Adriamycin-based Chemotherapy Research Articles

Abstract PO1-23-08: Exosome-based delivery of microRNAs confers adriamycin-resistance to sensitive cells through modulating the immune and metabolism-related gene PTEN in HER2-negative breast cancer

Abstract Background: Anthracycline-based chemotherapy is widely used to treat breast cancer. However, acquired drug resistance remains a challenge to successful treatment. Recently, increasing evidence has shown that changes in the tumour immune microenvironment (TIME), in addition to increasing drug resistance of tumour cells, consistently contribute to the development of chemoresistance. Methods: TIME scores and tumor-infiltrating immune cells (TICs) scores were used to investigate the prognosis, clinicopathological characteristics and gene transcriptome profiling of HER2-negative breast cancer patients who received anthracycline-based chemotherapy. Exosomes isolated from MCF/7-ADR (ADR-exos) and MCF/7-S (S-exos) cell lines were characterized. We identified dysregulated miRNAs using miRNA microarray analysis on MCF/7-ADR cells and their exosomes compared to MCF/7-S cells and their exosomes. Protein profiling was performed to identify differentially expressed proteins in up- and down-regulated miR-222 cells. The ability of ADR-exos to transfer drug-resistance mediated by miR-222 was assessed by immunofluorescence assay, flow cytometry and qRT-PCR. We optimized the conditions to load miR-222 mimic (or inhibitor) into exosomes produced by HBL-100 cells (H-exos). The influence of miR-222 inhibitor-containing exosomes (inhibitor-exos) on the downstream pathway of miR-222 and the potential therapeutic effects both in vitro and in vivo were evaluated. We also evaluated the relationship between miR-222/PTEN and drug resistance in circulating exosomes from mice after adriamycin-based chemotherapy. Results: Firstly, we discovered the complicated and heterogenous TICs subtypes and their unique biological behaviors in HER2-negative breast cancer. Then, we identified 85 differentially expressed immunologic signature gene sets and 7202 corresponding immune-related genes in three subtypes quantified by gene set variation analysis (GSVA). We identified 12 up-regulated and 13 down-regulated genes using miRNA microarray analysis in adriamycin-resistant cells and their exosomes. The TMT mass spectrometry found 45 differentially expressed proteins affected by the miR-222 level. Moreover, we successfully established miRNA mimic/inhibitor-containing exosomes to explore the solo function of exosomal miR-222 in adriamycin-resistance both in vitro and in vivo. More importantly, for the first time, we detected the levels of miR-222 and its target gene PTEN in circulating exosomes from mice after adriamycin-based chemotherapy and explored the potential clinical implications of miR-222/PTEN-containing exosomes in chemotherapy and immune suppression of breast cancer patients. Conclusions: HER2-negative breast cancer patients own unique TIME subtypes, leading to different outcomes of chemotherapy. We exhibit the potential applications of miR-222-mimic/inhibitor-containing exosomes for reversing chemo-resistance. Adriamycin-resistant cells can transmit drug-resistance to sensitive cells via delivering miR-222 by modulating the immune- and metabolism-related target gene PTEN both in vitro and in vivo without interference from other relevant drug-resistance factors in exosomes. Therefore, miR-222-containing exosomes as well as their target gene PTEN may be a promising biomarker for predicting the efficacy of chemo-resistance and tumor immunity regulation in breast cancer patients receiving anthracycline-based chemotherapy. Keywords: exosomes, breast cancer, tumor immune microenvironment, chemo-resistance, microRNAs Citation Format: Sujin Yang, Tian-cheng Cheng, Jia-hao Wu, Wei-xian Chen. Exosome-based delivery of microRNAs confers adriamycin-resistance to sensitive cells through modulating the immune and metabolism-related gene PTEN in HER2-negative breast cancer [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 PO1-23-08.

Pleomorphic liposarcoma of the extremity with solitary huge liver metastasis at initial diagnosis treated with conversion surgery combined with adjuvant chemotherapy: a case report

BackgroundPleomorphic liposarcoma is the rarest subtype of liposarcoma. Pleomorphic liposarcomas are generally unresponsive to chemotherapy and radiotherapy. Moreover, metastasis in the liver, as the first and sole site, from a primary extremity soft tissue sarcoma, including pleomorphic liposarcoma, is extremely rare. Information regarding the appropriate management of these lesions is limited.Case presentationA 50-year-old Japanese woman presented with a mass in the left thigh. Imaging examination revealed a soft tissue sarcoma on the left posterior thigh. The tumor was histologically diagnosed as pleomorphic liposarcoma. Computed tomography examination for assessment of metastases incidentally detected a huge liver mass. Wide excision of sarcoma was performed prior to chemotherapy. Right trisectionectomy was necessary to achieve hepatic clearance; however, the future liver remnant volume was insufficient. Therefore, we decided to administer anthracycline-based chemotheraphy to shrink the tumor. After seven courses of adriamycin-based chemotherapy, the liver tumor size was reduced from 211 mm × 106 mm × 180 mm to 105 mm × 66 mm × 90 mm. Finally, a right hemihepatectomy was performed. The patient was continuously monitored and was metastasis or local recurrence free within 5 months after liver surgery.ConclusionChemotherapy is effective in some cases for the treatment of unresectable liver metastases of pleomorphic liposarcoma, and complete resection is possible with conversion surgery. If the patient’s general condition permits, anthracycline-based chemotherapy can be used for the treatment of stage 4 pleomorphic liposarcoma.

