Dose-dense Adjuvant Chemotherapy Research Articles

Management of febrile neutropenia in a breast cancer patient with SARS-CoV-2 infection during dose-dense adjuvant chemotherapy

Management of febrile neutropenia in a breast cancer patient with SARS-CoV-2 infection during dose-dense adjuvant chemotherapy

Adjuvant Dose Dense Chemotherapy in Patients With Obesity: Short-Term Toxicities and Breast Cancer Outcome

BackgroundDose dense adjuvant chemotherapy is associated with improved outcomes in breast cancer compared to standard dosing. Despite current guidelines recommending that chemotherapy is dosed according to actual body weight, reviews have shown patients with obesity often receive a capped chemotherapy dose. The latter is commonly undertaken as clinicians have concerns that adverse events are more frequent if full doses are administered. This study assessed surgical, radiotherapy and chemotherapy related adverse events between patients with and without obesity receiving dose dense adjuvant chemotherapy for breast cancer. Materials and MethodsA retrospective review of prospective collected data for patients receiving adjuvant chemotherapy from 30 April 2018 from a single institution was analyzed. Data collected included demographic data, height, weight, pathological information, comorbidities, surgical, radiotherapy chemotherapy treatment, and toxicity. Primary outcomes were surgical complications at 30 days, radiotherapy skin toxicity at 30 days and chemotherapy side-effects. Secondary outcomes were rates of recurrence and time to recurrence. ResultsA total of 280 patients were included in the analysis: 55 obese and 225 nonobese. Obese status was associated with higher rates of grade >2 skin toxicity and this difference was significant after adjusting for age, comorbidity and radiotherapy field (P = .017). Obese status was not associated with higher rates of surgical or chemotherapy related adverse events. All patients regardless of obese status received adequate dose intensity with similar rates of recurrence and time to recurrence. ConclusionPatients with obesity who receive dose dense adjuvant chemotherapy do not experience higher rates of surgical or chemotherapy related adverse events although they do experience higher rates of grade >2 radiotherapy related skin toxicity. This supports the use of dose dense chemotherapy being based on actual body weight in patients with obesity.

Fluorouracil and dose-dense adjuvant chemotherapy in breast cancer: lessons learned from the 20-year-old GIM2 trial.

In 1976, approximately 50 years ago, the first randomised study leading to approval of adjuvant chemotherapy for breast cancer was reported. Chemotherapy remains a pillar of breast cancer treatment; however, in the past 50 years, we have learned that breast cancer is a heterogeneous disease and treatment should be tailored accordingly. We moved from a one-size-fits-all approach to a more personalised one, in which treatment decisions hinge upon the estimated risk of recurrence based not just on clinicopathological risk, but sometimes also on genomic information.

Association between CD8+ Tumor Infiltrating Lymphocytes and the Clinical Outcome of Patients with Operable Breast Cancer Treated with Adjuvant Dose-Dense Chemotherapy-A 10 Year Follow-Up Report of a Hellenic Cooperative Oncology Group Observational Study.

Tumor-infiltrating lymphocytes (TILs) contribute to breast cancer (BC) prognosis. We investigated the prognostic impact of CD8+ TILs in patients with early breast cancer treated with adjuvant chemotherapy in a large observational clinical trial. Along with a 10 year follow-up, considering the efficacy and safety, we report the results of the translational part of our study. We examined the patients' tumors for total (t), stromal (s), and intratumoral (i) CD8 lymphocyte density (counts/mm2) on tissue-microarray cores. The impact of CD8+ TILs counts on DFS and OS, and its correlation with breast cancer subtypes and standard clinicopathological parameters, were investigated, along with efficacy and safety data. Among the 928 eligible patients, 627 had available CD8+ data. Of which, 24.9% had a high expression of sCD8, iCD8, and total CD8, which were correlated with higher Ki67, TILs density, ER/PgR negativity, and higher histological grade. The 5year DFS and OS rates were 86.1% and 91.4%, respectively. Patients with high iCD8 and tCD8 had longer DFS and OS compared to those with low counts/mm2 (DFS: HR = 0.58, p = 0.011 and HR = 0.65, p = 0.034 and OS: HR = 0.63, p = 0.043 and HR = 0.58, p = 0.020, respectively). Upon adjustment for clinicopathological parameters, iCD8 and tCD8 retained their favorable prognostic significance for DFS and OS, whereas high sCD8 was only prognostic for DFS. Menopausal status, tumor size, and nodal status retained their prognostic significance in all examined multivariate models. CD8+ TILs, and especially their intratumoral subset, represent a potential favorable prognostic factor in early BC.

