Dose-dense Regimen Research Articles

Sustained lymphocyte decreases after treatment for early breast cancer

The role of adaptive immunity in long-term outcomes in early breast cancer is increasingly recognised. Standard (neo)adjuvant chemotherapy can have adverse effects on immune cells. We conducted a retrospective longitudinal study of full blood counts (FBC) of 200 patients receiving (neo)adjuvant chemotherapy for early breast cancer at a single institution. FBC results at four time points from pre-treatment to 12 months post-chemotherapy were analysed. Flow cytometry was performed for patients with matched pre- and post-chemotherapy peripheral blood mononuclear cell samples. A significant decrease in absolute lymphocyte count at 12 months post-chemotherapy was observed (p < 0.01), most pronounced in pre-menopausal patients (n = 73; p < 0.01), patients receiving dose-dense chemotherapy regimens (n = 60; p < 0.01) and patients receiving adjuvant radiotherapy (n = 147, p < 0.01). In pre-menopausal patients, significant changes in CD4+ T cells subsets post-chemotherapy were observed. Further investigation, including long-term clinical outcomes, is needed to meaningfully improve long-term anti-tumour immunity.

Dose dense versus 3 weekly AC during neoadjuvant chemoimmunotherapy for triple negative breast cancer

Neoadjuvant pembrolizumab plus chemotherapy (P + CT) has emerged as a standard of care for stage II-III triple-negative breast cancer (TNBC). However, the best anthracycline-cyclophosphamide (AC) schedule remains to be determined. While the KEYNOTE-522 regimen employs AC every 3 weeks (q3w AC), previous studies have shown overall survival benefits of dose-dense regimens for early-stage breast cancer. The Neo-Real study (GBECAM-0123) is a real-world data effort evaluating patients with TNBC treated with neoadjuvant P + CT in ten cancer centers since July 2020. The objective of this analysis was to evaluate the effectiveness and safety of dose-dense AC (ddAC) versus q3w AC. Among 333 patients included until November 2023, 311 completed neoadjuvant therapy and 279 underwent surgery with pathology reports available; ddAC was used in 58.2% and q3w AC in 41.8% of the cases. Most patients (69.1%) had stage II TNBC. A pCR was observed in 65.4% with ddAC and 58.7% with q3w AC (P = 0.260), while RCB 0-1 occurred in 82.4% and 73.5%, respectively (P = 0.115). Patients with stage III disease had a numerically higher pCR with ddAC (59% vs 40%, P = 0.155), while pCR rates were similar regardless of AC regimen in stage II disease (66.6% vs 64.5%; P = 0.760). While no significant disparities in drug discontinuation was noted, ddAC showed a trend towards higher rates of grade ≥3 AE (40.5% vs. 30.7%, P = 0.092). The Neo-Real study could not rule out a difference between ddAC and q3w AC during neoadjuvant P + CT. The observation of a potentially higher pCR with ddAC in stage III disease warrants further investigation.

Tailored Dose-Dense Versus Standard Adjuvant Chemotherapy for High-Risk Early Breast Cancer: End-of-Study Results of the Randomized PANTHER Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Although dose-dense adjuvant chemotherapy administered once every 2 weeks leads to superior outcomes compared with standard regimens once every 3 weeks, the observed improvement is largely limited to studies using the suboptimal paclitaxel schedule once every 3 weeks as control. PANTHER is an international phase III trial which compared sequential epirubicin/cyclophosphamide and docetaxel administered either once every 2 or once every 3 weeks, with tailored dosing at the dose-dense schedule according to hematologic toxicity. In this end-of-study analysis, the median follow-up was 10.3 years. Compared with standard adjuvant chemotherapy, dose-dense treatment improved breast cancer recurrence-free survival (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.98]; P = .030), event-free survival (HR, 0.78 [95% CI, 0.65 to 0.94]; P = .009), and distant disease-free survival (HR, 0.79 [95% CI, 0.64 to 0.98]; P = .030) while the improvement in overall survival was not statistically significant (HR, 0.82 [95% CI, 0.65 to 1.04]; P = .109). To our knowledge, this is the first trial that confirms the benefit of a dose-dense regimen over a control regimen containing docetaxel once every 3 weeks.

Controversies on chemotherapy for early HR+/HER2- breast cancer: the role of anthracyclines and dose intensification.

Use of adjuvant chemotherapy significantly reduces the risk of recurrence and improves overall survival (OS) in patients with early-stage breast cancer. However, few data are available on the efficacy of different adjuvant chemotherapy regimens and schedules in patients with hormone receptor positive/HER2-negative (HR+/HER2-) breast cancer. We aim to summarize the available evidence on the efficacy of adjuvant anthracycline-based chemotherapy and of the dose-dense schedule in this specific patient population. Moreover, current controversies in the management of patients with early-stage HR+/HER2- breast cancer are discussed. Patient-level meta-analysis evaluating the role of the addition of an anthracycline to taxane-based chemotherapy showed that recurrence rate was lower among patients receiving anthracycline-based treatment.Patient-level meta-analysis evaluating the role of different schedules of chemotherapy administration showed that the use of adjuvant dose-dense chemotherapy is associated with significant reduction in breast cancer recurrences and breast cancer mortality. Less evidence is available in the neoadjuvant setting. For patients with high-risk HR+/HER2- breast cancer, (neo) adjuvant anthracycline and taxane-based chemotherapy, and a dose-dense regimen should still be considered the standard of care. However, in patients with intermediate risk breast cancer candidates to chemotherapy, anthracycline-free regimens could be considered the preferred treatment option.

