Breast Sarcoma Research Articles

Secondary Malignancies: The Cost of Progress.

With advances in treatment of cancer, patients who survive their first malignancy are at risk of developing additional malignancies. Data on the risks of secondary malignancies after treatment of some of the more common cancers are lacking. Our prospectively maintained database was queried from 1996 to 2016 to identify patients with breast cancer, colorectal cancer, melanoma, sarcoma, gastric, and pancreatic adenocarcinoma who developed additional malignancies. Predisposing clinical factors were included in our analysis. We identified 756 patients diagnosed with a solid malignancy who developed a second malignancy, of which 606 (80.1%) had one of the most common treated cancers. 59.5% of patients were women. 810 additional malignancies were identified in the 606 patients with breast and colon cancer being the most common secondary malignancies. Of these 606 patients, 460 (76%) patients had two malignancies; 145 (23.9%) had 3 or more malignancies. 15.2% of patients were diagnosed under the age of 40.63years. 8.3% patients had a known genetic mutation, with BReast CAncer gene, and Lynch mutations being the most common. Advances in cancer treatment have led to higher cure rates. These patients should continue surveillance and undergo screening as they may be at risk of developing additional malignancies.

Metaplastic carcinomas of the breast without evidence of epithelial differentiation: a diagnostic approach for management.

Although rare, malignant sarcomatoid breast tumours without evidence of epithelial differentiation comprise a diagnostic challenge with management implications. Earlier studies have generally considered these to be primary breast sarcomas; however, supporting evidence is lacking and management remains variable. This study aimed to provide an evidence-based approach to improve the consistency of diagnosis and management for such cases. A large series (n=140) of metaplastic breast carcinoma (MBC) diagnosed in Nottingham over 18years was analysed. Only cases with available data on immunohistochemical expression of cytokeratins (CKs) were included. The prevalence and pattern of expression for various CKs were assessed and details of tumours negative for CKs were collected. A diagnostic approach based on our experience is provided. Forty-seven cases (34%) showed foci of conventional type invasive breast carcinoma or ductal carcinoma in situ (DCIS), while 93 cases (66%) were diagnosed as MBC based on morphology and/or CK expression. Ninety-seven cases (69%) were negative for one or more CKs, with 18 cases (13%) negative for five or more CKs. Eight cases (6%) lacked expression of all CKs tested. Further examination showed evidence of carcinomatous nature in five cases, and three were diagnosed as MBC following extensive diagnostic work-up and based on our experience. This study suggests that MBC represents a spectrum of neoplasms, with some lacking CK expression. Sarcomatoid neoplasms of the breast lacking evidence of carcinomatous morphology and CK expression may represent an extreme end of differentiation that can be considered as carcinomas rather than sarcomas for management purposes (following extensive work-up).

Hepatectomy for Breast Cancer Metastasis and Sarcoma are more likely to have Adverse Outcomes than Hepatectomy for Primary Hepatocellular Cancer or for Colorectal Metastasis

Outcomes for hepatectomy for breast cancer metastasis and sarcomatous disease processes are not well defined in literature. We sought to use a national database to identify outcomes in these patients compared to subset of patients more well studied in literature - primary Hepatocellular cancer patients and patients with colorectal metastasis. We identified patients undergoing major hepatectomy (≥ 3 segments) for primary hepatocellular cancer (HCC), sarcoma metastasis, breast cancer metastasis, and colorectal metastasis using NSQIP database. The Primary outcome measure was 30-day mortality. Secondary outcome measures were 30-day readmission and complication rates. A total of 5580 patients underwent major hepatectomy during the study period. Patients who underwent hepatectomy for breast cancer metastasis had higher incidence of in-hospital complications (37%) compared to sarcoma (29%), colon (26%), and HCC patients (24%) and 30-days readmission rate (37% vs. 29% - sarcoma vs. 26% - colon vs. 25% HCC). There was no difference in 30-days mortality among the groups. Patients undergoing major hepatectomies for breast cancer metastasis and sarcoma are more likely to have adverse outcomes than compared to their counterparts. This difference highlights the lack of experience in managing breast cancer and sarcoma with metastatic disease to the liver. This also highlights the difference in tumor biology among all the lesions we studied. An extensive discussion should take place when dealing with breast and sarcoma lesions in the liver because of these outcomes.