134O Dose-dense adjuvant chemotherapy in early-stage breast cancer patients: End-of-study results from a randomised, phase III trial of the Gruppo Italiano Mammella (GIM)

The GIM 2 trial compared in a 2x2 factorial design the dose dense (DD, every 2 weeks) schedule to the standard interval one (every 3 weeks) and the addition of fluorouracil (F) to epirubicin-cyclophosphamide (EC) and paclitaxel (P) as adjuvant chemotherapy for node-positive breast cancer. In the primary analysis (Del Mastro, Lancet 2015), disease-free survival (DFS) and overall survival (OS) were significantly improved with the DD schedule, while no benefit was observed with the addition of F. Here, we report the end-of-study analysis.

Dose-dense neoadjuvant chemotherapy in triple-negative breast cancer: Real-world data from a developing country.

e12594 Background: Dose-dense adjuvant chemotherapy has been shown to be associated with improved long-term survival outcomes in triple-negative breast cancer (TNBC). However, there is a lacuna of data on the benefits of dose-dense neo-adjuvant chemotherapy (NACT) in TNBC particularly with respect to pathological complete response (pCR) rates and with the relapse or overall survival. To our knowledge no studies have been reported regarding the use or benefit of dose-dense NACT (ddNACT) over conventional NACT (cNACT) among Indian women with TNBC. Methods: This retrospective study included, 217 newly diagnosed cases of TNBC, treated with sequential anthracycline and taxane based NACT followed by definitive surgery. Study groups consisted of 137 patients who received 3-weekly conventional chemotherapy (cNACT group) and 80 patients with 2-weekly dose-dense NACT (ddNACT group) with granulocyte-colony-stimulating factor (GCSF) prophylaxis. Primary endpoint of the study was pathological complete response (pCR) rate and secondary endpoints were relapse-free survival (RFS), overall survival (OS) and grade-3/4 chemotoxicities. Fisher’s exact test was used to compare pCR rates. Kaplan-Meier and cox regression survival analysis were used to compare survival outcomes. Results: Median age (Interquartile range) in overall population, cNACT and ddNACT group were 43 (37-50), 44 (37-50) and 42 (36.5-48) years respectively. Baseline parameters were comparable between study groups, except that ddNACT group had higher proportion of premenopausal patients as compared to cNACT group (72.5% vs 55.5%). Majority of the patients presented at advanced stage, with stage-III being predominant, constituted by 97 (70.1%) and 55 (67.5%) patients in cNACT and ddNACT group respectively. No significant difference in pCR rate (32.8% vs 31.3%; p=0.808) was observed across the study groups. In multivariate analysis, dose-dense chemotherapy was no better than conventional chemotherapy for achieving pCR (Odds ratio [OR]: 0.86, 95% confidence interval [CI]: 0.45-1.63; p=0.639 and had no RFS advantage over conventional chemotherapy [Median RFS: Not reached in ddNACT vs 56.1 months in cNACT; Hazard Ratio: 0.83, 95% CI (0.48-1.44)]. OS was also comparable in both the groups with 3-year survival rate of 78.8% (95%CI: 60.9-89.2) in ddNACT group vs 84.3% (95% CI: 74.8-90.4) in cNACT group. Grade-3/4 toxicities were comparable in both groups. Conclusions: This observational study focusing on ddNACT among TNBC patients demonstrated similar pCR and toxicity rates with no significant survival benefits compared to cNACT regimen. Cost-benefits of frequent hospital visits for GCSF administration associated with dose dense therapy need further consideration before implementing such these regimens in lower-middle income countries.

27P Association between CD8+ tumor infiltrating lymphocytes and the clinical outcome of patients with operable breast cancer treated with adjuvant dose-dense chemotherapy: A 10-year follow up report of a Hellenic Cooperative Oncology Group observational study

Tumor-infiltrating lymphocytes (TILs) and their subsets contribute to breast cancer prognosis. We investigated the prognostic impact of CD8+ TILs in patients with early intermediate/high-risk breast cancer treated with adjuvant anthracycline-based chemotherapy.