Phase II trial of weekly or bi-weekly tocilizumab with ipilimumab and nivolumab in advanced melanoma: Clinical outcomes and biomarker analysis.

9553 Background: Combination immune-checkpoint inhibitors (ICIs) improved outcomes in a plethora of cancer subtypes. However, up to 60% of patients (pts) receiving ipilimumab (ipi) plus nivolumab (nivo) experience grade 3/4 (G 3/4) immune-related adverse events (irAEs), often leading to treatment discontinuation. We evaluated two therapeutic strategies targeting interleukin-6 receptor (IL-6R) to reduce irAEs while enhancing ICls efficacy. Methods: Phase Il trial (NCT04940299) investigating safety/efficacy of frontline tocilizumab (toci; IL-6R inhibitor) combined with ipi 3mg/kg + nivo 1mg/kg Q3 weeks (wks) for 12 wks in advanced melanoma. Initially, toci was given as 162 mg subcutaneously (SQ) bi-weekly for 6 doses (regular dosing regimen; RD). Then, we escalated to a dose dense (DD) regimen (162 mg SQ weekly for 6 wks then bi-weekly for 6 wks; 9 doses total). Primary objective was rate of G 3/4 irAEs. Secondary objectives were objective response rates (ORR) and disease control rate (DCR) per RECIST 1.1. Exploratory objectives involved immune analysis (gene expression, CyTOF, cytokine analysis) on longitudinal blood and tissue samples to identify drivers of auto- vs antitumor immunity. Results: As of Feb 2024, 35 pts were enrolled (25 pts to RD regimen; 10 pts to DD regimen). In RD group, median follow-up is 18 months (6 - 25 months). By 12 wks, 44% of pts developed G 3/4 irAEs including colitis (20%), hepatitis (16%), pancreatitis (12%), type I diabetes and serum sickness (4% each) and 20% of pts required hospitalization due to irAEs. Median time to G 3/4 irAEs onset was 7.4 wks. 16% of pts discontinued ICIs due to irAEs. ORR was 56% at 12 wks including 40% in pts with high LDH and DCR was 80%. Gene expression analysis showed a trend towards higher expression of IL-17 pathway genes in pts who developed G 3/4 irAEs, suggesting IL-6/Th17 pathway was not sufficiently inhibited. Thus, we enrolled 10 pts into the DD regimen aiming to achieve better inhibition of the IL-6/Th17 pathway. In DD group, median follow-up is 7 months (3 - 13 months). By 12 wks, 40% of pts developed G 3/4 irAEs, including colitis (10%), hepatitis (20%), and uveitis (10%) and 30% of pts required hospitalization due to irAEs. Median time to G 3/4 irAEs onset was 4.9 wks. 30% of pts discontinued ICIs due to irAEs. ORR was 70% at 12 wks including 75% in pts with high LDH and DCR was 80%. Conclusions: To our knowledge, this is the first study to investigate toci in combination with high dose ipi3/nivo1. Although our cohort is small, preliminary data suggests IL-6R blockade using the DD regimen could decrease the rate of G 3/4 irAEs while maintaining antitumor responses of ipi3/nivo1. A randomized phase ll trial investigating this strategy is underway. Ongoing immune analysis comparing treatment regimens aims to identify distinct pathways involved in auto- vs antitumor immunity and IL-6/Th17 independent pathways of toxicity. Clinical trial information: NCT04940299 .

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.

Heterogeneous treatment effect of dose-dense paclitaxel plus carboplatin therapy for advanced ovarian cancer.

A Japanese clinical trial (JGOG3016) showed that dose-dense weekly paclitaxel in combination with carboplatin extensively prolonged overall survival (OS) in patients with advanced ovarian cancer. However, in other clinical trials, dose-dense paclitaxel regimens were not superior to triweekly paclitaxel regimens. In this study, causal tree analysis was applied to explore subpopulations with different treatment effects of dose-dense paclitaxel in a data-driven approach. The 587 participants with stage II-IV ovarian cancer in the JGOG3016 trial were used for model development. The primary endpoint was treatment effect in terms of 3-year OS in patients receiving dose-dense vs. conventional paclitaxel therapies. In patients <50 years, the 3-year OS was similar in both groups; however, it was higher in the dose-dense group in patients ≥50 years. Dose-dense paclitaxel showed strong positive treatment effects in patients ≥50 years with stage II/III disease, BMI <23 kg/m2, non-CC/MC, and residual tumor ≥1 cm. In contrast, although there was no significant difference in OS; the 3-year OS rate was 23% lower in dose-dense paclitaxel than conventional paclitaxel in patients ≥60 years with stage IV cancer. Patients in this group had a particularly lower performance status than other groups. Our causal tree analysis suggested that poor prognosis groups represented by residual tumor tissue ≥1 cm benefit from dose-dense paclitaxel, whereas elderly patients with advanced disease and low-performance status are negatively impacted by dose-dense paclitaxel. These subpopulations will be of interest to future validation studies. Personalized treatments based on clinical features are expected to improve advanced ovarian cancer prognosis.