Simultaneous diagnosis of liver PEComa in a family with known Li\u2013Fraumeni syndrome: a case report

BackgroundLi–Fraumeni syndrome (LFS) is an autosomal dominant hereditary disease. It is associated with the loss of function of the p53 protein and an increased risk of malignant tumor development at early age. The most frequently detected tumors include breast cancer, sarcomas, leukemia, brain tumors, and adrenocortical carcinomas. While sarcomas account for only 1% of solid tumors, they are more frequently detected in these families.Case presentationWe report a simultaneous diagnosis of hepatic perivascular epithelioid cell tumor (PEComa), a very rare subtype of sarcoma, in two siblings with a LFS.ConclusionsThe simultaneous diagnosis of PEComa in two siblings presented in this case allowed us to review the frequency of PEComa in this genetic syndrome previously reported, which was very little. Despite its rarity, PEComa must be considered in the differential diagnosis of new-onset liver lesions in patients who were previously diagnosed with LFS.

Radio-induced breast angiosarcoma: features of diagnostics and treatment (a clinical case and literature review)

Breast angiosarcoma (BAS) is an extremely rare and poorly studied neoplasm, the etiology of primary BAS remains controversial, and secondary BAS is most often radio-induced. Radio-induced breast tumors usually appear 10–20 years after the initial treatment; however, for BAS this period is much shorter and is about 4–7 years. This review presents literature data on the features of the clinic, diagnosis and treatment of BAS, as well as own clinical case observation of radio-induced sarcoma of the left breast, that developed 4 years after the primary breast cancer treatment.

Primary Leiomyosarcoma of the Breast Papilla: A Case Report

Background: Breast leiomyosarcoma is a rare subtype of breast sarcoma, constituting 5–10% of the cases. Less than one-third of reported cases are located in the nipple papillary region, making it an extraordinarily rare malignancy, responsible for less than 0.1% of all malignant breast tumors. As no radiological criteria allow definitive diagnosis of papillary leiomyosarcoma, histopathological and immunohistochemical examination of suspicious lesions is required. The prognosis is generally optimistic compared with those for other breast sarcomas.Case presentation: A 54-year-old previously healthy woman reported the appearance of a nodule in her right nipple in the preceding 9 months, associated with pruritus. Physical examination revealed that the lesion had a cystic consistency and measured approximately 3.0 cm. Imaging examinations showed no involvement of the adjacent breast parenchyma or axillary region and the lesion was classified as Breast Imaging-Reporting and Data System (BI-RADS) category IV. The lesion was excised, and the histopathological diagnosis was well-differentiated leiomyosarcoma of the mammary papilla, with immunohistochemical examination showing positivity for smooth-muscle tissue antigens. A staging CT examination was performed, showing no evidence of distant metastasis. After 2 years of follow-up, the patient shows no sign of tumor recurrence.Conclusion: Although rare, leiomyosarcoma must be included in differential diagnosis of breast masses, especially those involving the periareolar region. Due to its good prognosis, reporting on this type of tumor is important to guide therapeutic planning, and to identify and track possible complications of its underdiagnosis.

A need for clarity on surgical management of breast sarcoma: Scottish sarcoma network guidelines and regional audit

Currently, there are no comprehensive breast sarcoma guidelines in the UK. There is therefore a need for guidelines to clarify surgical management, which we have based on data from our regional audit, current evidence, and consensus between West of Scotland Breast Cancer and Scottish Sarcoma Managed Clinical Networks. Methods and results: From 2007 to 2019, 46 patients were treated with breast sarcoma in the West of Scotland. Sarcoma Centre versus Peripheral Hospitals: Incomplete excision rate was 0% at sarcoma centre and 50% at peripheral hospitals (p = 0.0002, Odds Ratio 43). For angiosarcoma, 0% positive margin at the sarcoma centre versus 62.5% at the peripheral unit (p = 0.0036, odds ratio 39.3). Tumours treated at the sarcoma centre were larger than those treated at peripheral hospitals (92.5 versus 39.7 mm, p = 0.0009). WLE (wide local excision) versus mastectomy: Out of eight WLE patients, seven (87.5%) had positive margins, with 6 of these patients proceeding to mastectomy (i.e. 75% WLE patients ultimately had a mastectomy). The positive margin rate was significantly higher in WLE (87.5%) than in mastectomy (10.3%) (p = 0.0001, odds ratio 60.7). Survival: No difference was noted between the sarcoma centre and peripheral hospitals for overall survival (p = 0.43), stratified for tumours <5 cm (p = 0.16), and disease-free survival (p = 0.45). Conclusions: Our data strongly suggest that specific guidelines are needed for breast sarcoma, and that managing these patients according to breast carcinoma protocols in peripheral hospitals is sub-optimal. We recommend centralisation of breast sarcoma patient care to a specialist sarcoma centre, with WLE not recommended as a firstline surgical option given both the high rates of incomplete excision and subsequent need for completion mastectomy.