Abstract P1-12-01: Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: Final long-term results of the hellenic cooperative oncology group phase III HE10/05 trial

Abstract Background: Dose-dense sequential chemotherapy based on anthracyclines and taxanes has achieved an 18% reduction of recurrence risk in the adjuvant setting of early breast cancer (BC). However, the optimal chemotherapy schedule and the preferable interval between cycles are still under investigation. Methods: A total of 990 eligible BC patients were randomized to receive either 3 cycles of epirubicin (E,110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by 3 cycles of intensified CMF (Control Arm A, E-T-CMF; 333 patients) or three cycles of epirubicin followed by 3 cycles of CMF followed by 9 consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Experimental Arm B, E-CMF-wD; 331) or 9 consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Experimental Arm C, E-CMF-wT; 326). Trastuzumab was administered for HER2-positive disease. The primary endpoint was disease-free survival (DFS). Results: At a median follow-up of 13.3 years, 330 DFS events (33.3%) had been reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus control arm A either in the entire cohort (HR=0.90, p=0.38 and HR=0.85, p=0.20) or among HER2-positive, trastuzumab-treated patients (HR=0.69, p=0.13 and HR=0.67, p=0.13). Thirty-four patients (3.4%) developed secondary neoplasms. Conclusions: Overall, no significant differences in DFS or OS were found amongst the studied regimens after a long-term observational period. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12610000151033 Citation Format: Flora Zagouri, Georgia-Angeliki Koliou, Foteinos Dimitrakopoulos, Christos Papadimitriou, Ioannis Binas, Angelos Koutras, Pavlos Papakostas, Christos Markopoulos, Vasileios Venizelos, Grigorios Xepapadakis, Charisios Karanikiotis, Amanda Psyrri, Dimitrios Bafaloukos, Paris Kosmidis, Gerasimos Aravantinos, Eleni Res, Davide Mauri, Anna Koumarianou, Kalliopi Petraki, Anna Tsipoura, Dimitrios Pectasides, Helen Gogas, George Fountzilas. Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: Final long-term results of the hellenic cooperative oncology group phase III HE10/05 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-12-01.

First Person Profile: Clifford Hudis, MD: The chief executive officer of the American Society of Clinical Oncology previously had an esteemed career as a physician-scientist and executive at the Memorial Sloan Kettering Cancer Center's Breast Medicine Service: The chief executive officer of the American Society of Clinical Oncology previously had an esteemed career as a physician-scientist and executive at the

First Person Profile: Clifford Hudis, MD: The chief executive officer of the American Society of Clinical Oncology previously had an esteemed career as a physician-scientist and executive at the Memorial Sloan Kettering Cancer Center's Breast Medicine Service: The chief executive officer of the American Society of Clinical Oncology previously had an esteemed career as a physician-scientist and executive at the

PULMONARY EMBOLISM CAUSING INACCURATE READINGS OF CARDIOMEMS

TOPIC: Pulmonary Vascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: The CardioMEMS™ HF System is a wireless pulmonary artery (PA) pressure monitoring system implanted in the left lower lobe (LLL) PA branch; FDA approved in the management of heart failure (HF) patients with New York Heart Association (NYHA) class III symptoms and at least one hospitalization within the last year. This hemodynamic data is useful to reduce HF hospitalizations and mortality (1,2). We present the first reported case of a device-unrelated acute LLL pulmonary embolism (PE) leading to discordant CardioMEMS readings in a breast cancer patient with HF. CASE PRESENTATION: Patient is a 56 year-old female with past medical history of triple negative right breast cancer in 1998 treated with lumpectomy, anthracyclines, and radiation therapy that was complicated by recurrence in 2018 which was treated with bilateral mastectomy followed by adjuvant dose dense chemotherapy with doxorubicin, cyclophosphamide, and paclitaxel that resulted in anthracycline-induced cardiomyopathy with reduced left ventricular ejection fraction (LVEF) of 30%. LVEF eventually recovered to 60% after the initiation of optimal medical therapy for HF. Unfortunately, she remained with persistent NYHA class III symptoms requiring frequent hospitalizations. Thus, a CardioMEMS device was inserted to optimize HF management and reduce recurrent hospitalization by remote monitoring of PA pressure. Eight months later, she developed an acute PE within the LLL PA branch (originating from her left leg). She was eventually treated with anticoagulation therapy with resolution of her dyspnea and was eventually discharged home. On her post-hospitalization appointment, she reported worsening HF symptoms despite being euvolemic on exam. CardioMEMS (2 months after PE) showed persistently elevated PA pressures. Due to concerns for PE into the LLL affecting the CardioMEMS readings, a right heart catheterization was performed which showed marked discrepancy between PA pressure and CardioMEMS readings. DISCUSSION: In the setting of a recent PE to the same PA branch where the CardioMEMS implant was located, it was presumed that the PE caused device malfunction by falsely elevating CardioMEMS readings. It is worthy to mention, however, that the PE spared the actual implant. Despite proper management of the acute PE, PA pressure remained falsely elevated even after 2 months of anticoagulation therapy. Thus, given the discordant PA pressure readings, it was necessary to recalibrate the device. As a result of the recalibration, the patient's HF management was appropriately optimized using data from the recalibrated CardioMEMS device. CONCLUSIONS: In the correct clinical context, discordance between implantable hemodynamic monitoring device readings and physical exam should prompt right heart catheterization, as an acute PE at the sensor site is a rare, but diagnosable and easily treatable cause of CardioMEMS malfunction. REFERENCE #1: CardioMEMS TM HF System. (2014, May). Retrieved from https://www.accessdata.fda.gov/cdrh_docs/pdf10/p100045c.pdf. REFERENCE #2: Abraham, W. T., Stevenson, L. W., Bourge, R. C., Lindenfeld, J. A., Bauman, J. G., & Adamson, P. B. (2016). Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart. REFERENCE #3: failure therapy: Complete follow-up results from the CHAMPION randomised trial. The Lancet, 387(10017), 453-461. doi:10.1016/s0140-6736(15)00723-0. DISCLOSURES: No relevant relationships by Rafael Garcia-Cortes, source=Web Response No relevant relationships by Saarik Gupta, source=Web Response no disclosure on file for KATHLEEN MORRIS; No relevant relationships by Amjed Zidan, source=Web Response

