Anthracycline-based Treatment Research Articles

A Real-World Comparison Between Adjuvant Docetaxel with Cyclophosphamide (TC) and Anthracycline–Taxane Chemotherapy in Early HER-2 Negative Breast Cancer

Background: Anthracycline–taxane chemotherapy is the gold standard in high-risk breast cancer (BC), despite the potential risk of congestive heart failure (CHF). A suitable alternative for anthracycline-sparing chemotherapy is through the combination of docetaxel and cyclophosphamide (TC). Methods: Through a retrospective study of stage I-III HER2-negative BC, using administrative databases, we analyzed a total of 10,634 women treated with adjuvant chemotherapy in Ontario, Canada, between 2009 and 2017. We compared TC versus standardized anthracycline–taxane chemotherapies (ACT and FEC-D). We investigated the overall survival (OS), and explored the incidence of CHF, emergency department (ED) visits and febrile neutropenia. Results: With a median follow-up of 5.5 years, the 5-year analysis showed an increased OS in patients treated with TC, versus those treated with ACT, HR 0.77 (0.63–0.95, p = 0.015). Among ER + BC, there was an increased OS in patients treated with ACT and FEC-D, versus those treated with TC, HR 0.70 (0.52–0.95, p = 0.021) and HR 0.71 (0.56–0.91, p = 0.007), respectively. There were no substantial differences in CHF, between TC and anthracycline-based treatments. Patients treated with TC and FEC-D had more ED visits, compared to those treated with ACT. Conclusion: Our study shows that anthracycline–taxane regimens were the most commonly prescribed adjuvant chemotherapy options in HER2-negative BC. Women who received ACT had the lowest OS, likely due to their unfavorable pathology.

Abstract PO5-12-03: Cardiovascular Toxicities in Breast Cancer Survivors

Abstract Background: Chemotherapy, despite its effectiveness, presents drawbacks in breast cancer patients due to its side effects. Fatigue, hair loss, nausea, and anemia are among the many symptoms associated with chemotherapy. Moreover, chemotherapy can lead to cardiovascular diseases, including cardiac arrhythmias, hypertension, heart failure, heart attacks, and cardiomyopathy, particularly with the use of anthracyclines and HER-2-targeted agents. Risk factors such as weight, age, race, comorbidities (e.g., obesity, diabetes, hyperlipidemia), and radiation exposure further increase these risks. Despite these potential complications, guidelines are just emerging aiming to prevent these cardiovascular complications in breast cancer patients. Untreated cardiovascular abnormalities can have long-term effects on breast cancer survivors. Our aim is to analyze the relationships between breast cancer treatment and cardiovascular abnormalities, examining associations with various factors, including race, BMI, and age in a majority Hispanic cohort of breast cancer survivors. Methods: retrospective, single institution study data from a total of 53 patients treated with chemotherapy with either anthracyclines and/or HER 2 directed therapy with curative intent between 2018-2020. Our analysis included basic demographic information, menopausal status, breast cancer type, treatment types, use of cardio-protective medications, and cardiovascular effects (both pre-existing and developed during treatment). Results: Our sample of 50 women primarily comprised Hispanic individuals (73%), most of whom were postmenopausal (86%), with an average age of 63 years (range 35-86). Among the breast cancer types identified, 35 were hormone-positive, 8 were HER-2 positive, and 10 were triple negative. 72% of the patients received adjuvant hormonal therapy. 18% of the population received anthracycline-based treatment, 8% received Her 2 directed therapy and 2 % received Immune check point inhibitors. Radiation therapy was administered to 50% of the patients. The most prevalent cardiovascular disease observed was hypertension, affecting 62% of patients, followed by type 2 diabetes (38%), hyperlipidemia (34%), stroke (8%), and heart attack (6%). The predominant cardioprotective medications used were ACE inhibitors/ARBs (48%), followed by statins (46%), beta-blockers (20%), aspirin (16%), and GLP-1 agonists (14%). Conclusion: Our analysis revealed a high prevalence of cardiovascular conditions among breast cancer survivors treated with chemotherapy in a majority Hispanic cohort of patients. This population has been linked to higher risk of developing comorbidities such as diabetes, obesity and hypertension. Further analysis evaluating risk factors and implementation of treatment strategies to minimize adverse effects is needed in this population. Citation Format: Victoria Ayodele, Emily Sherry, Marcela Mazo-Canola. Cardiovascular Toxicities in Breast Cancer Survivors [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 PO5-12-03.

The efficacy of combining ondansetron with dexamethasone in delayed chemotherapy-induced nausea and vomiting

Background: Chemotherapy is the primary recourse for patients with cancer that cannot be treated using local surgery or radiotherapy. Its practical application often leads to adverse effects, including nausea and vomiting. Objective: This study determined the efficacy of oral ondansetron and oral dexamethasone as an antiemetic regimen among patients covered by the National Health Insurance. Methods: This cross-sectional study, conducted at one of the largest hospitals in South Kalimantan, Indonesia, involved 114 chemotherapy patients who received a combination antiemetic regimen of ondansetron and dexamethasone. Data on the incidence of delayed nausea and vomiting after chemotherapy were collected using the Index Nausea Vomiting and Retching (INVR) questionnaire from March to May 2023. Results: A cohort of 114 individuals were enrolled in the present investigation, with 57.02% and 42.98% of the participants receiving non-anthracycline and anthracycline-based treatment protocols, respectively. The results showed that only 1.84% of patients did not experience chemotherapy-related adverse events, 13.16% experienced mild symptoms, 21.84% had moderate symptoms, 55.26% faced severe symptoms, and 7.89% suffered from intense symptoms of nausea and vomiting. Conclusion: The antiemetic regimen covered by Badan Penyelenggara Jaminan Sosial (BPJS) (Social Insurance Administration Organization), consisting of a combination of ondansetron and dexamethasone, is moderately effective in preventing chemotherapy-induced delayed nausea and vomiting.

Left atrial reservoir longitudinal strain and its incremental value to the left ventricular global longitudinal strain in predicting anthracycline-induced cardiotoxicity.