Abstract P3-03-06: Prediction of response to neoadjuvant systemic therapy in triple negative breast cancer using baseline tumor MRI characteristics and imaging patterns of response

Abstract Background: Triple negative breast cancer (TNBC) has a poor prognosis. In particular, TNBC patients who have significant residual disease at the time of surgery following completion of neoadjuvant systemic therapy (NST) have an especially poor prognosis. In an effort to identify patients who are unlikely to achieve pathologic complete response (pCR), we investigated if pre-treatment breast MRI morphological characteristics and imaging response patterns during NST can predict pCR in TNBC patients. Materials and Methods: As part of a prospective IRB-approved clinical trial (ARTEMIS, NCT02276443), 199 patients with biopsy-proven stage I-III TNBC received NST and were classified as pCR or non-pCR based on histopathology at surgery. Patients underwent breast MRI at baseline (BL), after 2 cycles (C2), and 4 cycles (C4) of Adriamycin-based chemotherapy (AC). Subsequently, patients received either taxane-based NST or targeted therapy guided by mid-treatment imaging response. MRI studies were reviewed by two fellowship-trained breast radiologists who were blinded to the pathology results. ACR MRI BIRADS lexicon (5th Ed) was used to describe BL tumor morphology. Imaging response pattern at C2 and C4 MRI was classified as follows: type 0 (complete), type 1 (concentric shrinkage), type 2 (crumble), type 3 (diffuse enhancement), type 4 (stable), or type 5 (progression). Morphological baseline features and response patterns were summarized and compared to the pCR status on surgical pathology using Fisher’s exact test. P values less than 0.05 were considered statistically significant. Results: Median age was 53 years, range 24-79. Of 199 patients, 95 (48%) had pCR and 104 (52%) had non-pCR. At BL MRI, an irregularly-shaped mass and homogenous or clumped non-mass enhancement were associated with pCR (p=0.026 and p=0.013, respectively). Multifocality, peritumoral edema, and intratumoral necrosis were independent of pCR. Following NST, the most common MRI response pattern was type 1, seen with equal frequency in pCR and non-pCR at C2 (58% and 42%, respectively) and C4 (47% and 53%, respectively). The following response pattern associations were found: type 0 was associated with pCR at both C2 and C4 timepoints (p<0.001), while types 4 and 5 were associated with non-pCR at C2, (p<0.001). The four patterns: types 2, 3, 4, 5, were associated with non-pCR at C4 (p<0.001). Conclusion: Baseline MRI tumor morphological characteristics and MRI imaging response patterns during NST may be valuable markers for pCR prediction in TNBC. Qualitative breast MRI assessment may act as an accessible tool to identify TNBC patients who are unlikely to achieve pCR and may benefit from targeted therapies. Citation Format: Mary S Guirguis, Beatriz E Adrada, Rosalind P Candelaria, Jia Sun, Gary J Whitman, Wei T Yang, Medine Boge, Rania M Mohamed, Nabil A Elshafeey, Deanna L Lane, Huong Le-Petross, Jessica WT Leung, Lumarie Santiago, Marion E Scoggins, David A Spak, Miral Patel, Frances Perez, Peng Wei, Debu Tripathy, Jason White, Elizabeth Ravenberg, Lei Huo, Jennifer Litton, Banu Arun, Vincente Valero, Alastair Thompson, Stacy Moulder, Clinton Yam, Gaiane M Rauch. Prediction of response to neoadjuvant systemic therapy in triple negative breast cancer using baseline tumor MRI characteristics and imaging patterns of response [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-03-06.