Composite risk and benefit from adjuvant dose-dense chemotherapy in hormone receptor-positive breast cancer

The GIM2 phase III trial demonstrated the benefit of dose-dense chemotherapy in node-positive early breast cancer (eBC). To better define the dose-dense effect in the hormone receptor-positive subgroup, we evaluated its benefit through a composite measure of recurrence risk. We conducted an ancillary analysis of the GIM2 trial evaluating the absolute treatment effect through a composite measure of recurrence risk (CPRS) in patients with hormone receptor-positive HER2-negative eBC. CPRS was estimated through Cox proportional hazards models applied to the different clinicopathological features. The treatment effect was compared to the values of CPRS by using the Sub-population Treatment Effect Pattern Plot (STEPP) process. The Disease-Free Survival (DFS)-oriented STEPP analysis showed distinct patterns of relative treatment effect with respect to CPRS. Overall, 5-year DFS differed across CPRS quartiles ranging from 95.2 to 66.4%. Each CPRS quartile was characterized by a different patients’ composition, especially for age, lymph node involvement, tumor size, estrogen and progesterone receptor expression, and Ki-67. A number needed to treat of 154 and 6 was associated with the lowest and the highest CPRS quartile, respectively. Dose-dense adjuvant chemotherapy showed a consistent benefit in node-positive eBC patients with hormone receptor-positive HER2-negative disease, but its effect varied according to CPRS.

Postoperative adjuvant dose-dense chemotherapy with bevacizumab and maintenance bevacizumab after neoadjuvant chemotherapy for advanced ovarian cancer: A phase II AGOG/TGOG trial.

5540 Background: The objective of this study is to evaluate the safety and efficacy of adding bevacizumab to dose-dense adjuvant chemotherapy with bevacizumab maintenance after neoadjuvant chemotherapy (NAC) and interval debulking surgery (IDS) for stage III/IV ovarian, tubal, and primary peritoneal cancer. Methods: This phase II clinical trial using Simon's minimax two-stage design was conducted. At the first stage, 13 subjects were enrolled, and the trial would proceed to second stage if ≤3 subjects discontinued treatment for study-defined significant adverse events (AEs). Patients with stage III/IV ovarian, tubal, and primary peritoneal cancer deemed not feasible for primary cytoreductive surgery were enrolled after 3 to 4 cycles of NAC and IDS without disease progression. NAC could be either weekly paclitaxel (80mg/m2) (dose-dense) plus 3-weekly carboplatin (AUC5-6) or 3-weekly conventional schedule. After IDS, postoperative dose-dense adjuvant chemotherapy for 3 cycles at least (best to 6 cycles), and 3-weekly bevacizumab 15mg/kg was given since postoperative cycle 2. Further 3-weekly maintenance bevacizumab 15mg/kg was given intravenously for 17 cycles. Results: Of the 22 enrolled subjects, 13 (59.1%) had no gross lesion after IDS. Of the 13 subjects enrolled on the 1st stage, one study-defined significant AE occurred, therefore the trial proceeded to the 2nd stage (n = 9). The median progression-free survival (PFS) was 22.1 months (95% confidence interval [CI], 13.7 – 30.5), and the median overall survival (OS) was 49.2 months (95% CI, 33.8 – 64.6). Peritoneal Cancer Index score at entering abdomen during IDS was significant for PFS (>12 vs ≤ 12: p = 0.003). One of the 22 subjects did not receive any study treatment. In the safety analysis (n = 21), grade 3/4 AEs included thrombocytopenia of 38.1%, neutropenia 71.4%, and anemia 28.6%. Study-defined significant AEs of bowel perforation, poor-healing wound, and hypertension were found in 1 case each, respectively. Conclusions: This phase II trial demonstrated adding bevacizumab to dose-dense adjuvant chemotherapy with bevacizumab maintenance after NAC was feasible with tolerable toxicity and comparable PFS/OS as compared to other studies using bevacizumab in the NAC phase or dose-dense scheduling throughout. Clinical trial information: NCT02022917.