Left ventricular global longitudinal strain (LVGLS) has been recommended by current guidelines for diagnosing anthracycline-induced cardiotoxicity. However, little is known about the early changes in left atrial (LA) morphology and function in this population. Our study aimed to evaluate the potential usefulness of LA indices and their incremental value to LVGLS with three-dimensional echocardiography (3DE) in the early detection of subclinical cardiotoxicity in patients with lymphoma receiving anthracycline. A total of 80 patients with diffuse large B-cell lymphoma who received six cycles of anthracycline-based treatment were enrolled. Echocardiography was performed at baseline (T0), after four cycles (T1), and after the completion of six cycles of chemotherapy (T2). Left ventricular ejection fraction (LVEF), LVGLS, LA volumes, LA emptying fraction (LAEF), LA active emptying fraction (LAAEF), and LA reservoir longitudinal strain (LASr) were quantified with 3DE. Left atrioventricular global longitudinal strain (LAVGLS) was calculated as the sum of peak LASr and the absolute value of peak LVGLS (LAVGLS=LASr+|LVGLS|). LV cardiotoxicity was defined as a new LVEF reduction by ≥10 percentage points to an LVEF of ≤50%. Fourteen (17.5%) patients developed LV cardiotoxicity at T2. LA volumes, LAEF, and LAAEF remained stable over time. Impairment of LASr (28.35±5.03vs. 25.04±4.10, p<.001), LVGLS (-22.77±2.45vs. -20.44±2.62, p<.001), and LAVGLS (51.12±5.63vs. 45.61±5.22, p<.001) was observed by the end of the fourth cycle of chemotherapy (T1). Statistically significant declines in LVEF (61.30±4.73vs. 57.08±5.83, p<.001) were only observed at T2. The relative decrease in LASr (ΔLASr), LVGLS (ΔLVGLS), and LAVGLS (ΔLAVGLS) from T0 to T1 were predictors of LV cardiotoxicity. A ΔLASr of>19.75% (sensitivity, 71.4%; specificity, 87.9%; area under the curve (AUC),.842; p<.001), a ΔLVGLS of>13.19% (sensitivity, 78.6%; specificity, 74.2%; AUC,.763; p<.001), and a ΔLAVGLS of>16.80% (sensitivity, 78.6%; specificity, 93.9%; AUC,.905; p<.001) predicted subsequent LV cardiotoxicity at T2, with the AUC of ΔLAVGLS significantly larger than that of ΔLVGLS (.905vs..763, p=.027). Compared to ΔLVGLS, ΔLAVGLS showed improved specificity (93.9%vs. 74.2%, p=.002) and maintained sensitivity in predicting LV cardiotoxicity. LASr could predict anthracycline-induced LV cardiotoxicity with excellent diagnostic performance. Incorporating LASr into LVGLS (LAVGLS) led to a significantly improved specificity and maintained sensitivity in predicting LV cardiotoxicity.

Patient Profile and Survival Rate of Breast Cancer Patients with FEC Chemotherapy Regimen at H. Adam Malik Hospital

Breast cancer is a prevalent disease that impacts public health worldwide, including Indonesia. There are various chemotherapy regimens that are currently available. One widely utilized chemotherapy regimen for breast cancer is the FEC regimen, which combines 5-fluorouracil, epirubicin, and cyclophosphamide. This study provides a study of patient profiles and survival rates among breast cancer patients undergoing FEC chemotherapy at H. Adam Malik Hospital. The study utilized a descriptive-retrospective approach with data collected from the medical records of patients who underwent FEC therapy at RSUP H. Adam Malik during January-December 2019. A total of 157 patients were administered anthracycline-based treatment, with 54 patients receiving FEC (34.39%). The majority of individuals under the FEC regimen were primarily luminal B (51.75%) and IBC (33.33%). The survival rate for individuals using the FEC chemotherapy regimen was found to be 37.98 months. Additionally, patients with risk factors associated with invasive breast cancer (IBC) exhibited a 1.20-fold increased risk of mortality compared to individuals with other forms of breast cancer. The first-line FEC chemotherapy regimen continues to be a feasible therapeutic option for subtypes of breast cancer, and there is no discernible variation in survival rate observed across these characteristics.

Optimizing Circulating Tumor DNA Limits of Detection for DLBCL during First Line Therapy