Efficacy and safety of the VEGFR2 inhibitor Apatinib for metastatic soft tissue sarcoma: Chinese cohort data from NCT03121846

BackgroundThere is no standard treatment for stage IV soft tissue sarcoma (STS) after the failure of Adriamycin-based chemotherapy. This phase II study (NCT03121846) assessed the efficacy and safety of apatinib (YN968D1), a new tyrosine kinase inhibitor that targets VEGFR-2, for patients with stage IV STS after chemotherapy failure. MethodsForty-two subjects with stage IV STSs who had failed chemotherapy and who received Apatinib were recruited between September 2015 and February 2018. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the PFS rate (PFR), objective response rate (ORR), and disease control rate (DCR) at week 12. Treatment-related adverse effects (AEs) were evaluated. ResultsForty-two subjects were evaluated for AEs and 38 subjects were evaluated for efficacy. At 12 weeks, the PFR, ORR, and DCR were 70%, 26.32% (10/38), and 86.84% (33/38), respectively. Regarding overall responses, the ORR and DCR were 23.68% (9/38) and 57.89% (22/38), respectively. The median PFS was 7.87 months, and the median overall survival (OS) was 17.55 months. The most common AEs included hypertension (n = 18, 42.86%), hand-foot-skin reaction (n = 15, 35.71%), apositia (n = 13, 30.95%), and proteinuria (n = 11, 26.19%). No subjects had grade 4 AEs and 11 subjects (26.19%) experienced grade 3 AEs, mainly hypertension, hand-foot-skin reaction, proteinuria, apositia, fatigue, pain, and dysgeusia. Notably, the subjects who experienced hypertension, hand-foot-skin reaction, or proteinuria had significantly longer OS than those without these AEs (P = 0.0003). ConclusionWith the largest Chinese STS cohort to date, we report that apatinib show good efficacy in advanced STS subjects with significant higher ORR and some adverse events may predict prognosis.

HIF-1α forms regulatory loop with YAP to coordinate hypoxia-induced adriamycin resistance in acute myeloid leukemia cells.

Despite the improvement in acute myeloid leukemia (AML) treatments, most patients had a poor prognosis and suffered from chemoresistance and disease relapse. Therefore, there is an urgent need for elucidation of mechanism(s) underlying drug resistance in AML. In the present study, we found that AML cells showed less susceptibility to adriamycin (ADR) in the presence of hypoxia, while inhibition of hypoxia-inducible factor 1α (HIF-1α) by CdCl2 can make AML cells re-susceptibile to ADR even under hypoxia. Moreover, HIF-1α is overexpressed and plays an important role in ADR-resistance maintenance in resistant AML cells. We further found hypoxia or induction of HIF-1α can significantly upregulate yes-associated protein (YAP) expression in AML cells, and resistant cells express a high level of YAP. Finally, we found that YAP may not only enhance HIF-1α stability but also promote HIF-1α's activity on the target gene pyruvate kinase M2. In conclusion, our data indicate that HIF-1α or YAP may represent a therapeutic target for overcoming resistance toward adriamycin-based chemotherapy in AML.

Chemotherapy for Soft Tissue Sarcoma: Development of New Standard Treatments and Clinical Trials in Japan

Abstract Recently, pembrolizumab has been approved for microsatellite instability-high cancers, and genome profiling panel has also been approved for advanced refractory cancers including soft tissue sarcomas (STS) in Japan. However, efficacy and cost-benefit balance of these new strategies for STS should be confirmed by the future clinical trials. For localized STS, efficacy of perioperative chemotherapy has remained controversial. Meta-analysis of randomized controlled trials (RCT) comparing chemotherapy with surgery showed significant survival benefit of the chemotherapy for localized STS. Subsequently, recent RCT have compared chemotherapy regimens with each other especially in neoadjuvant setting, not with surgery. The Italian Sarcoma Group study ISG-STS1001 demonstrated significantly better survival by neoadjuvant epirubicin plus ifosfamide than histology-tailored regimens for high-risk STS. The 10-year follow-up of our trial, JCOG0304, also showed good stable results of neoadjuvant chemotherapy using adriamycin and ifosfamide (AI) for high-risk STS. These observations suggest that neoadjuvant AI could be recommended for localized high-risk STS. Besides high efficacy of AI, significant toxicities of the regimen should also be noted. We are now conducting a randomized phase II/III study, JCOG1306, to confirm the non-inferiority of neoadjuvant gemcitabine plus docetaxel (GD) to AI for high-risk STS. For advanced STS, adriamycin-based chemotherapy remains standard first-line treatment since phase III study of olaratumab resulted in negative. On the other hand, the standard second-line regimen for advanced STS has not been established yet. There are several options including GD, pazopanib, trabectedin and eribulin, however, no evidence has been shown which regimen is the best as second-line therapy. To establish the standard therapy of second-line treatment for advanced STS, we are currently conducting randomized phase II study comparing pazopanib, trabectedin and eribulin.