Prognostic impact of recurrence score, endocrine response and clinical-pathological factors in high-risk luminal breast cancer: Results from the WSG-ADAPT HR+/HER2- chemotherapy trial.

504 Background: In HR+/HER2- N0-1 early BC, postmenopausal patients (pts) with RS™ > 25 and a substantial proportion of premenopausal pts seem to benefit from addition of adjuvant chemotherapy (CT) to endocrine therapy (ET). However, the magnitude of absolute benefit from this treatment intensification seems to depend on clinical-pathological and biological prognostic factors. For the first time, we present outcome from the CT part of the prospective phase III WSG-ADAPT HR+/HER- trial combining both static (RS in baseline core biopsy (CB) and dynamic (Ki67 response) biomarkers to optimize adjuvant therapy in luminal EBC. Methods: Pts with clinically high-risk HR+/HER2- EBC (cT2-4 OR clinically N+ OR G3 OR Ki67>15%) were initially treated by 3 (+/-1) weeks of standard ET (postmenopausal: mostly AI; premenopausal: TAM) before surgery or sequential CB. Pts with cN2-3 or G3/Ki67>40% were randomized directly to the CT trial. pN0-1 pts with RS0-11 OR RS12-25/ET-response (central Ki67postendocrine<10%) received ET alone; the remaining high-risk cohort was randomized to the CT trial: (neo)adjuvant dose-dense CT (4xPaclitaxelà4xEC q2w vs. 8xNab-Paclitaxel q1wà4xEC q2w) followed by ET. Primary endpoint is efficacy comparison of CT schedules for survival; secondary endpoints reported here involve impacts of key prognostic factors on survival. Kaplan-Meier and Cox proportional hazard models were used to estimate survival curves and hazard ratios. For this analysis, subgroups free of selection bias by RS/ET-response were defined. Results: 5625 pts were screened and 4621 (ITT) entered the trial. After 4.9y median follow-up, higher baseline and post-endocrine Ki-67 levels were associated with poorer iDFS (both p < 0.001). In the CT cohort (n = 2331), higher RS, nodal status, and tumor size were generally associated with poorer iDFS. However, iDFS differed between N1 and N0 status only among younger pts (<50 years). In pts with >4 positive LN (n = 390), lower RS was associated with improved iDFS (RS0-11 vs RS > 25: plog-rank= 0.016, 5y-iDFS 90% vs. 64%). In pts with RS > 25 (n = 965), low Ki67postendocrine, N0 status, and c/pT1 status were associated with improved iDFS. In particular, ET-responders had higher 5y-iDFS (84%) than ET-non-responders (77%; plog-rank= 0.040). Younger patients (<50 years old) with N0-1 RS 12-25/ ET-non-responders treated by CT had non-significantly poorer 5-year iDFS (89%) compared to those with ET-response treated by ET only (92%) (plog-rank= 0.249). Conclusion: First results from the prospective high risk cohort from a large prospective phase III ADAPT trial provide evidence for good prognosis in some pts with >4 positive LN and e.g. low RS. Moreover combination of lower post-endocrine Ki-67 and limited tumor burden may be a promising criterion for CT de-escalation strategies even in patients with high RS. Clinical trial information: NCT01779206.

Postoperative adjuvant dose-dense chemotherapy with bevacizumab and maintenance bevacizumab after neoadjuvant chemotherapy for advanced ovarian cancer: A phase II AGOG/TGOG trial