Implications of Incidental Germline Findings Identified In the Context of Clinical Whole Exome Sequencing for Guiding Cancer Therapy.

Identification of incidental germline mutations in the context of next-generation sequencing is an unintended consequence of advancing technologies. These data are critical for family members to understand disease risks and take action. A retrospective cohort analysis was conducted of 1,028 adult patients with metastatic cancer who were sequenced with tumor and germline whole exome sequencing (WES). Germline variant call files were mined for pathogenic/likely pathogenic (P/LP) variants using the ClinVar database and narrowed to high-quality submitters. Median age was 59 years, with 16% of patients ≤ 45 years old. The most common tumor types were breast cancer (12.5%), colorectal cancer (11.5%), sarcoma (9.3%), prostate cancer (8.4%), and lung cancer (6.6%). We identified 3,427 P/LP variants in 471 genes, and 84% of patients harbored one or more variant. One hundred thirty-two patients (12.8%) carried a P/LP variant in a cancer predisposition gene, with BRCA2 being the most common (1.6%). Patients with breast cancer were most likely to carry a P/LP variant (19.2%). One hundred ten patients (10.7%) carried a P/LP variant in a gene that would be recommended by the American College of Medical Genetics and Genomics to be reported as a result of clinical actionability, with the most common being ATP7B (2.7%), BRCA2 (1.6%), MUTYH (1.4%), and BRCA1 (1%). Of patients who carried a P/LP variant in a cancer predisposition gene, only 53% would have been offered correct testing based on current clinical practice guidelines. Of 471 mutated genes, 231 genes had a P/LP variant identified in one patient, demonstrating significant genetic heterogeneity. The majority of patients undergoing clinical cancer WES harbor a pathogenic germline variation. Identification of clinically actionable germline findings will create additional burden on oncology clinics as broader WES becomes common.

The spectrum of pathological diagnoses in non-sentinel axillary lymph node biopsy: A single institution's experience

Although axillary lymphadenopathy is a common clinical encounter, systemic evaluation of non-sentinel lymph node biopsy is sparse. We reviewed our institution's 15-year experience to delineate the spectrum of diagnoses in non-sentinel axillary lymph nodes. 1165 non-sentinel axillary lymph node biopsies were retrieved and the diagnosis and relevant clinical information was reviewed. This spectrum of diagnoses was further stratified by gender, age, and oncologic history. The spectrum of diagnoses included: breast carcinoma (27.6%), lymphoma (29.2%), melanoma (3.5%), other carcinoma (2.9%), sarcoma (0.4%), and benign changes (36.3%). The most common diagnoses in men were lymphoma (61.8%) and benign changes (23.6%); while in women they were benign change (41.2%), breast carcinoma (37.8%) and lymphoma (16.7%). Besides benign changes, lymphoma and breast carcinoma were most common in women younger and older than 30 years, respectively. In patients with a history of malignancy, the most common diagnoses were metastasis from the known tumor and benign change; while in patients with a negative oncologic history and female patients without a history of breast cancer, the diagnosis was generally either lymphoma or benign change. Anaplastic large cell lymphoma was rare but may be mistaken as metastatic carcinoma thus a high index of suspicion is warranted. Thus through retrospective review of a large cohort of non-sentinel axillary lymph node biopsies, we described the spectrum of pathological entities based on the gender, age, and clinical history, which could provide valuable information for further work-up of axillary lymph node biopsy.