Chinese largest cohort data from NCT03120846: Efficacy and safety of VEGFR2 inhibitor apatinib for metastatic soft tissue sarcomas.

e22532 Background: There is no standard treatment for stage IV soft tissue tumor (STS) after the failure of Adriamycin-based chemotherapy. This opening, single-arm, multi-center phase II study (NCT03120846) assessed the efficacy and safety of Apatinib (YN968D1), a new tyrosine kinase inhibitor that targets VEGFR-2, for patients with stage IV soft tissue tumor after the failure of chemotherapy. Methods: Between September 2015 and February 2018, we recruited 42 patients with stage IV STS who had failed chemotherapy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were progression-free survival rate (PFR), objective response rate (ORR), and disease control rate (DCR) at week 12. Secondary endpoint was overall survival (OS). Treatment-related adverse effects (AEs) were evaluated. Results: Patients (19 men, 23 women; 14-83 years, average age: 47.67years) received 500 mg apatinib on Days 1–28 of 4-week cycles (median 5.7 cycles; range: 0–23 cycles). Median follow-up was 9 months (range: 1–28 months). We assessed 42 patients for AEs and 38 for efficacy. At 12 weeks, PFR was 70% and the ORR was 26.32% (10/38) and DCR was 86.84% (33/38). For the overall responses, the ORR was 23.68% (9/38) and DCR was 57.89% (22/38). The median PFS was 7.87 months and median OS was 17.55 months. The top AEs included hypertension ( n= 18, 42.86%), hand-foot-skin reaction ( n= 15, 35.71%), Apositia (13, 30.95%), and proteinuria ( n= 11, 26.19%). No patients had grade-4 AEs. 11 (26.19%) had grade-3 AEs. 2 patients (4.76%) quit because the AE. Notably, the 26 patients (61.90%) who suffered hypertension, hand-foot-skin reaction or proteinuria had significantly longer OS than those without these AEs (20.94 vs. 8.93 months; Log Rank (Mantel-Cox) = 12.94, P= 0.0003). Conclusions: Apatinib is effective and well tolerated in patients with advanced soft tissue sarcomas. The adverse events hypertension, hand-foot-skin reaction, or proteinuria may indicate a favorable prognosis, representing a novel finding in STS patients. Clinical trial information: NCT03120846.

Abstract P3-12-16: Five year outcomes of a prospective study of proton radiotherapy for breast cancer regional nodal irradiation

Abstract Purpose: Through improved nodal coverage and decreased dose to the heart and lung, proton therapy (PT) may improve the therapeutic ratio for treatment of breast cancer requiring regional nodal irradiation (RNI). The purpose of this study is to report 5 year disease control and toxicity. Methods: From May 2012 to February 2014, 18 women (stage IIA-IIIB) prospectively enrolled on a pilot study. Median age was 52 years (range, 42-73), with equal division between breast-conserving therapy (BCT) and mastectomy and right and left-sided cancers. Median number of positive nodes among the 16 node-positive patients was 2 (range, 1-14). Five patients had ≥ 10 nodes positive on axillary dissection (N3a). Treatment targets (CTVs for breast/chest wall, supraclavicular, axillary, internal mammary nodes (IMNs)) and organs at risk were delineated on CT scans. Double scatter PT alone was used for 10 patients (9 post-mastectomy, 1 after BCT) and combined proton-photon in 8 (all BCT). Toxicity was prospectively recorded using CTCAE v4.0. Results: Median follow-up was 4 years (range, 0.3 – 6). 5 year overall survival was 82% and locoregional control was 100%. 5 year distant metastases-free survival was 82%. No grade 4+ toxicity developed. Four patients developed grade 3 cellulitis, which was the only grade 3 toxicity. One patient had a reconstructive failure associated with a post-surgical cellulitis. A right-sided patient was diagnosed with CHF within 2 months of completion of PT, following diagnosis of a pulmonary embolus 1 month prior. She had an elevated BNP (1101) prior to PT following adriamycin-based chemotherapy. Mean heart dose was 0 Gy and cardiac V5 0%. Atrial fibrillation developed in two patients. One patient developed grade 2 pneumonitis (she received concurrent chemotherapy). One patient, with a history of rib fractures prior to PT, developed an ipsilateral rib fracture 7 months after PT. Conclusion: In a population of women with locally advanced breast cancer, PT for RNI has proven feasible after either mastectomy (with or without reconstruction) or BCT with excellent locoregional control. PT allows for highly conformal radiation delivery without compromise of target coverage or excess exposure of normal tissue. Documentation of the ultimate benefits of PT in this population, freedom from radiation induced cardiac disease and breast cancer recurrence will require prospective study of a larger numbers of patients. Citation Format: Bradley JA, Dagan R, Liang X, Ho MW, Rutenberg M, Mailhot R, Morris C, Mendenhall NP. Five year outcomes of a prospective study of proton radiotherapy for breast cancer regional nodal irradiation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-12-16.