Abstract PO2-01-03: Efficacy of dose-dense and anthracycline-free regimens in neoadjuvant chemotherapy of HER2-positive breast cancer: a single-center matched-cohort study. Preliminary results

Abstract Introduction: The efficacy of dose-dense (dd) adjuvant chemo has been proved in numerous clinical trials and meta-analysis. However, it remains unclear whether the intensification of AC (doxorubicine/cyclophosphamide) regimen affects the rate of pathological complete response (pCR) in HER2+ subtype, since the efficiency of thе ddAC-THP (docetaxel/trastuzumab/pertuzumab) regimen with dual anti-HER2-blocade in the neoadjuvant (NA) setting has not been assessed. Anthracycline (A)–containing and A-free regimens (TCHP -docetaxel/carboplatin/trastuzumab/pertuzumab) are considered equivalent, although there are no direct comparative studies to date. Methods: The aim of the study was to assess the rate of pCR of ddAC (once every 2 weeks)-THP NA regimen in comparison with ACq3w (once every 3 weeks)-THP and A-free TCHP regimen in HER2+ stage II-III breast cancer (BC). The study included patients with early HER2+ BC who received NA chemo in a single center from Jan 2017 to Nov 2022. Statistical hypothesis. The study has a 2-step design. It is assumed that the rate of pCR with ddAC will be ≥65%, and with ACq3w≤50%. With a unilateral type I error (α) = 0.05 and a type II error (β) = 0.2, 170 patients should be included in each group. In the absence of significant differences between ddAC and 4ACq3w, groups may be merged into one cohort and compared with TCHP group. It is assumed that A-containing regimens (H1 - pCR 55%) are not inferior to A-free regimen (H0 - pCR 55%). A non-inferiority design is planned, with delta 15%, type I error (α) = 0.05 and type II error (β) = 0.2, 173 people in each group should be included. Here we present preliminary results. Results: A total of 400 patients were included, of which 138 received 4xddAC- 4xTHP, 102 – 4xACq3w-4 x THP, 160 – 6xTCHP. The pCR rate in the whole ddAC-THP group was 55,8%. The majority of patients (77,5%) had stage III disease. After propensity matching analysis to adjust for selection bias 102 patients in each A-containing group were included in the final analysis. The pCR rate was 50% in the ddAC group vs 48% in the ACq3w group (p=0.67). Subgroup analysis, including T, N stage, age, ER status, G, ki67 revealed no advantage of ddAC regimen. Next, both A-groups were merged and after propensity matching analysis 143 patients were included both in A- and TCHP-group. The pCR rate was 53,8% in the A-group vs 60,1% in the TCHP group (p=0.34). Subset analysis demonstrated no benefit of A-regimen across subgroups. Conclusion: Our preliminary results suggest that A-containing and TCHP regimens appear to be equivalent in terms of pCR. In case of choosing AC-THP for NA chemo there’s no need to perform the AC arm in dd way since it does not improve efficacy. Citation Format: Elena Kovalenko, Yaroslav Zhulikov, Maxim Khoroshilov, Igor Vorotnikov, Alexander Petrovskiy, Elena Artamonova. Efficacy of dose-dense and anthracycline-free regimens in neoadjuvant chemotherapy of HER2-positive breast cancer: a single-center matched-cohort study. Preliminary results [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-01-03.

Abstract PO4-01-12: Efficacy of neoadjuvant dose-dense versus standard chemotherapy regimens in ER+ HER2-negative breast cancer: a single-center matched-cohort study. Exploratory analysis of immune markers

Abstract Introduction: Dose-dense adjuvant CT improves long-term outcomes, which has been proved in clinical trials and meta-analysis. However, the efficiency of thе modern dose dence (dd) anthracycline-taxane (A-T) sequential regimens in the neoadjuvant (NA) setting of ER+HER2- breast cancer (BC) has not been assessed. Tumour-infiltrating lymphocytes (TILs) play a key role in the formation of anti-tumor immunity and can be one of the markers of treatment efficacy and prognosis. Studies evaluating TILs in ER+ BC have mixed results. Materials and methods. The aim of the study was to assess the rate of RCB 0-I of 4xddAC (doxorubicine/cyclophosphamide)–T (4xdocetaxel once every 3 weeks or 12xpaclitaxel weekly) NA chemo compared to standart regimen and to study the subpopulation composition of the lymphoid infiltrate and its effect on achieving RCB 0-I. RCB 0-I as a primary end point was chosen due comparable long-term results in ER+HER2- BC as per meta-analisys. Results: The study included pts with stage II-III ER+(ER≥10%) HER2- BC who received NA A-T chemo in a single center from Jan 2017 to Aug 2022. The majority of patients (85,2%) had stage III disease. Statistical hypothesis: NA ddAC–T chemo would increase the rate of RCB 0-1 to 32% from 22% with ACq3w (once every 3 weeks)-T, with a study power of 80%, ά = 0.05, 138 patients should be included in the study. A total of 315 patients were included, 147 received ddAC-T and 168 - ACq3w-T. After propensity matching analysis 138 patients in each group were included in the final analysis. TILs were studied in core-biopsy samples before NA chemo in 79 patients by flow cytometry. The following 8 subpopulations of lymphocytes were assessed as percentage in the cell pool: CD3+, CD3+CD4+, CD3+CD8+, CD4+CD127+CD25+, CD3-CD19+, CD3-CD16+CD56+, CD3+CD16+CD5+, CD8+CD279+(PD-1). The results are presented in medians (Me) due to abnormal distribution. The RCB 0 rate was 18.8% in the ddAC-T group vs 14.5% in the ACq3w-T group (p=0.379), RCB 0-1 - 33.3% vs 21.7% respectively (p=0.04). According to subgroup analysis, significant benefit of ddAC regimen found in patients ≤ 50 y.o., cN0, with PR ≥20%. For the following populations of TILs significant differences in Me for RCB0-I vs RCB II-III were observed: CD3+CD8+, CD3–CD19+, CD3–CD19+, CD8+CD279+. In multivariative analisys CD8+CD279+(PD-1)≤Me proved to be an independent predictive factor for RCB 0-I (p=0,048). Immunological signature CD8+CD279+ ≤ Me, CD3+CD8+ ≤ Me, CD4+CD25+ &amp;gt; Me, CD3-CD19+ &amp;gt; Me was associated with the rate of 66,7% of RCB 0-I vs 0% with the signature with the opposite values. Conclusion: ddAC-T NA chemo compared to standart regimen in ER+HER2- BC increases RCB0-1 rate. CD8+CD279+(PD-1)≤Me is an independent predictive factor for RCB 0-I. Citation Format: Elena Kovalenko, Elena Artamonova, Yaroslav Zhulikov, Maxim Khoroshilov, Alexander Petrovskiy, Igor Vorotnikov, Tatiana Zabotina, Zaira Kadagidze. Efficacy of neoadjuvant dose-dense versus standard chemotherapy regimens in ER+ HER2-negative breast cancer: a single-center matched-cohort study. Exploratory analysis of immune markers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-01-12.

