47 years (range, 27 to 75 years). Median LVEF pre-ddAC was 68% (range, 52% to 82%). LVEF post-ddAC was available in 241 patients (98%) and the median was unchanged at 68% (range, 47% to 81%). Per protocol no patients were ineligible for subsequent targeted biologic therapy based on LVEF decline post-ddAC. In addition, LVEF was available in 222 patients (92%) at 6 months, at which time the median LVEF was similar at 65% (range, 24% to 80%). Within 6 months of initiating chemotherapy, three patients (1.2%; 95% CI, 0.25% to 3.54%) developed CHF, all of whom received T. Dose-dense AC with or without concurrent bevacizumab is not associated with frequent acute or short-term declines in LVEF.

The Safety of Dose-Dense Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Trastuzumab in HER-2/neu Overexpressed/Amplified Breast Cancer

Dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (P) is superior to every 3-weekly AC followed by P. Given the demonstrated cardiac safety for trastuzumab (T) with conventionally scheduled AC followed by P, we tested the safety of dd AC followed by P with T. The primary end point was cardiac safety, and the secondary end points were time to recurrence and overall survival. Patients with HER-2/neu immunohistochemistry (IHC) 3+ or fluorescent in situ hybridization (FISH)-amplified breast cancer and baseline left ventricular ejection fraction (LVEF) of >or= 55% were enrolled, regardless of tumor size or nodal status. Treatment consisted of AC (60/600 mg/m(2)) x 4 followed by P (175 mg/m(2)) x 4 every 2-weekly with pegfilgrastim (6 mg on day 2) + T x1 year. LVEF by radionuclide scan was obtained at baseline, at months 2, 6, 9, and 18. From January 2005 to November 2005, 70 patients were enrolled. The median age was 49 years (range, 27 to 72 years); median LVEF at baseline was 68% (range, 55% to 81%). At month 2 in 70 of 70 patients, the median LVEF was 67% (range, 58% to 79%); at month 6 in 67 of 70 patients, it was 66% (range, 52% to 75%); at month 9 in 68 of 70 patients, it was 65% (range, 50% to 75%); and at month 18 in 48 of 70 patients, it was 66% (range, 57% to 75%). As of December 1, 2007, the median follow-up was 28 months (range, 25 to 35 months). One patient (1%) experienced congestive heart failure (CHF). There were no cardiac deaths. Dose-dense AC followed by P/T followed by T is feasible and is not likely to increase the incidence of cardiac events compared to established regimens.

Updated cardiac safety results of dose-dense (DD) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) with trastuzumab (H) in HER2/neu overexpressed/amplified breast cancer (BCA)

582 Background: DD q 2 weekly (w) AC → T is superior to conventionally scheduled (cs) AC → T and safe w/long follow-up (Hudis et al, SABCS 2005). With q 3 wk AC, adjuvant (adj) H is safe and effective (Romond et al and Perez et al, NEJM 2005). We therefore tested DD q 2 w AC → T + H × 1 year (y) as adj treatment (Rx) of patients (pts) with HER2/neu (+) BCA to determine cardiac safety. Based on the reported cardiac event (CE) rate of ≤ 4% in the randomized trials using cs chemotherapy (CRx) + H, we evaluated DD q 2 w AC → T + H with a 1° endpoint of cardiac safety defined as discontinuation (DC) of H due to 1) cardiac death or 2) congestive heart failure (CHF). The 2° endpoint is time to recurrence and overall survival. Methods: Pts with HER2/Neu IHC 3+ or FISH-amplified BCA were enrolled, regardless of tumor size or nodal status. Rx consisted of AC at 60/600 mg/m2 × 4 → T at 175 mg/m2 × 4 q 2 w w/pegfilgrastim 6 mg on d 2 + H × 1 y. Multi-gated radionuclide angiography scan (MUGA) is obtained at baseline and at months (mo) 2 (after AC × 4), 6 (after T × 4), 9, and 18. Pts w/baseline LVEF of ≥ 55% and w/o cardiac illnesses are eligible. Pts w/significant (sig) asymptomatic (asx) LVEF ↓ after DD AC based on mo 2 MUGA did not receive H, and pts w/sig asx LVEF ↓ during H had it DC’d. If the CE rate is > 4%, Rx is deemed not feasible. Results: From January 4, 2005 to November 1, 2005, 70 pts were enrolled. Median (med) age is 49 years (range, 27–72). Forty one of 70 pts (60%) had node (+) BC and 27/70 pts (40%) had (-) nodes. Med baseline LVEF is 68% (range, 55%-81%). As of January 9, 2005, all pts had mo 2 MUGA after DD AC and there is no sig LVEF ↓ and the med LVEF is 67% (range, 58%-79%). To date 39 pts had mo 6 MUGA w/med LVEF of 66% (range, 56%-75%) and one pt had a sig asx LVEF ↓ from baseline of 74% to 56%; H was DC’d. Twenty-three pts had mo 9 MUGA w/a med LVEF of 64% (range, 57%-69%). One patient had clinical CHF at mo 4 w/EF of 45% and improved sig w/cardiac medications. One had pneumonitis during radiation (RT). One had atrial fibrillation w/pericarditis after completion of RT. Discussion: DD AC → T + H appears to have an acceptable cardiac toxicity profile w/1/70 pts having a CE. Updated cardiac safety data will be presented. [Table: see text]

Targeted Inhibition of Farnesyltransferase in Locally Advanced Breast Cancer: A Phase I and II Trial of Tipifarnib Plus Dose-Dense Doxorubicin and Cyclophosphamide

To determine the recommended phase II dose (RPTD) of the farnesyltransferase (FTase) inhibitor tipifarnib when combined with doxorubicin and cyclophosphamide (AC) in patients with advanced breast cancer, the pathologic complete response (pCR) rate after preoperative treatment with four cycles of the combination in locally advanced breast cancer (LABC), and the effect of tipifarnib on primary tumor FTase enzyme activity in vivo. Thirty-two patients with metastatic breast cancer (n = 11) or LABC (n = 21) received AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) administered intravenously on day 1 plus tipifarnib (100, 200, or 300 mg bid for 6 to 14 days) without (n = 2) or with (n = 30) granulocyte colony-stimulating factor (G-CSF) for up to four cycles. Patients with LABC underwent surgery after up to four cycles of the combination. When combined with AC every 2 weeks plus G-CSF, the RPTD of tipifarnib was 200 mg bid administered on days 2 to 7. Seven (33%) of 21 patients (95% CI, 15% to 55%) with LABC treated with up to four cycles of the combination at the RPTD had a pCR in the breast at surgery. The five patients had serial biopsies that demonstrated at least 50% FTase enzyme inhibition in the primary tumor (median, 100%; range, 55% to 100%) after tipifarnib. Tipifarnib may be safely combined with dose-dense AC using a dose and schedule that significantly inhibits FTase enzyme activity in human breast cancer in vivo and may enhance the pCR rate after four cycles of preoperative dose-dense AC.