Background: Circulating tumor DNA (ctDNA) assessment is effective in diffuse large B-cell lymphoma (DLBCL) monitoring and risk stratification, with prognostic utility throughout first-line (1L) therapy. DLBCL ctDNA assays vary in analytical sensitivity, or limit of detection (LOD), which range from parts per thousand to below 1 part per million (1 in 10 6). With differing assays and time-points assessed in DLBCL studies, the relationship between analytical and clinical sensitivity for outcome prediction remains unclear. We assessed the prognostic ability of ctDNA at various LODs and used modeling strategies to project the efficacy of assays for minimal residual disease (MRD) detection. Methods: We previously reported a DLBCL dataset assessing plasma ctDNA before, during and after curative-intent 1L anthracycline-based treatment from multiple prospective studies, including RCHOP or EP[O]CH with acalabrutinib, lenalidomide, obinutuzumab, and polatuzumab (Roschewski et al. ASH 2022). In this study, ctDNA was evaluated by Phased Variant Enrichment Detection and Sequencing (PhasED-Seq, Foresight Diagnostics), a ctDNA MRD assay with LOD below 1 in 10 6. Samples from this study and a prospective DLBCL cohort treated with standard 1L therapy at Samsung Medical Center were considered in this analysis. We assessed the prognostic ability of ctDNA detection, considering LODs from 1 in 100 (10 2)to 1 in 10 6 to predict progression free survival (PFS) before, during and after 1L treatment. We assessed the desired sensitivity for ctDNA MRD during treatment by generating patient-specific log-linear models assuming exponential decay. We projected the distribution of variant allele frequencies (VAFs) during therapy from cycles 2 to 5 for patients who progressed to determine the minimal acceptable analytical sensitivity. Results: We included 230 patients consisting of 588 ctDNA samples, with 201 before therapy, 71 at C2D1, 101 at C3D1, 70 at C4D1 and 145 at end of therapy (EOT). Median follow-up was 17.5 months and 62 patients (27%) progressed. To evaluate the impact of LOD at treatment milestones, we applied a threshold for ctDNA positivity ranging from 1 in 10 2 to 1 in 10 6. Increased LOD had no effect on the performance of ctDNA before therapy (Figure A &amp; B). At C2D1, if the LOD was at least 1 in 10 4, there was no difference in MRD prognostic performance. Starting at C3D1, improving the LOD for ctDNA positivity down to 1 in 10 6 showed superior predictive power for PFS at 24 months. The power of ctDNA to predict PFS at 24 months improved later in therapy, with area under the receiver operator curves (AUROCs) for PFS24 of 0.68, 0.73, 0.77, 0.88, and 0.86, at pretreatment, C2D1, C3D1, C4D1, and EOT time-points respectively (Figure A). To further understand the desired LOD for ctDNA MRD, we developed personalized models of ctDNA VAFs. Exponential models fit the data well in 43/44 cases with ≥ 3 MRD-detectable samples through C4D1, with a median correlation of 0.91, confirming their utility for modeling ctDNA. We generated log-linear models for 106 patients with ≥ 2 MRD-detectable samples, and used log-fold change in VAF per cycle (i.e. the slope) to compare patients by progression. Median log-fold change in VAF per cycle was worse for patients who progressed at -1.1 (IQR -1.4, -0.7) compared to those who remained disease-free with median -1.5 (IQR -2.0, -1.1) (p&amp;lt;0.0001). Patients with primary refractory DLBCL on EOT imaging had less robust log-fold change per cycle with median of -0.9 (IQR -1.3, -0.5) compared to those who relapsed after CR with median -1.3 (IQR -1.7, -0.9) (p=0.0004). We used the distribution of slopes to project VAFs for cycles 2 to 5 for patients who progressed to determine the LODs that provide acceptable clinical sensitivity. We found the analytical sensitivity for detecting DLBCL extended lower for each cycle, demonstrating the need for a LOD at least 1 in 10 6 for robust MRD detection at late time-points during 1L treatment. Conclusion: When using an ultrasensitive assay, MRD assessment at later timepoints better predicts PFS than at early timepoints. While the technical LOD does not affect disease burden assessment before therapy, using more sensitive assays during and after therapy improves disease detection and outcome prediction. Utilizing the most sensitive ctDNA MRD assays in 1L DLBCL therapy will maximize the efficacy of MRD-driven therapeutic strategies and MRD as a surrogate endpoint in future trials.

Activity and Event-Free Survival in Intermediate Grade Non-Hodgkin's Lymphoma Treated with Chemoimmunotherapy Utilizing Single Dose Intravenous Methylprednisolone in Lieu of Oral Prednisone

Schein et al first noted that patients with intermediate grade lymphoma treated with combination chemotherapy leading to complete response lasting 24 months were likely to remain relapse-free (Schein, Chabner, Canellos, Young, Berard, DeVita,1975). Subsequent changes in that original C-MOPP regimen have included the use of anthracyclines and rituximab. The University of Iowa/Mayo Clinic Molecular Epidemiology Resource and the Groupe d'Etude des Lymphomes de l'Adulte (GELA) program found that patients with diffuse large B-cell lymphoma achieving event-free status at 24 months with chemoimmunotherapy have subsequent overall survival equivalent to that of the general population (Maurer, 2014). While Rituximab, Cyclophosphamide, Hydroxydaunorubicin [doxorubicin], Oncovin [vincristine] and Prednisone (RCHOP) has served as the reference therapy for intermediate grade non-Hodgkin's lymphoma for two decades (Coiffier, 2002; Pfreundschuh, 2006), oral prednisone given daily for 5 days is problematic for individuals with underlying medical conditions such as diabetes, sleep or psychiatric disorders, or gastrointestinal symptoms. In this retrospective study between January, 2007 and March, 2023, 33 patients with intermediate grade Non-Hodgkin's Lymphoma, (26 with Diffuse Large B-cell subtype, 6 with follicular grade III, 1 with T-cell Immunoblastic) received Methylprednisolone 125 mg intravenously on day 1 instead of oral prednisone for 5 days as part of anthracycline-based treatment that consisted of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 2 mg (total dose) all given intravenously on day 1 with peg-filgastrim 6 mg subcutaneously on day 2 every 21 days. Three patients received mitoxantrone 12 mg/m2 intravenously on day 1 instead of doxorubicin. Patient characteristics: 23 males/10 females, median age-55 (range: 24-85), stages: IV (17 patients), III (4 patients), II (12 patients), B symptoms (16), subtypes: non-germinal center (13), germinal center (12), diffuse B-cell NOS (1), follicular grade III (6), T-cell Immunoblastic (1). Median cycles received (range): 6 (5-8). No patients required dose reduction or omission of methylprednisolone. Complete responses (determined by PET/CT) occurred in 26 (81%). 1 additional patient was PET negative but was lost to follow-up and is not counted as CR here. Three patients having PR after chemoimmunotherapy were converted to CR after involved site radiation. Two other patients achieved only short-lived PR. One patient is too early to evaluate. The median event-free survival has not been reached at 24.8+ months. Median overall survival exceeds 32.6+ months. Chemoimmunotherapy with the substitution of intravenous methylprednisolone on day 1 in place of 5 days of oral prednisone displays activity in intermediate-grade non-Hodgkin lymphoma and event-free survival beyond 24 months.