Abstract PO2-16-09: Dose-dense versus 3-weekly AC during Neoadjuvant Chemoimmunotherapy for Early-Stage Triple-Negative Breast Cancer (TNBC): a Real-World Safety and Efficacy Data Analysis

Abstract Background: The Keynote-522 (KN-522) study established the use of pembrolizumab in combination with neoadjuvant carboplatin-paclitaxel, followed by 3-weekly (3w) anthracycline-cyclophosphamide (AC), as the standard of treatment for stage II-III TNBC. However, dose-dense chemotherapy (CT) improves survival rates compared to the standard schedule in early-stage breast cancer and several groups have been modifying the KN-522 regimen with dose-dense AC (ddAC). The objective of this study was to compare the safety and effectiveness of ddAC versus the q3w schedule. Methods: We conducted a multicentric real-world analysis of patients (pts) with early-stage TNBC who received neoadjuvant CT plus pembrolizumab at nine cancer centers. Safety endpoints included grade ≥ 3 adverse events (AEs), drug discontinuation, hospitalization due to AEs, and the use of antibiotics during neoadjuvant therapy. Pathologic complete response (pCR) was used as the effectiveness endpoint, and we performed univariate and multivariable logistic regression to evaluate factors associated with pCR. Results: To date, we included 168 pts in this study of which 137 pts have finished the neoadjuvant therapy phase and constituted our safety cohort. Among them, 86 pts (62.8%) received ddAC and 51 pts (37.2%) were treated with the 3w schedule. The two groups exhibited no significant differences in baseline characteristics; the median age was 42 years (range 29 - 75), 70.8% had stage II and 25.5% had stage III TNBC, 46.7% had positive lymph nodes, and 74.4% had a Ki67-index ≥ 50%. Overalls, 30.2% and 27.4% presented grade ≥ 3 AEs with ddAC and 3w AC, respectively, with no significant difference between the two groups (p=0.177). Grade ≥ 3 immune-related AEs (irAEs), occurred in 8.1% with ddAC and 3.9% with 3w AC (0.335). The most common grade ≥ 3 irAEs were pneumonitis (n=4) and hepatitis (n=2). The ddAC group had a higher rate of any drug discontinuation due to toxicities (24.4% vs. 11.8%, p=0.043) and a greater use of antibiotics (27.9% vs. 11.8%, p=0.009) compared to the 3w group. There was a trend toward more rates of hospitalization due to AEs in the ddAC group, although this was not statistically significant (17.4% vs 11.8%, p=0.131). At the time of data analysis cutoff, a total of 119 pts underwent surgery and have pathology report available and were included in the efficacy cohort. In the univariate analysis, the pCR rates were 65.8% with ddAC and 55.8% with 3w AC (OR 1.52, 95% CI 0.70-3.27, p=0.282). The rates of RCB (residual cancer burden) 0-1 were 81.2% and 67.6%, respectively (OR 2.06, 95% CI 0.82 – 5.16, p=0.120). Factors influencing rates of pCR were Ki67 index ≥ 50% and tumor staging, which remained significant in the multivariable analysis (Table). In the 3w AC group, no difference in pCR was observed between pts who used or not granulocyte colony stimulating-factors (61.1% vs 52%, p=0.553). Conclusion: No difference in grade ≥ 3 AEs was observed between ddAC and 3w AC in pts with early-stage TNBC receiving neoadjuvant CT plus pembrolizumab. Nevertheless, the dose-dense regimen was linked to higher rates of drug discontinuation and antibiotic use. Although the pCR rates numerically favored ddAC, the difference was not statistically significant. Thus, the medical community should consider carefully risks and benefits of using ddAC within the KN522 regimen. Larger studies and longer follow-up are warranted to assess the long-term outcomes of the CT schedules. Multivariable regression of factors associated with pCR Citation Format: Renata Colombo Bonadio, Fernanda Madasi, José Bines, Rafael Ferreira, Daniela Rosa, Candice Santos, Zenaide Souza, Daniele Assad-Suzuki, Julio Araujo, Débora Gagliato, Carlos dos Anjos, Bruna Zucchetti, Anezka Ferrari, Mayana Lopes, Renata Cangussu, Maria Marcela Monteiro, Paulo Hoff, Laura Testa, Romualdo Barroso-Sousa. Dose-dense versus 3-weekly AC during Neoadjuvant Chemoimmunotherapy for Early-Stage Triple-Negative Breast Cancer (TNBC): a Real-World Safety and Efficacy Data Analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-16-09.