ObjectiveThe objective of this study is to evaluate the safety and efficacy of adding bevacizumab to dose-dense adjuvant chemotherapy with bevacizumab maintenance after neoadjuvant chemotherapy (NAC) and interval debulking surgery (IDS) for stage III/IV ovarian, tubal, and primary peritoneal cancer. Study designThis phase II clinical trial using Simon's minimax two-stage design was conducted. At the first stage, 13 subjects were enrolled, and the trial would proceed to second stage if ≤3 subjects discontinued treatment for study-defined significant adverse events (AEs). Patients with stage III/IV ovarian, tubal, and primary peritoneal cancer deemed not feasible for primary cytoreductive surgery were enrolled after 3–4 cycles of NAC and IDS without disease progression. NAC could be either weekly paclitaxel (80 mg/m2) (dose-dense) plus 3-weekly carboplatin (AUC5−6) or 3-weekly conventional schedule. After IDS, postoperative dose-dense adjuvant chemotherapy for 3 cycles at least (best to 6 cycles), and 3-weekly bevacizumab 15 mg/kg was given since postoperative cycle 2. Further 3-weekly maintenance bevacizumab 15 mg/kg was given intravenously for 17 cycles. ResultsOf the 22 enrolled subjects, 13 (59.1 %) had no gross lesion after IDS. Of the 13 subjects enrolled on the 1 st stage, one study-defined significant AE occurred, therefore the trial proceeded to the 2nd stage (n = 9). The median progression-free survival (PFS) was 22.1 months (95 % confidence interval [CI], 13.7–30.5), and the median overall survival (OS) was 49.2 months (95 % CI, 33.8–64.6). Peritoneal Cancer Index score at entering abdomen during IDS was significant for PFS (>12 vs ≤ 12: p = 0.003). One of the 22 subjects did not receive any study treatment. In the safety analysis (n = 21), grade 3/4 AEs included thrombocytopenia of 38.1 %, neutropenia 71.4 %, and anemia 28.6 %. Study-defined significant AEs of bowel perforation, poor-healing wound, and hypertension were found in 1 case each, respectively. ConclusionThis phase II trial demonstrated adding bevacizumab to dose-dense adjuvant chemotherapy with bevacizumab maintenance after NAC was feasible with tolerable toxicity and comparable PFS/OS as compared to other studies using bevacizumab in the NAC phase or dose-dense scheduling throughout.

Effect of dose-dense adjuvant chemotherapy in hormone receptor positive/HER2-negative early breast cancer patients according to immunohistochemically defined luminal subtype: an exploratory analysis of the GIM2 trial

BackgroundLuminal A-like and luminal B-like subtypes have different sensitivity to (neo)adjuvant chemotherapy, but their role in predicting dose-dense (DD) efficacy in the high-risk setting is unknown. In this exploratory analysis of the Gruppo Italiano Mammella 2 (GIM2) trial, we investigated DD efficacy according to luminal-like subtypes. MethodsPatients with node-positive early breast cancer were randomised to receive either DD or standard-interval (SI) anthracycline-based chemotherapy followed by paclitaxel. In our analysis, luminal A-like cohort was identified as having a Ki67 < 20% and a progesterone receptor (PgR) ≥ 20%; luminal B-like cohort as having a Ki67 ≥ 20% and/or a PgR < 20%. ResultsOut of 2003 patients enrolled in the GIM2 trial, 412 had luminal A-like and 638 luminal B-like breast cancer. After a median follow-up of 7.9 years, disease-free survival (DFS) was 80.8% (95% confidence interval [CI] 76.4–84.5) and 70.5% (66.5–74.2) in luminal A-like and luminal B-like cohorts; overall survival (OS) was 91.6% (88.2–94.1) and 85.1% (81.7–87.9), respectively. We found no significant interaction between treatment and luminal subtype (interaction p = 0.603 and 0.535 for DFS and OS, respectively). When DD efficacy was investigated separately in each cohort, luminal-B like cohort appeared to benefit more from the DD schedule both in terms of DFS (unadjusted hazard ratio [HR] 0.72 [95% CI 0.54–0.96]) and OS (unadjusted HR 0.61 [95% CI 0.40–0.94]), compared with the luminal A-like cohort (unadjusted HR for DFS 0.89 [95% CI 0.59–1.33]; unadjusted HR for OS 0.83 [95% CI 0.45–1.54]). ConclusionsNo significant interaction between luminal-like subtype and treatment was observed. Patients in the luminal B-like cohort seemed to benefit more from DD schedule.

Dose-dense adjuvant chemotherapy in early breast cancer patients: 15-year results of the Phase 3 Mammella InterGruppo (MIG)-1 study

BackgroundAdjuvant chemotherapy is the standard of care in high-risk early breast cancer patients. Dose-dense should be the preferred schedule of administration. However, its long-term benefit is unknown.MethodsIn the Italian multicentre Phase 3 randomised MIG-1 trial, node-positive and high-risk node- negative breast cancer patients were randomised to receive six cycles of adjuvant fluorouracil, epirubicin and cyclophosphamide regimen administered every 3 (FEC21) or 2 (FEC14) weeks. The primary endpoint was overall survival (OS), and the secondary endpoint was event-free survival (EFS).ResultsFrom 1992 to 1997, 1214 patients were included. Median follow-up was 15.8 years. In all, 15-year OS was 71% and 68% in the FEC14 and FEC21 groups, respectively (HR = 0.89; p = 0.25). In all, 15-year EFS was 47% and 43% in the FEC14 and FEC21 groups, respectively (HR = 0.87; p = 0.18). In a pre-planned subgroup analysis, among patients with hormone receptor-negative tumours, 15-year OS was 70% and 65% in the FEC14 and FEC21 groups, respectively (HR = 0.73; 95% CI: 0.51–1.06); 15-year EFS was 58% and 43% in the FEC14 and FEC21 groups, respectively (HR = 0.70; 95% CI: 0.51–0.96).ConclusionsUpdated results from the MIG-1 study are numerically in favour of dose-dense chemotherapy, and suggest a long-term benefit of this approach in high-risk early breast cancer patients.