CNSC-04. DIAGNOSIS AND TREATMENT OF PERIPHERAL AND CRANIAL NERVE TUMORS WITH EXPERT RECOMMENDATIONS: AN EUROPEAN NETWORK FOR RARE CANCERS (EURACAN) INITIATIVE

Abstract BACKGROUND The 2021 WHO classification of the CNS Tumors identifies as “Peripheral nerve sheath tumors” (PNST) some entities with specific clinical and anatomical characteristics, histological and molecular markers, imaging findings, and aggressiveness. Material and methods. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is particularly low due to the rarity, and drawn recommendations accordingly. RESULTS Tumor diagnosis is primarily based on hematoxylin and eosin-stained sections and immunohistochemistry. Molecular analysis is not essential to establish the histological nature of these tumors, although genetic analyses on DNA extracted from PNST (neurofibromas/schwannomas) is required to diagnose mosaic forms of NF1 and SPS. MRI is the gold-standard to delineate the extension with respect to adjacent structures. Gross-total resection is the first choice, and can be curative in benign lesions; however, the extent of resection must be balanced with preservation of nerve functioning. Radiotherapy can be omitted in benign tumors after complete resection and in NF-related tumors, due to the theoretic risk of secondary malignancies in a tumor-suppressor syndrome. Systemic therapy should be considered in incomplete resected plexiform neurofibromas/MPNSTs. MEK inhibitor selumetinib can be used in NF1 children ≥2 years with inoperable/symptomatic plexiform neurofibromas, while anthracycline-based treatment is the first choice for unresectable/locally advanced/metastatic MPNST. Clinical trials on other MEK1-2 inhibitors alone or in combination with mTOR inhibitors are under investigation in plexiform neurofibromas and MPNST, respectively. CONCLUSIONS Given the heterogeneity and rarity of these tumors, there is a paucity of well-powered clinical trials, thus it is not possible to generate evidence-based treatment recommendations for non-surgical modalities. However, some clinical trials have been reported on targeted therapies in plexiform neurofibromas of NF1 patients or in heterogenous cohorts of soft-tissue tumors, including MPNSTs, with initial data of efficacy that need to be further investigated.

Impact of the Current Treatments on the Survival of Patients with Mantle Cell Lymphoma (MCL): A Real-Life Study on Behalf of the Spanish Group of Lymphoma (GELTAMO)

Background: MCL remains incurable and its management is highly heterogeneous due to the lack of standard treatment. Since the results from prospective clinical trials are not always reproducible in real-life patients, the aim of this study was to analyze the management in clinical practice of patients with MCL in Spain and its impact on their survival. Methods: We retrospectively analyzed the clinical-biological characteristics and treatment patterns of patients (pts) with MCL from Spanish GELTAMO centers and their impact on overall (OS) and progression-free survival (PFS). First-line treatments (1L) were grouped as HiDAC (high-dose cytarabine or HiDAC-based) or non-HiDAC; second-line treatments (2L) as BTKi (BTK inhibitors), CIT (chemoimmunotherapy) or other (targeted agents other than BTKi). In patients receiving 1L at diagnosis, early progression/relapse (E-POD) was considered when occurring within 24 months (m) from diagnosis and late or L-POD beyond 24 m or no relapse at data cut-off. A follow-up time (FU) of ≥24m was required for patients to be evaluable for POD, except for those dying from MCL &amp;lt;24m, recorded as E-POD. Statistical analyses were performed with the R-4.1.0 software. Results: From January 2000-March 2023, 505 patients were diagnosed with MCL in 17 GELTAMO centers, their baseline characteristics are summarized in Table 1. At data-cut-off, 242 (47.9%) were alive, 17 (3.4%) lost to FU and 246 (48.7%) had died, being the lymphoma the main cause of death (50.4%). Sixty-five (12.8%) pts did not receive treatment at diagnosis, out of which 18 (28%) remain on observation at a median (M) FU=26 m (3-92). Out of 479 pts receiving 1L, 245 (51%) received 2L, 143 (30%) 3L, 75 (15.6%) pts 4L and &amp;lt;10% received 5-8 lines. Among 432 pts treated upfront (no observation prior to 1L), 423 were evaluable for response: 190 (44.9%) HiDAC and 233 (55%) non-HiDAC, with a predominance of anthracycline-based treatments (Figure 1). Overall (OR) and complete responses (CR) were higher with HiDAC vs. non-HiDAC (91%/78.4% vs. 82.8%/65.2%, respectively). In 394/432 pts evaluable for POD (149 E-POD and 245 L-POD), HiDAC was more frequently associated with L-POD (73.2% L-POD vs. 26.8% E-POD) than non-HiDAC (53.1% L-POD vs. 46.9% E.POD). Rituximab maintenance (RM) was given to 167 pts (prior HiDAC 48.5%, non-HiDAC 51.5%) and 80.7% of them were L-POD. ASCT was performed in 135 pts (prior HiDAC 83.7%, non-HiDAC 16.3%, followed by RM in 46%) and 86.1% were L-POD. In 2L, 232/245 were evaluable, 92 (39.6%) received iBTK (60 monotherapy, 11 with CT and/or rituximab), 122 (52.6%) CIT (bendamustine-based 24.6%, gemcitabine-based 36.5%) and 18 (7.75%) other salvage options (Figure 1), with no significant differences between iBTK and CIT regarding baseline characteristics or efficacy (OR/CR 60.8%/39.1% vs. 72%/56.5% for BTKi and CIT, respectively). With a M FU= 87.6m, M OS= 6.56 years (5.6-8.2) and M PFS= 34.3 m (29.86-43.43). Age&amp;gt;65 at diagnosis (HR=2.09, p&amp;lt;.001), blastoid variant (HR=1.77, p=.012), Ki67≥30% (HR=1.93, p=.001), non-CR after 1L (HR=2.20, p&amp;lt;.001) and E-POD (HR=5.21, p&amp;lt;.001) were associated with shorter OS (MVA) and blastoid variant (HR=1.83, p=.001) and Ki67≥30% (HR=1.65, p=.003) with PFS. ASCT and RM were significantly associated with longer PFS (HR=0.33 and HR=0.32, p&amp;lt;.001) in the MVA but only MR had impact on OS (HR=0.62, p=.031). After 2L, M OS-2= 30.01 m (25.23-46.42) and PFS-2= 12.42m (8.97-17.02), with no impact of BTKi in 2L (vs. CIT) on OS-2 (HR=0.64, p=.12) or PFS-2 (HR=0.73, p=.12). E-POD and HR-MIPI, however, were significantly associated with shorter OS-2 (HR=1.72, p=.03 and HR=2.08, p=.03, respectively) and PFS-2 (HR=1.91, p&amp;lt;.001 and HR=1.88, p=.005 respectively). Conclusions: The impact on survival of known risk factors such as older age at diagnosis, high Ki67, HR-MIPI, blastoid morphology, non-CR after 1L or E-POD was confirmed in our series, as well as the advantage in efficacy and risk of E-POD of HiDAC-based regimens vs. non-HiDAC in 1L. Regarding RM and ASCT in 1L, our results are in line with other studies, with RM associated with longer PFS and OS and ASCT showing advantage in PFS but not in OS. In 2L, the rate of OR/CR with BTKi in our cohort is like that reported in pivotal studies, but we did not find the survival advantage of BTKi over CIT observed in other retrospective studies.