Retrospective Observational Study to Determine the Epidemiology and Treatment Patterns of Patients with Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) poses a serious therapeutic challenge due to the occurrence of frequently aggressive, heterogenic, and metastatic tumours. The absence of therapeutic targets for traditional therapies is a hindrance to establishing a standardised therapy for TNBC. There is limited TNBCs epidemiological and real-world data about TNBC treatment regimens in Poland. We retrospectively analysed clinical data from our hospital registry from 2015 and 2020. A total of 8103 individuals with breast cancer were admitted to the MSCI, while 856 (10.6%) were diagnosed with TNBC. Most of the early-stage or locally advanced TNBC individuals had underlying conditions, presented mostly poorly differentiated (G3) stage II tumours and featured a bi-modal age distribution. On average, one-third of all tested TNBCs carried BRCA mutations and its identification impacted surgery preference. We observed a significant increase in the use of systemic therapy among TNBCs, whereas carboplatin and dose-dense regimens showed the most prominent upsurge in the neoadjuvant setting. Moreover, the use of neoadjuvants was positively correlated with less invasive breast and lymph node surgeries. The presented data align with general trends observed in other countries and will contribute to expanding knowledge in the planning of treatment regimens and their outcomes.

Dose-Dense Mini-Hyper-CVD, Inotuzumab Ozogamicin and Blinatumomab Achieves Rapid MRD-Negativity in Philadelphia Chromosome-Negative B-cell Acute Lymphoblastic Leukemia

BackgroundThe combination of low-intensity chemotherapy and inotuzumab ozogamicin (INO), with sequential blinatumomab, is highly effective in older adults with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and in relapsed or refractory B-cell ALL. Earlier, “dose-dense” administration of blinatumomab could lead to earlier and deeper measurable residual disease (MRD) responses and better outcomes. Patients and MethodsWe performed a retrospective analysis of the safety and efficacy of a dose-dense regimen of mini-hyper-CVD (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with mini-methotrexate and cytarabine), INO, and blinatumomab in patients with B-cell ALL. ResultsTwenty-one patients were treated (frontline, n = 9; MRD consolidation, n = 4; relapsed/refractory, n = 8). In the frontline cohort, all patients achieved CR/CRi and MRD negativity by flow cytometry at the end of cycle 1. Across the frontline and MRD consolidation cohorts, 10/11 patients (91%) achieved next-generation sequencing MRD negativity at a sensitivity of 10−6, including 6/10 evaluable patients (60%) who achieved next-generation sequencing MRD negativity after cycle 1. The CR/CRi rate in the relapsed/refractory cohort was 63%, and all responders achieved MRD negativity by flow cytometry at the end of cycle 1. The 1-year overall survival rate for the combined cohort of the frontline and MRD-positive patients was 83%. No new safety signals were observed with the dose-dense mini-hyper-CVD, INO, and blinatumomab regimen. ConclusionDose-dense delivery of mini-hyper-CVD, INO, and blinatumomab was safe and resulted in rapid and deep MRD negativity in patients with B-cell ALL. This regimen is now being prospectively evaluated in both the frontline and relapsed/refractory settings.

Dose-Dense Chemotherapy Regimen for Breast Cancer Associated with Significant Decline in Ovarian Reserve.

Purpose: To determine the impact of dose-dense chemotherapy administration on ovarian reserve in women undergoing treatment for breast cancer. Patients and Methods: We conducted a retrospective cohort study of reproductive age women who underwent dose-dense chemotherapy regimens with doxorubicin hydrochloride and cyclophosphamide with or without paclitaxel for a new diagnosis of breast cancer. We compared pre- and post-treatment serum antimullerian hormone (AMH) levels and assessed changes in AMH over time. Results: Fifty-seven patients met inclusion criteria. Median pre-treatment AMH was 2.9 ng/mL, whereas post-treatment AMH was 0.1 ng/mL, demonstrating a dramatic reduction in AMH levels after treatment with a dose-dense regimen. This change was independent of age and was sustained over 12 months from treatment completion. Conclusions: Dose-dense chemotherapy regimens for breast cancer lead to marked and sustained decreases in AMH irrespective of patient age.