Abstract P3-11-22: Efficacy of two kinds of granulocyte colony-stimulating factors to support neoadjuvant dose-dense chemotherapy in primary breast cancer

Abstract Background and objective: Adjuvant chemotherapy is a critical part of systematic treatment of primary breast cancer. Chemotherapy induced neutropenia (CIN) is a common adverse event during adjuvant chemotherapy as well as a major factor limiting the implementation of the planned schedule of chemotherapy, causing the delay and drug reduction. Recombinant human granulocyte-colony stimulating factor (rhG-CSF) effectively stimulates the proliferation of neutrophil progenitors, promotes differentiation of these cells into mature neutrophils, and promote the release of neutrophils from the marrow, thus reducing the probability of CIN and related complications. Dose-Dense (DD) chemotherapy has become a commonly recommended regimen for primary breast cancer because of improvement of disease-free survival (DFS) and Overall Survival (OS). rhG-CSF should be administered prophylactically due to the high incidence of marrow suppression during dose-dense regimen. Little high-level clinical evidence to determine a unified rhG-CSF regimen. Single injection of long-acting pegfilgrastim and continuous multiple usage of short-acting filgrastim are two major ways to support dose-dense adjuvant chemotherapy. Based on a single database, we retrospectively assessed the efficacy and safety of two different rhG-CSF in supporting the dose-dense adjuvant chemotherapy (ddEC) in primary breast cancer, aiming to test the effectiveness of two different rhG-CSF as well as comparison of the advantages and disadvantages of the two methods. Methods: Data of patients who received dose-dense neoadjuvant chemotherapy with support of rhG-CSF at Peking University Cancer Hospital Breast Cancer Prevention and Treatment Center from Jul, 2015 to Jun, 2018 were retrospectively collected. All of these patients were planned to receive four cycles of ddEC (Epirubicin 100mg/m2 and cyclophosphamide 600 mg/m2) with using one of the following rhG-CSF schedules in parallel: 1) filgrastim 200-300μg/d on day 4, 6, 8, 10; 2) pegfilgrastim 6mg on day 2. The relative dose intensity (RDI) was calculated. Results: A total of 555 patients were enrolled and 2,176 cycles were completed in this study, 254 were treated with pegfilgrastim and 301 were treated with short-term filgrastim. 536 patients (96.6%, 95%CI: 95.1%-98.1%) completed all four cycles of treatment. Chemotherapy delay occurred in 42 patients (7.6%, 95%CI: 5.4%-9.8%) for 47 cycles (2.2%, 95%CI:11.6%-2.8%). 18 patients (3.2%, 95%CI:1.7% - 4.7%) had CIN-related chemotherapy delay. 532 patients achieved RDI≥85% (99.4%, 95%CI:98.7%-100%). FN occurred in 25 patients (4.5%, 95%CI:2.8% - 6.2%). In the subgroup of using pegfilgrastim, Chemotherapy delay occurred in 10 patients (3.9%, 95%CI:1.5%-6.3%), 243 patients achieved RDI≥85% (99.4%, 95%CI: 98.7%-100%), and FN occurred in 11 patients (4.3%, 95%CI: 1.8%-6.8%). In the subgroup of using short-term filgrastim, chemotherapy delay occurred in 15 patients (5.0%, 95%CI: 2.5%-7.5%), 289 patients achieved RDI≥85% (96%, 95CI: 93.8%-98.2%), and FN occurred in 14 patients (4.7%, 95%CI: 2.3%-7.1%). FN is more likely in patients using short-term filgrastim (6.3%vs2.8%, p=0.048), causing more chemotherapy delay (10.8%vs4.1%, p=0.003). Age, tumor size, status of axillary lymph nodes, pathological type and baseline of ANC were not correlated with non-febrile neutropenia in patients using short-term filgrastim. Conclusion: Two schedules of rhG-CSF are effective and safe in supporting four cycles of neoadjuvant ddEC. The effects of these two methods were similar in the completion rate of chemotherapy(RDI≥85%) and safety(incidence of FN). Citation Format: Jingyi Zhao, Yingjian He, Zhaoqing Fan, Jinfeng Li, Xinguang Wang, Yang Yang, Xue Chen, Tao Ouyang. Efficacy of two kinds of granulocyte colony-stimulating factors to support neoadjuvant dose-dense chemotherapy in primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-22.