P20.04.B DIAGNOSIS AND TREATMENT OF PERIPHERAL AND CRANIAL NERVE TUMORS WITH EXPERT RECOMMENDATIONS: AN EUROPEAN NETWORK FOR RARE CANCERS (EURACAN) INITIATIVE

Abstract BACKGROUND The 2021 WHO classification of the CNS Tumors identifies as “Peripheral nerve sheath tumors” (PNST) some entities with specific clinical and anatomical characteristics, histological and molecular markers, imaging findings, and aggressiveness. MATERIAL AND METHODS The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is particularly low due to the rarity, and drawn recommendations accordingly. RESULTS Tumor diagnosis is primarily based on hematoxylin and eosin-stained sections and immunohistochemistry. Molecular analysis is not essential to establish the histological nature of these tumors, although genetic analyses on DNA extracted from PNST (neurofibromas/schwannomas) is required to diagnose mosaic forms of NF1 and SPS. MRI is the gold-standard to delineate the extension with respect to adjacent structures. Gross-total resection is the first choice, and can be curative in benign lesions; however, the extent of resection must be balanced with preservation of nerve functioning. Radiotherapy can be omitted in benign tumors after complete resection and in NF-related tumors, due to the theoretic risk of secondary malignancies in a tumor-suppressor syndrome. Systemic therapy should be considered in incomplete resected plexiform neurofibromas/MPNSTs. MEK inhibitor selumetinib can be used in NF1 children ≥2 years with inoperable/symptomatic plexiform neurofibromas, while anthracycline-based treatment is the first choice for unresectable/locally advanced/metastatic MPNST. Clinical trials on other MEK1-2 inhibitors alone or in combination with mTOR inhibitors are under investigation in plexiform neurofibromas and MPNST, respectively. CONCLUSION Given the heterogeneity and rarity of these tumors, there is a paucity of well-powered clinical trials, thus it is not possible to generate evidence-based treatment recommendations for non-surgical modalities. However, some clinical trials have been reported on targeted therapies in plexiform neurofibromas of NF1 patients or in heterogenous cohorts of soft-tissue tumors, including MPNSTs, with initial data of efficacy that need to be further investigated.

Cardiac safety of reduced surveillance for cancer therapy related cardiac dysfunction in patients with breast cancer treated with HER2-targeted therapy.

12083 Background: Non-anthracycline-based therapy is a treatment option for patients (pts) with HER2-positive breast cancer (BC) and is associated with lower risk of cancer therapy related cardiac dysfunction (CTRCD) compared to anthracycline-based treatment. Given the reduced CTRCD risk with non-anthracycline HER2-targeted therapies, updates to practice guidelines that recommend surveillance echocardiograms (TTE) every 3 months are needed. We evaluated the cardiac safety of reduced CTRCD surveillance in pts receiving non-anthracycline HER2-targeted therapies. Methods: Pts with BC treated with non-anthracycline HER2-targeted therapy were enrolled in this single-arm prospective study. Pts with previous anthracycline exposure, uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg), or significant cardiovascular disease were excluded. TTEs were performed at baseline, 6 months, and 12 months during HER2-targeted treatment. The primary endpoint was a cardiac event, defined by clinical heart failure (New York Heart Association Class III/IV) or cardiovascular death, with a prespecified non-inferiority margin of 2.9% relative to a cardiac event rate of 1.1% based upon prior studies. Secondary endpoints were CTRCD, defined by decline of left ventricular ejection fraction (LVEF) ≥10% to &lt; 53%, and interruption of HER2-targeted treatment secondary to CTRCD. Results: Between May 2019 and January 2022, 190 pts (age 52 ± 11 y) with HER2-positive BC were enrolled: 143 (75%) had stage I disease, 8 (4%) had diabetes, 38 (20%) had hypertension, and baseline LVEF was 64 ± 5% (Table). Additional TTEs outside the prespecified 6- and 12-month timepoints were performed for 35 (18%) pts, of which 20 were to assess for possible cardiac symptoms. After 1-year follow-up, there were 0 (0%; 97.5% CI 0- 1.9%) cardiac events. Two (1.1%) pts developed CTRCD and 1 (0.5%) pt had a temporary CTRCD-related treatment interruption. Conclusions: Reduced CTRCD surveillance every 6 months is feasible and safe for selected pts with HER2-positive BC receiving non-anthracycline HER2-targeted therapy. Our findings support the need to update cardio-oncology practice guidelines and allow for less frequent surveillance TTEs among pts at low-risk for CTRCD. Clinical trial information: NCT03983382 . [Table: see text]

The Impact of Polymorphisms in ATP-Binding Cassette Transporter Genes on Anthracycline-Induced Early Cardiotoxicity in Patients with Breast Cancer.

Cardiac side effects associated with anthracycline-based treatment may seriously compromise the prognosis of patients with breast cancer (BC). Evidence shows that genes that operate in drug metabolism can influence the risk of anthracycline-induced cardiotoxicity (AIC). ATP-binding cassette (ABC) transporters could serve as one of the potential biomarkers for AIC risk stratification. We aimed to determine the link between single-nucleotide polymorphisms (SNPs) in several ABC genes (ABCB1 rs1045642, ABCC1 rs4148350, ABCC1 rs3743527) and cardiotoxicity. The study included 71 patients with BC, who were treated with doxorubicin-based chemotherapy. Two-dimensional echocardiography and speckle-tracking echocardiography were performed. AIC was defined as a new decrease of 10 percentage points in the left ventricular ejection fraction (LVEF). SNPs in ABCB1 and ABCC1 genes were evaluated using real-time PCR. After a cumulative dose of 236.70 mg/m2 of doxorubicin, 28.2% patients met the criteria of AIC. Patients who developed AIC had a larger impairment in left ventricular systolic function compared to those who did not develop AIC (LVEF: 50.20 ± 2.38% vs. 55.41 ± 1.13%, p < 0.001; global longitudinal strain: -17.03 ± 0.52% vs. -18.40 ± 0.88%, p < 0.001). The ABCC1 rs4148350 TG genotype was associated with higher rates of cardiotoxicity (TG vs. GG OR = 8.000, 95% CI = 1.405-45.547, p = 0.019). The study showed that ABCC1 rs4148350 is associated with AIC and could be a potential biomarker to assess the risk of treatment side effects in patients with BC.