Efficacy of dose-dense versus standard neoadjuvant chemotherapy regimensin luminal HER2-negative breast cancer: Interim results of single-centre study

Introduction. The efficacy of dose-dense AC in adjuvant chemotherapy of luminal breast cancer (ER+ BC) compared with the standard dosing regimen followed by switching to taxanes has been proven in numerous clinical trials and in a large meta-analysis of the EBCTCG group. However, no study about efficiency of this regimen in neoadjuvant setting has been published.The aim of the study. To assess the effectiveness of dose-dense regimens of neoadjuvant chemotherapy (NAC) of ER + HER2-BC (4 AC once every 2 weeks (dose dense, ddAC), then 4 courses of Docetaxel once every 3 weeks or 12 weekly injections of Paclitaxel [4D/12P]) and their comparison with the standard ones (AC once every 3 weeks [ACq3w], hereinafter 4D/12P). Primary end points are complete response rate (pCR) and RCB0–I.Methods. This retrospective study included patients with resectable or locally advanced luminal HER2-negative breast cancer who received NAC from Janu 2017 to Aug 2022. Statistical hypothesis – the dose-dense regimen AC increases the frequency of RCB0–I from 22 to 32% compared to the standard dosing regimen with subsequent switching to taxanes, with a study power of 80%, ά = 0.05, 138 patients should be included in the study. A total of 315 patients were included in the study, of which 147 and 168 patients received dose-dense (ddAC) and standard chemotherapy (ACq3w), respectively. After propensity matching analysis 138 patients in each group were included in the final analysis.Results. The pCR rate was 18.84% in the ddAC group versus 14.49% in the AC q3w group, the differences were not statistically significant (p = 0.379). The frequency of RCB0–I was higher in the ddAC – group 33.33% versus 21.74% in the AC q3w (p = 0.040). According to the subgroup analysis, rate of RCB0–I was significantly higher in patients younger 50 years, cN0, with the expression of progesterone receptors in ≥ 20%.Conclusions. This is the first study to compare the efficacy of a ddAC NAC with a standard regimen for ER + HER2-BC. NAC with ddAC is associated with an increase in RCB0–I rate.

“Dose-Dense” Mini-Hyper-CVD, Inotuzumab Ozogamicin and Blinatumomab Achieves High Rates of Rapid MRD-Negativity in Patients with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia: A Retrospective Analysis

Background: Mini-hyper-CVD plus inotuzumab ozogamicin (InO) followed by sequential blinatumomab (Blina) is effective in both older adults with newly diagnosed B-cell ALL and in relapsed/refractory disease. We hypothesized that concomitant administration of these agents in a “dose-dense” (DD) fashion would also be safe and effective in B-cell acute lymphoblastic leukemia (ALL), leading to rapid measurable residual disease (MRD) negativity. Methods: This is a retrospective analysis of patients (pts) with B-cell ALL who received DD mini-hyper-CVD + InO + Blina outside of a clinical trial. All pts received mini-hyper-CVD alternating with mini-methotrexate and cytarabine in combination with InO. To be evaluable for this analysis, Blina must have started prior to day 21 of the first cycle of therapy. Pts were included if they received this regimen for 1.) frontline induction, 2.) treatment of MRD-positive remission, or 3.) salvage therapy for relapsed/refractory (R/R) disease. Results: Between 7/2020 and 1/2023, 21 eligible pts were treated (Table 1 ). The median age was 48 years (range, 6-74 years); 3 pts (all in the R/R cohort) were &amp;lt;18 years old. 9 pts (43%) were treated as frontline therapy, 4 (19%) for treatment of MRD (3 for flow-positive MRD and 1 for persistent FISH for t[4;11]), and 8 (38%) for R/R disease. In the MRD cohort, 3 pts were in first CR and 1 was in second CR; 1 pt received prior InO and 1 had prior allogeneic stem cell transplant (alloSCT). In the R/R cohort, pts were heavily pretreated, with a median number of prior therapies of 3 (range, 1-7); 2 pts received prior InO, 3 pts received prior Blina, 3 pts had undergone prior allo SCT, and 3 pts had received prior chimeric antigen receptor T-cell (CAR-T cell) therapy. Three pts (all in the R/R cohort) had extramedullary (EM) disease, 2 outside of the CNS without marrow disease and 1 with CNS disease and bone marrow MRD by flow. Pts received a median of 2 cycles (range, 1-5) of a dose-dense regimen. All pts received 0.9 mg/m 2 InO in cycle 1, except for 1 pt in the R/R cohort who received 0.6 mg/m 2 due to myelosuppression with prior InO. Themedian cumulative dose of InO was 1.2 mg/m 2 (range, 0.6-2.7 mg/m 2). Blina was started on a median of day 4 (range, day 4-17) of the first cycle of chemotherapy. Blina was started by day 7 in 16 pts (76%). In the frontline cohort, all pts (100%) achieved CR/CRi (CR in 8 pt and CRi in 1 pt), all after cycle 1 ( Table 2). All pts in the frontline cohort achieved flow MRD negativity. 7 pts were evaluable for bone marrow next generation sequencing (NGS) MRD (sensitivity 10 -6). Of these, 4/6 (67%) achieved NGS MRD negativity after cycle 1, and all 7 evaluable pts (100%) achieved NGS MRD negativity. In the MRD cohort, all 3 flow-positive pts became flow MRD negative after cycle 1; the pt with positive FISH for t(4;11) became FISH-negative after cycle 2. 3 of the 4 pts in the MRD cohort (75%) became NGS MRD negative. Overall, 5 of the 8 pts (63%) in the R/R cohort achieved CR/CRi. Among 5 evaluable pts in the R/R cohort with marrow disease (including the pt with CNS disease and MRD-positive marrow), all achieved flow MRD negativity after cycle 1. Overall, 7 pts (33%) underwent consolidative alloSCT (2 in the MRD cohort and 5 in the R/R cohort), and 1 pt in the MRD cohort underwent consolidative CAR-T cell therapy. The treatment regimen was well tolerated. No patients developed sinusoidal obstruction syndrome/veno-occlusive disease. One pt had grade 1 CRS, and 2 pts had grade 1 tremor. With a median follow-up of 13.4 months (range, 0.5-20.6 months), 6 pts (29%) have died (1 in the frontline cohort, 1 in the MRD cohort and 4 in the R/R cohort). 3 deaths were due to complications of alloSCT, 2 were due to sepsis (1 in the setting of refractory leukemia and 1 during MRD-negative CR), and 1 from unknown cause. Among 18 responding pts, only 1 pt relapsed; the pt with MRD-positive t(4;11) by FISH relapsed 4.5 months after alloSCT. The median OS for the R/R cohort was 5.8 months and was not reached for the frontline or MRD cohorts. The 1-year OS rate for the frontline + MRD cohort was 83%. Conclusion: Dose-dense mini-hyper-CVD in combination with InO and Blina achieves rapid MRD-negative remissions in patients with B-cell ALL. All responding patients achieved flow MRD negativity after 1 cycle of therapy, with the majority also achieving NGS MRD negativity. This regimen is now being prospectively evaluated in an ongoing clinical trial in pts with R/R B-cell ALL and in older adults with newly diagnosed B-cell ALL.