"Single-cell pattern" of adenocarcinoma cells in effusion cytology: Morphologic challenges of lung cancer.

Lung adenocarcinomas present as tight clusters and three-dimensional balls in effusion specimens. Unlike carcinomas of breast and stomach where singly lying malignant cells are seen in effusion samples, lung adenocarcinomas usually show cohesive morphology. This single-cell pattern may also be confused with reactive mesothelial cells. We studied the frequency of pulmonary adenocarcinoma with single-cell pattern cytomorphology in pleural effusion specimens. All cases reported as either suspicious or positive for malignancy on pleural effusion cytology (PFC) over the past 1 year were retrieved. The clinical details were obtained from requisition forms. Cases with predominant single-cell pattern, clinically suspicious of carcinoma lung were segregated. These were de-stained and immunocytochemistry (ICC) for TTF-1 was performed. Of 103 cases reported as either suspicious or positive for malignancy on PFC, 29 had a predominant single-cell pattern. Of these, 13 (44.8%) were primary lung carcinoma. The rest were metastasis from ovary (5; 17.2%), breast (2; 6.9%), stomach (2; 6.9%), lymphoma (1; 3.5%), and Ewing's sarcoma (1; 3.5%). Five (17.2%) were those with unknown primary. All cases of lung carcinoma were positive for TTF-1 ICC. Single-cell pattern of pulmonary adenocarcinoma is commoner than popularly believed. This pattern may be difficult to differentiate from carcinoma cells of other sites as well as from reactive mesothelial cells. A high degree of suspicion is therefore needed to perform relevant ICC to clinch the correct diagnosis.

Cowden syndrome is a risk factor for multiple neoplasm: a case report

BackgroundCowden’s syndrome is an autosomal dominant disease with variable penetrance, involving the tumor suppressor phosphatase and tension homolog gene, located on chromosome 10q22-23, responsible for cell proliferation, migration, and cellular apoptosis. Its clinical presentation encompasses mucocutaneous lesions, which are present around 99% of the time; macrocephaly; and cognitive impairment, and it precedes the appearance of neoplasms such as thyroid carcinoma, breast cancer, among others.In addition to these malformations, arteriovenous malformations of the brain and spine, endocrine abnormalities, skeletal defects, and cardiopulmonary lesions may also be found.The relevance of the case is due to the fact that, through a certain phenotype, the patient’s genotype can be inferred and thus followed up closely.Case representationThe clinical case concerns a 28-year-old Caucasian and Portuguese woman with palmar pits, macrocephaly, and cognitive impairment. She was diagnosed with papillary thyroid carcinoma at 22 years of age and proposed total thyroidectomy.At age 27, a pregnancy was diagnosed with a Breast Imaging-Reporting and Data System 2-rated breast lump. After the histological verification, it was concluded that it was a high metastatic breast sarcoma, opting for palliative mastectomy. A genetic evaluation confirmed alteration in the phosphatase and tension homolog gene, confirming Cowden’s syndrome. The patient died at age 29 due to neoplastic pathology.ConclusionThis report aims to alert to the clinical signs of this entity and the clinical supervision and follow-up of these patients. In order to prevent premature deaths and to improve patient’s quality of life, genetic diseases with cancer impact should be diagnosed as early as possible.

Primary breast stromal sarcoma: A rare case report

Primary sarcoma of the breast comprises less than 1% of all the breast malignancies. It is a locally aggressive neoplasm with only a few hundred cases published till date. The index case is being reported due to rarity of this entity. Breast sarcoma should always be considered whenever spindle cells are seen in the histological sections. The main diagnostic confusion arises with malignant phyllodes tumor and metaplastic carcinoma from which distinction is important from prognosis as well as treatment point of view. Herein, we report a case of a 47-yr-old female, who presented with a right-sided breast lump which was diagnosed as suspicious of carcinoma breast on fine needle aspiration (FNAC). Thereafter, modified radical mastectomy was performed, and on histopathology, a possibility of fibro-histiocytic tumor of intermediate malignancy was rendered, which was subsequently confirmed by immunohistochemistry (IHC).