Racial and Ethnic Differences in Cardiac Surveillance Evaluation of Patients Treated With Anthracycline-Based Chemotherapy.

Background Anthracyclines remain a key treatment for many malignancies but can increase the risk of heart failure or cardiomyopathy. Specific guidelines recommend echocardiography and serum cardiac biomarkers such as BNP (B-type natriuretic peptide) or NT-proBNP (N-terminal proBNP) evaluation before and 6 to 12 months after treatment. Our objective was to evaluate associations between racial and ethnic groups in cardiac surveillance of survivors of cancer after exposure to anthracyclines. Methods and Results Adult patients in the OneFlorida Consortium without prior cardiovascular disease who received at least 2 cycles of anthracyclines were included in the analysis. Multivariable logistic regression was performed to estimate the odds ratios (ORs) and 95% CIs for receiving cardiac surveillance at baseline before anthracycline therapy, 6 months after, and 12 months after anthracycline exposure among different racial and ethnic groups. Among the entire cohort of 5430 patients, 63.4% had a baseline echocardiogram, with 22.3% receiving an echocardiogram at 6 months and 25% at 12 months. Non-Hispanic Black (NHB) patients had a lower likelihood of receiving a baseline echocardiogram than Non-Hispanic White (NHW) patients (OR, 0.75 [95% CI, 0.63-0.88]; P=0.0006) or any baseline cardiac surveillance (OR, 0.76 [95% CI, 0.64-0.89]; P=0.001). Compared with NHW patients, Hispanic patients received significantly less cardiac surveillance at the 6-month (OR, 0.84 [95% CI, 0.72-0.98]; P=0.03) and 12-month (OR, 0.85 [95% CI, 0.74-0.98]; P=0.03) time points, respectively. Conclusions There were significant racial and ethnic differences in cardiac surveillance among survivors of cancer at baseline and following anthracycline-based treatment in NHB and Hispanic cohorts. Health care providers need to be cognizant of these social inequities and initiate efforts to ensure recommended cardiac surveillance occurs following anthracyclines.

Association of Preexisting Heart Failure With Outcomes in Older Patients With Diffuse Large B-Cell Lymphoma

Anthracycline-containing regimens are highly effective for diffuse large B-cell lymphoma (DLBCL); however, patients with preexisting heart failure (HF) may be less likely to receive anthracyclines and may be at higher risk of lymphoma mortality. To assess the prevalence of preexisting HF in older patients with DLBCL and its association with treatment patterns and outcomes. This longitudinal cohort study used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare registry from 1999 to 2016. The SEER registry is a system of population-based cancer registries, capturing more than 25% of the US population. Linkage to Medicare offers additional information from billing claims. This study included individuals 65 years and older with newly diagnosed DLBCL from 2000 to 2015 with Medicare Part A or B continuously in the year prior to lymphoma diagnosis. Data were analyzed from September 2020 to December 2022. Preexisting HF in the year prior to DLBCL diagnosis ascertained from billing codes required one of the following: (1) 1 primary inpatient discharge diagnosis, (2) 2 outpatient diagnoses, (3) 3 secondary inpatient discharge diagnoses, (4) 3 emergency department diagnoses, or (5) 2 secondary inpatient discharge diagnoses plus 1 outpatient diagnosis. The primary outcome was anthracycline-based treatment. The secondary outcomes were (1) cardioprotective medications and (2) cause-specific mortality. The associations between preexisting HF and cancer treatment were estimated using multivariable logistic regression. The associations between preexisting HF and cause-specific mortality were evaluated using cause-specific Cox proportional hazards models with adjustment for comorbidities and cancer treatment. Of 30 728 included patients with DLBCL, 15 474 (50.4%) were female, and the mean (SD) age was 77.8 (7.2) years. Preexisting HF at lymphoma diagnosis was present in 4266 patients (13.9%). Patients with preexisting HF were less likely to be treated with an anthracycline (odds ratio, 0.55; 95% CI, 0.49-0.61). Among patients with preexisting HF who received an anthracycline, dexrazoxane or liposomal doxorubicin were used in 78 of 1119 patients (7.0%). One-year lymphoma mortality was 41.8% (95% CI, 40.5-43.2) with preexisting HF and 29.6% (95% CI, 29.0%-30.1%) without preexisting HF. Preexisting HF was associated with higher lymphoma mortality in models adjusting for baseline and time-varying treatment factors (hazard ratio, 1.24; 95% CI, 1.18-1.31). In this study, preexisting HF in patients with newly diagnosed DLBCL was common and was associated with lower use of anthracyclines and lower use of any chemotherapy. Trials are needed for this high-risk population.

Diagnosis and Treatment of Peripheral and Cranial Nerve Tumors with Expert Recommendations: An EUropean Network for RAre CANcers (EURACAN) Initiative.