Real-world data analysis of perioperative chemotherapy patterns, G-CSF use, and FN status in patients with early breast cancer

PurposeThis study aimed to describe perioperative chemotherapy patterns, granulocyte colony-stimulating factor (G-CSF) use, and febrile neutropenia (FN) status in patients with early breast cancer (EBC) using real-world data in Japan.MethodsThis retrospective observational study used anonymized claims data. The included patients were ≥ 18 years old, were female, and had breast cancer diagnosis and surgery records between January 2010 and April 2020. Measures included perioperative chemotherapy, G-CSF use (daily and primary prophylaxis [PP]), and FN and FN-related hospitalization (FNH), all examined annually. Perioperative chemotherapy was examined separately for human epidermal growth factor receptor 2-positive/negative (HER2±). A multivariate logistic regression was used to explore the factors associated with FNH.ResultsOf 32,597 patients, those with HER2 + EBC treated with anthracycline-based regimens followed by taxane + trastuzumab + pertuzumab increased since 2018, and those with HER2 − EBC treated with doxorubicin/epirubicin + cyclophosphamide followed by taxane and dose-dense regimens increased after 2014. The proportion of patients prescribed daily G-CSF declined after 2014, whereas that of pegfilgrastim PP increased. The incidence proportion of FN remained at approximately 24–31% from 2010 to 2020, while that of FNH declined from 14.5 to 4.0%. The odds of FNH were higher in those aged ≥ 65 years and lower with pegfilgrastim PP administration.ConclusionDespite the increasing use of escalated regimens in the last 5–6 years, FNH continuously declined, and the odds of FNH were lower among patients treated with pegfilgrastim PP. These results may suggest the contribution of PP in part to suppressing FNH levels over the last 5–6 years.

Therapy decision-making after pre-operative endocrine therapy in HR+ HER2- early breast cancer.

e12520 Background: Nowadays, the right way for therapy decision-making in HR+ HER2- early breast cancer (BC) includes the complex of validated multigene assays (VMA) result with clinical and IHC evaluation. Given the inability to use VMA in routine clinical practice, the short-term pre-operative endocrine therapy (P-ET) allows to estimate more precisely plan the further adjuvant therapy (AT) in the patients (pts) with early HR+ HER2- BC. Our work is aimed to share of pts with P-ET benefit, or tumor phenotype reversion for proper treatment planning in pts with early HR+ HER2- BC. Methods: HR+ HER2- BC pts stages I-II any level of Ki67 and any grade (G) have received P-ET (letrozole (L)/anastrozole (A)/tamoxifen (TAM)) no less than 2 weeks until surgery in A.S. Loginov MCSC, Russia. Enrollment period was Jun’20 - Jan’23. The study was aimed to access P-ET efficiency in pts with baseline Ki67&gt;10% downgrading to ≤10% (1), tumor ET sensitivity in the whole group (2) and/or phenotype transformation during P-ET followed by changing AT strategy (3). Results: At the data cut-off (Jan’23) 998 pts (5 pts were men) with HR+ HER2- BC were enrolled with median age 63,5 (range:26-85). The median time of P-ET was ≈19,5 days (range: 14-42). Pts flow according to tumor Ki67 level dynamic is show. 54% (434) pts with initially Ki67 level &gt;10% decreased Ki67≤10% after P-ET in whom 36% (314) pts avoided adjuvant chemotherapy. In Ki67≤10% baseline group (n=187) tumor Ki67 level after P-ET increased &gt;30% in every fifth case (n=35, 19%), that may reflect the initial ET resistance. Ki67 level dynamic change under P-ET was observed regardless of the TAM/IA use. 4% (38) pts has resulted the phenotype change to HER2+ BC (n=32) and TNBC (n=6) with subsequent AT decisions (anti-HER2-based or dose dense regimens, respectively). In this group there weren’t any Ki67 decrease after P-ET that additionally confirms the unmet need for treatment plan correction. Conclusions: In HR+ HER2- BC pts the results of P-ET with TAM or IA before surgery helps to estimate pts prognosis and further AT strategy: to identify the pts population of whom chemotherapy can be avoided while maintaining treatment efficacy with a better quality of life (1), to assess the initial ET tumor sensitivity (Ki67 baseline level independently) (2), to radically change the planned AT to achieve optimal treatment results (3). Mature data of long-term pts outcome are awaited. [Table: see text]