Effect of neoadjuvant chemotherapy regimen on relapse-free survival among patients with breast cancer achieving a pathologic complete response: an early step in the de-escalation of neoadjuvant chemotherapy

BackgroundPatients with breast cancer who have a pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) have improved survival. We hypothesize that once pCR has been achieved, there is no difference in subsequent postsurgical recurrence-free survival (RFS), whichever NACT regimen is used.MethodsData from patients with breast cancer who achieved pCR after NACT between 1996 and 2011 were reviewed. RFS was estimated by the Kaplan-Meier method, and differences between groups were assessed using log-rank testing. Cox proportional hazards regression analysis adjusted for age, menopausal status, stage, grade, tumor subtype, and adjuvant endocrine HER2-targeted radiation treatment.ResultsAmong 721 patients who achieved pCR after NACT, 157 (21.8%) were hormone receptor-positive (HR), 310 (43.3%) were HER2-amplified, and 236 (32.7%) were triple-negative; 292 (40.5%) were stage IIA, 153 (21.2%) were stage IIB, 78 (10.8%) were stage IIIA, 66 (9.2%) were stage IIIB, and 132 (18.3%) were stage IIIC. Most patients (367 [50.9%]) had been treated with adriamycin-based chemotherapy plus taxane (A + T), 56 (7.8%) without taxane (A no T), 227 (31.5%) with HER2-targeted therapy, and 71 (9.8%) provider choice. Median follow-up was 7.1 years. Adjuvant chemotherapy was employed in 196 (27%) patients, adjuvant endocrine in 261 (36%), and adjuvant radiation in the majority (559 [77.5%]). There was no statistically significant difference in RFS by NACT group. Adjusted RFS hazard ratios, comparing each treatment with the reference group A + T, were 1.25 (95% CI 0.47–3.35) for A no T, 0.90 (95% CI 0.37–2.20) for HER2-targeted therapy, and 1.28 (95% CI 0.55–2.98) for provider choice.ConclusionsThese data suggest that postsurgical RFS is not significantly influenced by the choice of NACT or cancer subtype among patients achieving pCR.

Knockdown of Long Noncoding RNA HOXA-AS2 Suppresses Chemoresistance of Acute Myeloid Leukemia via the miR-520c-3p/S100A4 Axis

Background/Aims: Among different molecular candidates, there is growing data to support that long noncoding RNAs (lncRNAs) play a significant role in acute myeloid leukemia (AML). HOXA-AS2 is significantly overexpressed in a variety of tumors and associated with anti-cancer drug resistance, however, little is known regarding the expression and function of HOXA-AS2 in the chemoresistance of AML. In this study, we aimed to determine the role and molecular mechanism of HOXA-AS2 in adriamycin-based chemotherapy resistance in AML cells. Methods: Quantitative real-time PCR was used to detect HOXA-AS2 expression in the BM samples and ADR cell lines, U/A and T/A cells. Furthermore, the effects of HOXA-AS2 silencing on cell proliferation and apoptosis were assessed in vitro by CCK8 and flow cytometry, and on tumor growth in vivo. Furthermore, bioinformatics online programs predicted and luciferase reporter assay were used to validate the association of HOXA-AS2 and miR-520c-3p in AML. Results: In this study, we showed that HOXA-AS2 is significantly upregulated in BM samples from AML patients after treatment with adriamycin-based chemotherapy and in U/A and T/A cells. Knockdown of HOXA-AS2 inhibited ADR cell proliferation in vitro and in vivo and promoted apoptosis. Bioinformatics online programs predicted that HOXA-AS2 sponge miR-520c-3p at 3’-UTR with complementary binding sites, which was validated using luciferase reporter assay and anti-Ago2 RIP assay. HOXA-AS2 could negatively regulate the expression of miR-520c-3p in ADR cells. S100A4 was predicted as a downstream target of miR-520c-3p, which was confirmed by luciferase reporter assay. Conclusion: Our results suggest that HOXA-AS2 plays an important role in the resistance of AML cells to adriamycin. Thus, HOXA-AS2 may represent a therapeutic target for overcoming resistance to adriamycin-based chemotherapy in AML.

A Rare Case of Malignant Phyllodes Tumor of Breast Metastatic to the Skeletal Muscle

Malignant phyllodes tumors are rare fibroepithelial tumor accounting for 0.3 to 0.9% of all breast neoplasms. Distant metastasis occurs in 10–20% of patients, most common sites being the lung and bones. Skeletal muscle metastasis is rarely seen in malignant phyllodes. So far, only one case of malignant phyllodes tumor metastatic to skeletal muscle has been reported in the literature. A 45-year-old perimenopausal woman presented with a lump in her left breast and swelling over the right calf region. Workup showed mass in left breast and metastasis to the right calf muscle along with the lung and multiple bone metastases. She was started on ifosfamide- and adriamycin-based chemotherapy along with zolendronic acid. She received palliative radiotherapy to the spine and right calf region for pain. After 3 cycles, there was progression, so patient was started on second-line chemotherapy with gemcitabine and docetaxel. Patient developed severe pancytopenia after 3 cycles, so further chemotherapy was stopped as patient was not tolerating it.