The 2021 WHO classification of the CNS Tumors identifies as "Peripheral nerve sheath tumors" (PNST) some entities with specific clinical and anatomical characteristics, histological and molecular markers, imaging findings, and aggressiveness. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is particularly low due to the rarity, and drawn recommendations accordingly. Tumor diagnosis is primarily based on hematoxylin and eosin-stained sections and immunohistochemistry. Molecular analysis is not essential to establish the histological nature of these tumors, although genetic analyses on DNA extracted from PNST (neurofibromas/schwannomas) is required to diagnose mosaic forms of NF1 and SPS. MRI is the gold-standard to delineate the extension with respect to adjacent structures. Gross-total resection is the first choice, and can be curative in benign lesions; however, the extent of resection must be balanced with preservation of nerve functioning. Radiotherapy can be omitted in benign tumors after complete resection and in NF-related tumors, due to the theoretic risk of secondary malignancies in a tumor-suppressor syndrome. Systemic therapy should be considered in incomplete resected plexiform neurofibromas/MPNSTs. MEK inhibitor selumetinib can be used in NF1 children ≥2 years with inoperable/symptomatic plexiform neurofibromas, while anthracycline-based treatment is the first choice for unresectable/locally advanced/metastatic MPNST. Clinical trials on other MEK1-2 inhibitors alone or in combination with mTOR inhibitors are under investigation in plexiform neurofibromas and MPNST, respectively.

Abstract P5-02-40: Anthracycline improves the outcome of neoadjuvant trastuzumab-treated breast cancer patients with FcγRIIIA F/F genotype by decreasing the ratios of CD8+PD1+ and CD68+PDL1+ cells

Abstract Background: Antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the most important mechanisms of trastuzumab. Fragment C Gamma receptor (FcγR) IIA and IIIA polymorphisms influence the affinity of immunoglobin G (IgG). Recently, FcγRIIA and FcγRIIIA polymorphisms have identified with the efficacy of trastuzumab. However, whether FcγR polymorphisms are associated with the efficacy of trastuzumab in the neoadjuvant setting was unclear. Patients and methods: We retrospectively enrolled 101 patients with HER2-positive breast cancer receiving chemotherapy plus trastuzumab at least four cycles as neoadjuvant therapy and mastectomy in Sun Yat-sen university cancer center from May 2015 to March 2021. Among them, twenty patients were excluded because lacking of blood samples. Polymorphisms of FcγRIIA(rs1801274) and FcγRIIIA(rs396991) were examined by nested polymerase chain reaction (PCR) and sanger sequencing. Lastly, we performed multiple immunohistochemistry (mIHC) to examine the expressions of CD8, CD68, CD57, PD1 and PDL1. Results: Blood samples (n=81) were successfully detected. No significant differences between FcγRIIA/FcγRIIIA genotypes and clinical characteristics, including age, clinical stages, menstrual status, molecular subtyping, treatment and pathological complete response (pCR) rate. In paclitaxel-based treatment subgroup (n=34), FcγRIIIA polymorphism was significantly correlated with pCR rate (P&amp;lt; 0.05,Table1), moreover, the disease-free survivals (DFS) in FcγRIIIA-158V carriers subgroup (high affinity) were significantly longer than that in FcγRIIIA-158 F/F genotype group (low affinity) (P=0.036), while that was not significant difference in patients with anthracycline-based treatment (n=47, P=0.248), indicating that anthracycline enhanced the efficacy of neoadjuvant therapy in patients with FcγRIIIA F/F genotype(low affinity). So far, there is no recurrence events in paclitaxel-based treatment group with FcγRIIIA-158V carriers genotype. The mIHC showed that the ratios of stroma CD8+PD1+ and CD68+PDL1+ cells were significantly higher in anthracycline-based treatment group (Table 2), respectively, indicating that anthracycline improved the efficacy of neoadjuvant targeted therapy by decreasing the ratios of exhausted immune cells. Conclusions: FcγRIIIA-158V genotype is associated with better outcome in HER2-positive breast cancer patients who received paclitaxel combined with trastuzumab as neoadjuvant therapy. Anthracycline improves the outcome of neoadjuvant trastuzumab-treated breast cancer patients with FcγRIIIA F/F genotype by decreasing the ratios of CD8+PD1+ and CD68+PDL1+ cells. Correlation between FcγRIIIA and pCR Correlation between FcγRIIIA and pCR in total population and paclitaxel-based treatment population. Ratios of immune cells Ratios of immune cells in anthracycline-based and paclitaxel-based treatment group. Citation Format: Kaping Lee, Rongzhen Luo, Qianyi Lu, Shusen Wang, Fei Xu. Anthracycline improves the outcome of neoadjuvant trastuzumab-treated breast cancer patients with FcγRIIIA F/F genotype by decreasing the ratios of CD8+PD1+ and CD68+PDL1+ cells [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-40.

Predictive value of topoisomerase IIα immunoreactivity in canine diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL) treated with a doxorubicin-based chemotherapy protocol

Topoisomerase IIα (TOPIIα) plays a key role in DNA replication and is a molecular target for TOPIIα inhibitor chemotherapy. A doxorubicin-based chemotherapy remains the most effective treatment for canine lymphoma, but there are no clear indications for its use in individual patients. The aim of this study was to assess the predictive value of TOPIIα expression in the treatment of canine lymphomas with TOPIIα inhibitors. Samples of formalin-fixed paraffin-embedded lymph nodes from 14 dogs with diffuse large B-cell lymphoma (DLBCL) and 5 dogs with peripheral T-cell lymphoma (PTCL) treated with a CHOP protocol were immunohistochemically labelled with anti-TOPIIα. Progression-free survival time (PFS) and overall survival time (OS) were estimated and compared with TOPIIα expression. Dogs with DLBCL had a higher level of TOPIIα expression compared to dogs with PTCL. The median PFS for dogs with DLBCL was significantly longer (260 days) than it was for dogs with PTCL (60 days). In DLBCL dogs with a high TOPIIα expression level, the median PFS was significantly longer (310 days) then it was in dogs with week or medium TOPIIα expression (51 days). The results of the study indicate that the immunohistochemical assessment of TOPIIα expression may be a valuable predictive indicator for anthracycline-based treatment of dogs with malignant lymphoma.

Serum Biomarkers for the Detection of Cardiac Dysfunction in Childhood Cancers Receiving Anthracycline-Based Treatment

Anthracyclines are routinely used in cancer chemotherapy in many childhood cancers. A serious adverse effect of doxorubicin chemotherapy is cardiotoxicity which may lead to congestive heart failure for long-term survivors years after treatment. Currently, echocardiography is used to control the heart function during anthracyclines therapy. B-type natriuretic peptide (BNP) and NT-proBNP as well as cardiac troponins have been proposed as clinical markers for subclinical anthracycline-induced cardiotoxicity. The BNP and pro-BNP can be easily measured in plasma and initial data indicate that the NT-proBNP could be sensitive predictor for the development of congestive heart failure.