Efficacy and safety study of a novel alpha-fetoprotein (AFP)-maytansine conjugate in an ovarian xenograft model.

e14570 Background: AFP receptor is an oncofetal antigen and a novel target for cancer therapeutics. It is highly expressed on the surfaces of many cancers and Myeloid Derived Suppressor Cells (MDSCs) but absent on normal tissues. By conjugating maytansine toxin to a recombinant human AFP, we selectively deliver toxin to cancer cells and MDSCs while sparing normal cells, enabling a combination of targeted and immune activating approaches. We previously reported high efficacy of AFP-maytansine conjugate in a xenograft model of colorectal cancer. Here we report the effect of this conjugate in an ovarian xenograft model and in 2 independent patient-derived 3D ovarian organoids, supporting the wider utility of this approach. Methods: Four dose regimens of AFP-maytansine conjugate were compared to control in a mouse A2780 ovarian xenograft model. The conjugate was administered IV 10 days after implantation, when tumor volumes reached ≈150 mm3. Mice were randomized into 4 treatment and 1 control group (10 mice/group, table below). Tumor growth, survival and clinical observations were assessed for 62 days post implantation. In addition, organoids were cultured from primary reprogrammed tumor cells from 2 separate patients with high-grade serous ovarian carcinoma. Conjugate, staurosporine, thapsigargin or DMSO (control) were added to the media. Cytotoxicity was assessed by staining for AnnexinV and TMRE. Results: A statistically significant dose-dependent reduction in tumor volume (p&lt;0.001) and increase in survival (p&lt;0.002) were seen in all treatment groups relative to control. All animals in Groups 1,3 and 4 survived to the end of the study and 6 of 10 mice survived in the lowest dose group. 100% of mice in Group 1, highest dose group had complete tumor regression with no regrowth seen by day 62. In the other treatment groups majority of animals had complete tumor regression with no regrowth. All control animals were dead by day 38 due to excessive tumor burden. No signs of toxicity, such as ocular toxicity or vascular scarring of the tail were seen. All mice gained weight during the study. Gross pathology at the time of sacrifice was unremarkable. In addition, in the 2 ovarian organoids the AFP-maytansine conjugate demonstrated a cytotoxic effect over 72 hours exposure similar to that of thapsigargin and staurosporine given at known effective concentrations. Conclusions: This ovarian xenograft study confirms high activity without obvious toxicity of the novel AFP-maytansine conjugate in a 2nd tumor type. The targeted cytotoxic activity is further confirmed by the effect of the conjugate in 2 different ovarian cancer organoids. These results support advancing this novel conjugate toward clinical use with a dose-dense regimen. [Table: see text]

Final analysis of a randomized phase II/III trial of conventional paclitaxel and carboplatin with or without bevacizumab versus dose-dense paclitaxel and carboplatin with or without bevacizumab, in stage IVB, recurrent, or persistent cervical carcinoma (JCOG1311)

ObjectiveTo assess the efficacy of dose-dense weekly paclitaxel plus carboplatin in metastatic or recurrent cervical carcinoma, we conducted a phase II/III randomized controlled study comparing dose-dense paclitaxel and carboplatin with...

Effectiveness of pegfilgrastim prophylaxis in preventing febrile neutropenia during R-FC chemoimmunotherapy for chronic lymphocytic leukemia: A multicenter prospective phase II study.

A chemotherapy of rituximab, fludarabine and cyclophosphamide (R-FC) has been accepted as a promising frontline chemotherapy in selected patients with chronic lymphocytic leukemia (CLL). Although R-FC regimen is a relatively dose-dense regimen and neutropenia incidence is more than 50%, primary prophylactic pegfilgrastim was not fully recommended in the clinical field. Therefore, the study evaluated the prophylactic effectiveness of pegfilgrastim to reduce the incidence of febrile neutropenia associated with R-FC of patients with CLL. A single-arm, multicenter, prospective phase II study was designed to assess the efficacy of prophylactic pegfilgrastim. Thirty-four CLL patients were enrolled and analyzed for neutropenia and other related factors, and comparative analysis was performed with historical cohort. Compared with our historical cohort, incidence of grade 3-4 neutropenia and febrile neutropenia was remarkably reduced during any cycle of chemotherapy (14.7% vs. 48.2% of study cohort vs. historical cohort during C1, 5.9% vs. 65.8% during C2, 12.9% vs. 80.6% during C3, 10% vs. 84.6% during C4, 3.4% vs. 83.6% during C5, and 10.7% vs. 85.7% during C6, p <0.001). Also, cumulative incidence of disrupted chemotherapy was noticeably reduced in study cohort on any cycles of R-FC regimen (8.8% vs. 22.2% of study cohort vs. historical cohort on C2, 9.7% vs. 25.2% on C3, 13.4% vs. 26.9% on C4, 13.8% vs. 45.2% on C5, 17.9% vs. 47.3% on C6, p=0.007). In addition, treatment-related mortality was 5.9%, which significantly reduced compared to 9.6% of our historical cohort (HR 0.64, 95% CI 0.42-0.79, P = 0.032). Primary prophylactic pegfilgrastim is effective in the prevention of neutropenia/febrile neutropenia, and infection-related mortality during R-FC regimen in patients with CLL.