Dose-dense adjuvant chemotherapy: a systematic review and meta-analysis of the Japanese Breast Cancer Society Clinical Practice Guideline, 2018 edition.

Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles may enhance efficacy. Dose-dense chemotherapy, which is adopted as adjuvant chemotherapy of high-risk breast cancer, is addressed in the Japanese Breast Cancer Society Clinical Practice Guideline for breast cancer, 2018 edition (in Japanese). To evaluate the benefits and safety of dose-dense adjuvant chemotherapy described in the guideline, we performed a systematic review and meta-analysis of data of randomized trials using the same drugs, doses, and numbers of cycles. The PubMed, Cochrane Library, and Ichushi-Web databases were searched for relevant publications reporting randomized trials published until November 2016. Overall survival (OS), disease-free survival (DFS), and toxicity were assessed. Three trials comprising 5190 patients were included. Compared with conventional chemotherapy, dose-dense chemotherapy lengthened OS (RR = 0.76; 95% CI = 0.64-0.90) and DFS (RR = 0.83; 95% CI = 0.75-0.92) and increased the risk of anemia (RR = 4.56; 95% CI = 2.01-10.34). We conclude that dose-dense chemotherapy can be highly recommended as adjuvant chemotherapy for patients with breast cancer with a high risk of recurrence risk and sufficient bone marrow function.

Dose-dense adjuvant chemotherapy in HER2-positive early breast cancer patients before and after the introduction of trastuzumab: Exploratory analysis of the GIM2 trial.

Dose-dense adjuvant chemotherapy is standard of care in high-risk early breast cancer patients. However, its role in HER2-positive patients is still uncertain. In this exploratory analysis of the GIM2 trial, we investigated the efficacy of dose-dense chemotherapy in HER2-positive breast cancer patients with or without exposure to trastuzumab. In the GIM2 trial, node-positive early breast cancer patients were randomized to receive four cycles of (fluorouracil)epirubicin/cyclophosphamide followed by four cycles of paclitaxel administered every 2 (dose-dense) or 3 (standard-interval) weeks. After approval of adjuvant trastuzumab, protocol was amended in April 2006 to allow use of trastuzumab for 1 year after chemotherapy completion in HER2-positive patients. The efficacy of dose-dense chemotherapy in terms of disease-free survival (DFS) and overall survival (OS) was assessed according to HER2 status and trastuzumab use. Out of 2,003 breast cancer patients, HER2 status was negative/unknown in 1,551 patients; among the 452 patients with HER2-positive breast cancer, chemotherapy alone or followed by trastuzumab was given to 320 and 132 patients, respectively. Median follow-up was 8.1 years. No significant interaction between HER2 status, trastuzumab use and chemotherapy treatment was observed for both DFS (p = 0.698) and OS (p = 0.708). Nevertheless, there was no apparent benefit in the HER2-positive group treated with trastuzumab (DFS: HR, 0.99; 95% CI 0.52-1.89; OS: HR, 0.95; 95% CI 0.37-2.41). Although dose-dense chemotherapy was associated with a significant survival improvement in high-risk breast cancer patients, its benefit appeared to be smaller (if any) in patients with HER2-positive disease who received adjuvant trastuzumab.

Role of dose-dense chemotherapy in high-risk early breast cancer.

Adjuvant chemotherapy for breast cancer significantly reduces the risk of recurrence and improves overall survival (OS). The purpose of the current article is to review available evidence on dose-dense chemotherapy, also focusing on special population, including premenopausal women and those with HER2-positive disease. A recent patient-level meta-analysis showed that the use of dose-dense chemotherapy is associated with significant reduction in disease recurrence, breast cancer mortality and improvement in OS. The benefit of dose-dense chemotherapy is irrespective from HER2 status, although women with HER2-positive disease enrolled in trials included in the meta-analysis did not receive the current standard of treatment with anti-HER2 agents. Among premenopausal women, dose-dense chemotherapy improved OS, and thus should be considered standard of care for them. In conclusion, high-risk early stage breast cancer patients should be treated with (neo)adjuvant dose-dense anthracycline-based chemotherapy followed by paclitaxel. In the era of trastuzumab, the benefit of dose-dense chemotherapy is still unclear for patients with HER2-positive breast cancer.