Fragement C Gamma receptor IIIa polymorphism is predictive of trastuzumab efficacy in the neoadjuvant setting of HER2-positive breast cancer patients.

e12607 Background: Antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the most important mechanisms of Trastuzumab. Fragement C Gamma receptor (FcγR) IIA and IIIA polymorphisms influence the affinity of immunoglobin G (IgG). Recently, FcγRIIA and FcγRIIIA polymorphisms have identified with the efficacy of trastuzumab. However, whether FcγR polymorphisms are associated with the efficacy of trastuzumab in the neoadjuvant setting was unclear. Methods: We retrospectively enrolled 101 patients with HER2-positive breast cancer receiving chemotherapy plus trastuzumab as neoadjuvant therapy and mastectomy in Sun Yat-sen university cancer center from May 2015 to March 2021. Among them, twenty patients were excluded because lacking of blood samples. Clinical and pathological characteristics, treatments and outcomes of patients were collected. We purified the genomic DNA from peripheral blood samples, performed nested polymerase chain reaction (PCR) and sanger sequencing to identify the polymorphisms of FcγRIIA(rs1801274) and FcγRIIIA(rs396991). Results: Patient samples (n=81) were successfully detected. No significant differences between FcγRIIA/FcγRIIIA genotypes and clinical characteristics, including age, clinical stage, menstrual status, molecular subtyping, treatment and pathological complete response (pCR) rate. In subgroup analyses, FcγRIIIA polymorphism was significantly correlated with pCR rate in the population who received paclitaxel plus trastuzumab therapy (n=34, P&lt;0.05). The Kaplan-Meier analyses showed that no significant difference in disease-free survivals (DFS) between FcγRIIA-131 H/H and R carriers genotype groups ( P=0.24), either that in the FcγRIIIA-158 F/F and V carriers genotype groups ( P=0.60). But the DFS in FcγRIIIA-158 V carriers genotype group were significant longer than that in FcγRIIIA-158 F/F genotype group in subgroup who received paclitaxel plus trastuzumab therapy (n=34, P=0.036), while that was not significant difference in patients with anthracycline-based treatment (n=47, P=0.248). DFS has not yet been reached. Conclusions: FcγRIIIA polymorphism is predictive of trastuzumab efficacy in the neoadjuvant setting of HER2-positive breast cancer patients who received paclitaxel plus trastuzumab therapy. Anthracycline-based treatment may improve the outcomes of HER2 positive breast cancer patients with FcγRIIIA-158 F/F genotype.[Table: see text]

The real-world experience of adjuvant docetaxel and cyclophosphamide (TC) chemotherapy in HER-2 negative breast cancer.

538 Background: Adjuvant chemotherapy in breast cancer (BC) substantially improves overall survival (OS) and the risk of recurrence. The short and long-term side effects of anthracycline, and its modest benefits in the adjuvant setting, led to controversy about its role in comparison with TC. We aim to compare the OS of TC with anthracycline-based regimens in Ontario, the most populous province in Canada. Methods: We conducted a retrospective population-based cohort study using the Institute for Clinical Evaluative Sciences (ICES) database, involving females with stage I-III BC HER2-negative. Patients were treated with adjuvant chemotherapy between January 2009 to December 2017. The anthracycline regimens for comparison were as follows, FEC-D: Fluorouracil, Epirubicin, Cyclophosphamide, followed by Docetaxel; and ACT: Doxorubicin, Cyclophosphamide, followed by Docetaxel or Paclitaxel. Exclusion criteria included missing baseline characteristics, a prior history of malignancy or chemotherapy starting more than 120 days from breast surgery. The end of follow-up was March 31st, 2018. Adjusted analyses to compare OS by positive axillary lymph nodes (LN) and chemotherapy regimens were conducted with Cox proportional hazards models. Results: Of a total 10634 female patients with BC, 60% were ≥ 50 years-old, with 19.6% stage I, 61.1% stage II, and 19.3% stage III and 7130 (67%) women were classified as ER+ and 2379 (22.4%) as ER-. Among 5764 (54.2%) patients with positive LN, 4300 (40.4%) had LN 1-3 and 1464 (13.8%) had LN ≥ 4. There were 4945 (46.5%) high-grade cases. There were 2487 (23.5%) patients treated with TC, 2981 (28%) with ACT, and 5166 (48.5%) with FEC-D. With a median follow-up of 5.5 years, the OS comparison for the entire study population showed hazard ratio (HR) of TC vs ACT was 1.47 (95% CI 1.14 – 1.90), p = 0.0027 and TC vs FEC-D HR was 1.48 (95% CI 1.18 – 1.86), p = 0.0007. For ER+ patients treated with TC, the OS comparison of LN 1-3 and LN ≥ 4 vs. LN 0 showed HR 1.34 (95% CI 0.81 – 2.21), p = 0.26, and HR 4.29 (95% CI 2.09 – 8.79), p &lt; 0.0001, respectively. For ER+ LN 0 patients, the OS HR of TC vs. ACT was 1.15 (95% CI 0.58 – 2.35), p = 0.67, and TC vs. FEC-D HR was 1.38 (95% CI 0.81 – 2.33), p = 0.23. For ER- patients treated with TC, the OS comparison of LN 1-3 and LN ≥ 4 vs. LN 0 showed HR 1.12 (95% CI 0.42 – 3.01), p = 0.82 and HR 4.41 (95% CI 1.33 – 14.59), p = 0.015, respectively. For ER- LN 0 patients, the OS HR for TC vs. ACT was 2.04 (95% CI 1.09 – 3.81), p = 0.025, and TC vs. FEC-D HR was 2.05 (95% CI 1.08 – 3.90), p = 0.028. Conclusions: Patients treated with adjuvant TC who had four or more axillary LN had significantly lower OS when compared to patients with LN 0. For women with ER- disease, TC demonstrated a significant unfavourable survival outcome when compared to anthracycline-based treatments.