A Case Report: First Report of a Primary Breast Leiomyosarcoma with Lymph Node Metastasis in Lebanon

Background: Primary leiomyosarcoma (LMS) of the breast is an extremely rare histologic subtype of malignant breast tumors. While breast sarcomas account for 0.0006% of all breast malignancies, primary leiomyosarcoma constitutes only 5-10% of breast sarcomas themselves. To date, the total number of reported cases in the literature is less than 70 cases with the first case reported in 1968. This is, to the best of our knowledge, the first case reported from Lebanon, with only 2 cases previously reported in the Middle East, specifically in Morocco. Case Report: We report the case of a 48-year-old, white, previously healthy female patient, presenting for a breast mass. She first noticed it three months prior to presentation in her left breast and reports that since then, the lump has been growing and her breast has become more painful and erythematous over time. Physical examination revealed an immobile and tender mass of around 12 cm in diameter. A core biopsy was done followed by a left modified radical mastectomy with lymph node dissection. Pathology of the specimen showed a tumor composed of spindle cells arranged in fascicles invading the dermis, with irregular nuclei and prominent nucleoli. Immunohistochemical staining confirmed the diagnosis of high-grade leiomyosarcoma. Conclusion: We presented this case of leiomyosarcoma with lymph node metastasis to contribute to the scarce literature regarding this disease. Due to the rarity of this diagnosis, not enough data exists regarding treatment and prognosis. Physicians need to review the literature for relevant cases to achieve the best outcome for their patients. Keywords: breast mass, leiomyosarcoma, rare, case report, breast sarcomas, lymph node

Sarcoma of the breast: breast cancer history as etiologic and prognostic factor\u2014A population-based case\u2013control study

PurposeSarcomas of the breast account for about 1% of all breast malignancies. The aim of this national survey was to explore etiologic and prognostic factors.MethodsUtilizing national Swedish registers, all patients registered with mesenchymal tumors in the breast during the period 1993–2013 (n = 344) were identified and compared to up to ten age and gender matched controls. Cancer history was retrieved for cases and controls. Conditional Poisson regression models were used for calculation of odds ratios.ResultsPrevious breast cancer was overrepresented among patients with angiosarcoma. The highest risk occurred ≥ 5 years after treatment for breast cancer (OR 73.9, 95% confidence interval, CI, 25.4–215; P < 0.001). An increase in incidence of angiosarcoma was observed during the study period (1.10, 95% CI 1.05–1.16; P < 0.001). The overall incidence of breast sarcoma increased from 1.52 to 2.04 cases per million per year. Angiosarcoma of the breast was associated with a significant excess mortality compared to age-matched controls (HR 4.65, 95% CI 3.01–7.19; P < 0.001).ConclusionsAngiosarcoma increased in incidence and displayed a more severe clinical course, with significantly shorter survival. The strong association between a history of breast cancer 5 years or more prior to the diagnosis of angiosarcoma points to radiotherapy as a contributing factor.

Development of molecularly imprinted magnetic iron oxide nanoparticles for doxorubicin drug delivery

In this study, we prepare a biocompatible and magnetic material coated with dopamine (Fe3O4/SiO2@DA) for drug delivery of doxorubicin. Doxorubicin is a commercially available drug for the treatment of several types of cancers such as metastatic breast carcinoma, blood, lungs, ovarian carcinoma, and sarcoma. Magnetic nanoparticles are synthesized by co-precipitation method and coated with dopamine. Characterization of materials is carried out by Fourier transform infrared spectroscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy. Magnetic properties of the particles are evaluated by magnetic moment measurements. Later, this material is applied to the targeted delivery of doxorubicin. Several experimental parameters such as loading time, release time, loading temperature, release temperature, desorption pH, amount of nanomaterial, salt concentration, and effect of solvent are optimized. Loading of a drug is maximum in basic pH while acidic pH (3.3) works best for the desorption process. With increasing the amount of material, loading of drug increase. Moreover, salt (NaCl) concentration does not affect the loading process. Loading of a drug is maximum at a lower temperature (room temperature) while the release is more efficient at a higher temperature (40–45 °C). This material showed superior efficiency (drug loading, drug release, and time) as compared to previously reported similar materials. These results indicate that Fe3O4/SiO2@DA has excellent potential to carry the drug and deliver to cancerous cells which have acidic pH and higher temperature as compared to normal healthy cells.