Effect of neoadjuvant chemotherapy regimen choice in patients with breast cancer with pathologic complete response.

570 Background: Breast cancer patients with a pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) have improved survival. We hypothesize there is no difference in post-surgical recurrence free survival (RFS) between regimens used if pCR has been achieved. Methods: Breast cancer patients treated with NACT (using various regimens) between 1996 and 2011 who achieved pCR were examined, using a prospectively maintained electronic database. RFS was estimated by Kaplan-Meier method, differences between groups assessed using log-rank test. Cox proportional hazards regression analysis adjusted for age, menopausal status, stage, grade, tumor subtype, and adjuvant treatments. Results: 721 patients were identified: 40.4% Stage IIA, 21.2% IIB, 10.8% IIIA, 9.2% IIIB, 18.3% IIIC. 21.8% were hormone receptor positive (HR), 43.3% HER2 amplified, 32.7% triple negative. 50.9% of patients were treated with adriamycin-based chemotherapy plus taxane (adriamycin+taxane), 7.8% without taxane (adriamycin-taxane), 31.5% HER2 targeted therapy, and 9.8% provider choice. Median follow up was 7.4 years. There was no significant difference in RFS by treatment group (table 1). Adjusted RFS hazard ratios comparing each treatment to adriamycin+taxane were 1.25 (95% confidence interval 0.47-3.35) adriamycin-taxane, 0.90 (CI 0.37-2.20) HER2 targeted, and 1.28 (CI 0.55-2.98) provider choice. Conclusions: These data suggest that post-surgical RFS among patients with pCR is not significantly influenced by the type of NACT. Meta-analysis of randomized trial data should be explored to evaluate these findings. If RFS of pCR patients is not affected by regimen, this could allow flexibility in treatment choice and length. [Table: see text]

Two-year outcomes of a prospective study of proton therapy for breast cancer regional nodal irradiation.

65 Background: Through improved nodal coverage and decreased dose to the heart and lung, proton therapy (PT) may improve the therapeutic ratio for treatment of breast cancer requiring regional nodal irradiation (RNI). The purpose of this study is to report 2-year disease control and toxicity. Methods: From May 2012 to February 2014, 18 women (stage IIA-IIIB) were prospectively enrolled on a pilot study. Median age was 51.8 yrs (range, 42-73), with equal division between breast-conserving therapy (BCT) and mastectomy and right- and left-sided cancers. Median number of positive nodes among the 16 node-positive patients was 2 (range, 1-14). Five patients had ≥ 10 nodes positive on axillary dissection (N3a). Treatment targets (clinical target volumes for breast/chest wall, supraclavicular, axillary, internal mammary nodes) and organs at risk were delineated on CT scans. PT alone was used for 10 patients (9 postmastectomy; 1 postBCT) and combined proton-photon in 8 (all BCT). Toxicity was prospectively recorded using CTCAE v4.0. Results: Median follow-up was 1.9 yrs (range, 0.3 – 1.7). Two-year overall survival was 94% and locoregional control was 100%. Two-year distant metastases-free survival was 76%. No grade 4+ toxicity developed. Two patients developed grade 3 cellulitis. One patient had a reconstructive failure associated with postsurgical cellulitis. A right-sided patient was diagnosed with congestive heart failure 2 months after completing PT after diagnosis of a pulmonary embolus 1 month prior. She had elevated B-type natriuretic peptide before PT after adriamycin-based chemotherapy. Mean heart dose was 0 Gy and cardiac V5 0%. Grade 2 toxicities included pneumonitis in 1 patient who received concurrent chemotherapy, fatigue (n = 1), breast atrophy after removal of a 10x6x3cm lumpectomy cavity (n = 1), and lymphedema in 1 patient with > 20 nodes surgically excised. One patient with a history of rib fractures developed an ipsilateral rib fracture 7 months after PT. Conclusions: For women with locally advanced breast cancer, PT for RNI has proven feasible after either mastectomy or BCT. PT allows for highly conformal radiation delivery without compromise of target coverage or excess exposure of normal tissue. Clinical trial information: NCT01365845.

Biomarkers of fatigue related to adjuvant chemotherapy for breast cancer: evaluation of plasma and lymphocyte expression.