Impact of upfront multidisciplinary tumor board (MTB) evaluation on breast sarcoma (BS) outcome.

e23546 Background: Although sarcomas may arise in any site of the body, the intrinsic challenge of BS is to affect the female most frequent cancer site with a completely different and rare set of heterogeneous tumors. Unfortunately, we lack BS-specific prospective trials to precisely guide the clinical decision-making and BS patients are often sent to sarcoma referral centers only after surgery without upfront BS MTB evaluation. Recent evidences reported a significant prognosis improvement with upfront MTB evaluation in retroperitoneal or extremity sarcomas, but whether this strategy might benefit also BS is still not defined. We retrospectively evaluated our prospectively collected database to test whether an upfront MTB evaluation at BS referral centers might impact prognosis and/or the need of subsequent surgeries. Methods: Detailed information on primary surgery, diagnosis, and ≥2 years of follow-up for non-recurring patients were required. We tested the following outcomes: event-free survival (EFS), local EFS (LEFS), distant metastases EFS (DMEFS), overall survival (OS), margin status, subsequent surgeries rate. We evaluated the different outcomes according to upfront MTB evaluation. Kaplan-Meier method was used for survival analyses. Comparisons used hazard ratios (HR). Results: We included 93 patients treated between 1/2000 and 10/2019 at 2 reference BS Centers, median age 53 years (IQR 41-70), ECOG (0;1;2) 67:16:10, high/low grade 60:33. Histotypes were: malignant phyllodes tumor 42 (45%), angiosarcoma 26 (28%), other STS 25 (27%). 27 (29%) cases were considered radiation-induced with a median time from RT of 105 months (IQR 70-127). 44 patients (47%) were discussed upfront in BS MTB, whereas 49 (53%) were not. With a median follow up of 43 months, 5-year EFS, LEFS, DMEFS, and OS for the whole population were 54%, 64%, 60%, and 62%, respectively. LEFS at 5 years had a strong association with margin status (R0 74%; R1 55%, R2 0%, p &lt; 0.001). Regardless of histology, upfront MTB was associated with a significant lower rate of subsequent surgeries (OR 0.16, 0.06-0.41), and with better EFS, LEFS, DMEFS, and OS (HRs 0.57, 0.54, 0.63, and 0.43, respectively). Conclusions: Though retrospective, this series is one of the largest reported to date in BS. Our results highlight the need for early inter-tumor board sharing of BS to take into account sarcoma specificity in the overall disease planning. Given BS rarity, these data will hardly ever be verified in a prospective fashion. Therefore, validation of these results in the Italian Sarcoma Group database is planned.

Impact of bolus versus continuous infusion of doxorubicin (DOX) on cardiotoxicity in patients with breast cancer (BC) and sarcomas: Analysis of real-world data.

e19123 Background: Doxorubicin continues to play a central role in management of breast cancer and sarcomas. Dose-dependent cardiomyopathy is a challenge in its use. Strategies have been proposed to mitigate this, including administration by continuous intravenous (CIV) infusion as an alternative to bolus (BOL) administration. This study used real world data to explore the impact of DOX administration mode on cardiotoxicity, duration of DOX and time to treatment failure (TTF). Methods: This study used IBM MarketScan claims to identify patients age ≥ 18 who received at least 2 DOX administrations after cancer diagnosis. Patients with history of cardiac events/toxicities were excluded. Cardiac events were compared for BOL versus CIV overall, by tumor site and by regimen during three follow-up periods, early (within 1 year), middle (&gt;1 to 5 years) and late (&gt;5 years), from DOX initiation using Fisher’s exact test. Duration of DOX and TTF, defined as time from initiation of DOX to subsequent systemic therapy, hospice or death, were evaluated using Kaplan-Meier method and unadjusted Cox proportional hazards models. Results: 62,597 patients were eligible, including 38,961 with BC and 1,772 with sarcoma. Most patients had codes for both modes; 1,941 and 7,094 patients had exclusive BOL and CIV codes, respectively. For these patients, mean duration of DOX was longer for BOL vs. CIV (83.9 vs. 65.4 days, p&lt;0.001). Cardiac events for BOL vs. CIV were 6.5% vs. 5.6% (p=0.098) during the early period, 4% vs. 5.1% (p=0.046) middle period, and 0.5% vs. 0.9% (p=0.068) late period. This pattern was consistent for BC and sarcoma and among those who were pre-treated. There were no differences in cardiac events for BOL vs. CIV for the chemotherapy naïve or DOX monotherapy groups (all periods p&gt;0.10) but statistically different for the breast during the middle period, sarcoma at any time, and pretreated subgroup middle period (all p&lt;0.05). TTF favored CIV over BOL among patients with BC (p&lt;0.0001) but BOL over CIV in sarcoma (p=0.002). TTF was not significantly different between BOL and CIV for BC monotherapy (p=0.067) but was significant for sarcoma monotherapy favoring BOL administration (hazard ratio 0.72, 95% confidence interval 0.54-0.95, p=0.02). Conclusions: These data suggest that cardiac events may occur at a similar rate irrespective of mode of DOX administration. Further analyses are needed to understand how these relationships are impacted by other potential risk covariates (eg, age, gender) and by protective factors (eg, dexrazoxane).