BackgroundFatigue is common in cancer patients receiving adjuvant chemotherapy. To further understand the mechanism of fatigue and search for potential biomarkers, we conducted this prospective study. MethodsWe enrolled breast cancer (BC) patients before their first adjuvant Adriamycin-based chemotherapy cycle. Patients responded to the brief fatigue inventory (BFI) and Chalder fatigue questionnaires and had their blood drawn for both plasma evaluation and evaluation of the peripheral mononuclear cell fraction (PMNCF) mRNA expression of various biomarkers. We evaluated FSH, LH, estradiol, DHEA, DHEAS, IL6, IL2, ILIRA, IL1β, CRP, Cortisol in the plasma and IL2, IL10, IL6, TGF-β, KLRC1, TNF, BTP, SNCA, SOD1, BLNK, PTGS2 and INF γ expression in the PMNCF.Results11 patients did not exhibit an increase in their BFI scores and served as controls, whereas 32 patients exhibited an increase in their BFI scores compared with the baseline scores. From the biomarkers we evaluated in the PMNCF, the only one significantly associated with fatigue was TGF-β (p = 0.0343), while there was a trend towards significance with KLRC1 (p = 0.0627). We observed no evidence of significant associations of any plasma biomarkers with the development of fatigue. However when we analyzed patients with more severe fatigue, plasma IL1-RA levels correlated directly with higher fatigue scores (p = 0.0136).ConclusionsWe conclude that fatigue induced by chemotherapy in BC patients is associated with changes in IL1-ra plasma levels and in TGF-β lymphocyte expression. Its mechanism may be different than that observed in long-term BC survivors or that induced by radiation therapy.Trial registrationNCT02041364 [ClinicalTrials.gov]

Hemangiopericytoma of the spleen

IntroductionHemangiopericytoma of the spleen is a very rare tumor, with 14 isolated reports. It was our aim to review our experience and compare it with all the reported cases in an attempt to standardize surgical treatment, adjuvant treatment and follow-up protocol of this infrequent condition. MethodsA consecutive case series study, with a mean follow-up of 44 months. Five patients (mean age, 49 years) underwent simple splenectomy for hemangiopericytoma limited to the spleen followed by adriamycin-based chemotherapy in one patient. ResultsAll the patients are alive and free from disease. ConclusionsFor tumors confined to the spleen, simple splenectomy can be considered curative, without any need for further adjuvant treatment. On review of the medical literature, cure can still be achieved with complete resection of recurrences, when feasible, with adjuvant chemotherapy being also indicated. The slow-growing pattern of the tumor suggests a 10-year follow-up.

Clinical outcome of thymic lymphoepithelioma-like carcinoma: Case report of a 14-year-old male.

Thymic carcinoma is a rare type of cancer, which arises from the thymic epithelium and accounts for ~1–4% of anterior mediastinal tumors in the USA. It rarely occurs in children, and is rarer among adults. Thymic lymphoepithelioma-like carcinoma (LELC) is an uncommon subtype of thymic carcinoma in children, however, it is one of the common histological subtypes of thymic carcinoma in adults. In the present study, a 14-year-old male patient presented to the Tokyo Metropolitan Cancer and Infectious diseases Center, Komagome Hospital (Tokoyo, Japan) with chest pain due to a large anterior mediastinal mass. The patient was histologically diagnosed with thymic LELC via a needle biopsy specimen, which was obtained from the primary site and indicated the Epstein-Barr virus infection, whose markers are also associated with oncogenesis. Immunohistochemical analysis demonstrated positive staining for keratin (AE1/AE3), epithelial membrane antigen, and latent membrane protein-1 and negative staining for cluster of differentiation 5. Thus, the patient was diagnosed with metastatic thymic LELC. First-line chemotherapy comprising of a cisplatin- and adriamycin-based chemotherapy regimen achieved a partial response, however, the patient succumbed within 10 months of the initial diagnosis due to rapid disease progression and refractory to subsequent cycles of chemotherapy. Thus, the current study, as well as previously reported cases, demonstrates that pediatric patients with thymic LELC continue to have a poor prognosis.

Acquired multidrug resistance in human K562/ADM cells is associated with enhanced autophagy

Autophagy, as a necessary process for survival in mammalian cells deprived of nutrients or growth factors, will be activated in many tumor cells while treated with chemotherapeutic drugs, but the role of autophagy in acquired multidrug resistance of human acute myelogenous leukemia to adriamycin-based chemotherapy remains to be clarified. Our aim was to address that question by surveying the autophagic activity in parental acute myelogenous leukemia cell line K562 and resistant sub cell line, K562/ADM, which were obtained by treating adriamycin with increasing concentrations. K562/ADM and K562 cells were exposed to PBS culture medium for 3 hours, then the stress-induced autophagy was measured. Real-time quantitative RT-PCR revealed the expression of LC3 mRNA was higher in K562/ADM than in K562 cells. LC3-II, as an autophagosomal marker, was more abundant in K562/ADM than in K562 cells measured by Western blotting. To determine the effect of 3-MA, a known specific inhibitor of autophagy, on overcoming acquired multidrug resistance induced by adriamycin, the MTT assay and flow cytometry were performed. We also found that 3-MA can enhance the growth inhibition and apoptotic effect of adriamycin in acquired resistant cells (K562/ADM). Collectively, our results provide evidence that the upregulation of autophagy plays a major role in multidrug resistance of K562/ADM cells induced by adriamycin.

Bortezomib for patients with previously untreated multiple myeloma: a systematic review and meta-analysis of randomized controlled trials

Multiple myeloma (MM) is an incurable disease with a poor survival, which has not been affected even by high-dose chemotherapy. This systematic review was performed to assess the efficacy and safety of the novel agent bortezomib for patients with previously untreated MM. We systematically searched biomedical literature databases and identified randomized controlled trials (RCTs) comparing bortezomib with placebo, no bortezomib, or other active agents for patients with previously untreated MM. Overall survival (OS), reported as hazard ratio (HR) with 95% confidence interval (CI), was the primary outcome measure. The secondary outcomes included time to progression (TTP), progression-free survival (PFS), and response rates. Five RCTs involving 2,728 patients were included. Three trials compared bortezomib with no bortezomib, and two compared bortezomib with other active agents (vincristine ± adriamycin-based chemotherapy). All included RCTs had methodological shortcomings, including no or unclear allocation concealment and blinding. Compared with no bortezomib or vincristine-based chemotherapy, the bortezomib-based regimen significantly improved the OS of patients with previously untreated MM. HR was 0.71 (95% CI 0.55-0.93) and 0.77 (95% CI 0.60-0.99), respectively. However, when compared with the vincristine + adriamycin-based regimen, the OS was similar (HR = 0.87, 95% CI 0.57-1.33). TTP, PFS, and response rates were also improved in patients receiving bortezomib-based regimen. However, the risk of peripheral neuropathy was found to be significantly higher. In summary, bortezomib appears to improve survival and response rates of patients with previously untreated MM in spite of higher risk of peripheral neuropathy.

A Screen for Genes Involved in Adriamycin Resistance in <i>Saccharomyces cerevisiae</i>

Adriamycin is an anthracycline antibiotic that is widely used in the treatment of various cancers. However, the efficacy of adriamycin-based chemotherapy is compromised by the development of adverse effects and the emergence of adriamycin-resistant cancer cells. In a search for novel mechanisms of resistance to adriamycin, we searched for genes that are related to adriamycin resistance using the budding yeast Saccharomyces cerevisiae and identified several genes (Akl1, Bsd2, Ssl2 and Erg13, etc.). We investigated the role of Akl1, a member of Ark/Prk kinase family, in adriamycin resistance and found that Akl1 might reduce adriamycin toxicity by inhibition of the internalization step in endocytosis via phosphorylation of component of endocytic complex. Furthermore, defects in vesicle trafficking from endoplasmic reticulum (ER) to vacuole reduced the degree of the adriamycin resistance induced by Akl1-overexpression, suggesting that inhibition of internalization step in endocytosis facilitates transport of protein from ER to vacuole, and decreases adriamycin toxicity.

1077P - Efficacy of the Anthracycline-Based Chemotherapy in Angioimmunoblastic T Cell Lymphoma Patients

ABSTRACT Background Peripheral T cell lymphoma (PTCL) is a heterogeneous disease, composed of five distinctive subtypes. Angioimmunoblastic T-cell lymphoma (AITL) represents a distinct clinicopathological entity in PTCLs, but there have been limited data concerning the efficacy of treatment for the rarity of this disease. Here, we report the efficacy of treatment with anthracycline-based chemotherapy in 49 AITL patients. Material and method A total of 49 patients diagnosed with AITL between April 1994 and October 2011 after the histopathological and immunohistochemical review were analyzed. All patients analyzed were treated with anthracycline-based chemotherapy. Overall survival (OS) was defined as the date of diagnosis to death. Progression free survival (PFS) was defined as the date of diagnosis to the first date of disease progression, relapse, death as a result of any cause, or the last date of follow-up. OS and PFS were analyzed according to the Kaplan-Meier methods. Results 14 of 49 patients (28.6%) were treated with adriamycin-based chemotherapy (CHOP), and 35 patients (71.4%) received epirubicin-based chemotherapy (CEOP). 4 patients (8.16%) received high-dose chemotherapy with autologous stem cell transplantation when the disease relapsed. Overall response rate was 69.4%, and complete remission was shown in 21 patients. (42.9%). 6 cases (12.2%) of the AITLs had progressive disease, and the response was not evaluated in 9 cases due to follow-up loss or early death. Only 2 patients of 49 (4.1%) were related to treatment related death, defined as death within 28 days after the initial day of therapy. 21-month OS rates were 77%, reaching a plateau level around 2 years. 2-year and 5-year PFS rates were 34% and 23%, respectively. Conclusion Anthracycline-based chemotherapy could be a choice of chemotherapy regimen, given the acceptable outcome of long term survival. The initial 2-year survival after initiation of the treatment is poor, and further analysis is required for factors associated with the initial poor treatment outcome in AITL patients. Disclosure All authors have declared no conflicts of interest.