Results of a completed first-in-human phase Ib dose-escalation study of oral CBL0137 in patients with advanced solid tumors.

3607 Background: Curaxin CBL0137 is a novel compound with broad anticancer activity in animal models. The drug is a non-genotoxic DNA intercalator that interferes with histone/DNA binding causing decondensation of chromatin in tumor cells, functional inactivation of histone chaperone FACT, activation of p53 and IFN responses, and inhibition of pro-cancer transcriptional factors, MYC, NF-kB, HSF1, and HIF1a. Methods: The study enrolled adults with advanced chemorefractory solid tumors, ECOG PS ≤2, and adequate organ function. The primary objective was to find the maximum tolerated dose (MTD) and recommended dosing regimen (RDR). Secondary objectives were to evaluate CBL0137 safety, pharmacokinetics, and efficacy. CBL1037 was given orally once daily (QD) for the first 14 days of repeated 28-day cycles. A 3+3 dose escalation determined the MTD, defined as the highest dose at which ≤1 of 6 pts had Cycle 1 dose-limiting toxicity (DLT). Pharmacokinetics were assessed on Days 1 and 13. Efficacy was evaluated every 8 weeks. Results: 60 pts were enrolled (females/males [n]: 42/18; median [range] age 56 [25-76] years; ECOG PS [n] 0/1/2: 8/49/3); cancer types [n]: ovarian cancer [15], colorectal cancer [14], breast cancer [11], others [20]) over 16 dose levels ranging from 4 mg to 200 mg QD. Durations of therapy ranged from 6 to 342 days. Three DLTs were observed: prolongation of QTc Gr 3 (88 mg QD), neutropenia/thrombocytopenia Gr 4 (200 mg QD), and LV dysfunction Gr 3 (200 mg QD). Dose-dependent nausea/vomiting was observed and was Gr 2-4 at 200 mg QD. Gr 1/2 photosensitization occurred in 11 subjects across doses from 48 to 200 mg QD but was successfully managed with sun protection and resulted in no dose modifications or discontinuations. On Day 1, mean (range) plasma CBL0137 Tmax values were 5.1 (1-10) hrs. Generally linear increases in AUC occurred with increasing CBL0137 dose. Mean (range) t1/2 values were 25.6 (0.3-166) hrs, with minor dose dependency. Mean (range) Day 13/Day 1 Ctrough ratios showed 3.6 (1.7-7.2)-fold accumulations. Disease control was registered in 11 pts who had stable disease (SD). Target lesion regressions up to 21% were documented in 4 patients with breast cancer (2), sarcoma (1), and ovarian cancer (1). Pts with breast cancer (1) and sarcoma (1) had SD for &gt; 36 weeks. Conclusions: The Phase 2 RDR for oral CBL0137 was established as 180 mg QD x 14 days in 28-day cycles based on bone marrow and gastrointestinal DLTs at 200 mg QD. CBL0137 showed a manageable safety profile with efficacy signals. Further study as a component of combinations is planned. Clinical trial information: 847 .

Patient and diagnostic intervals of sarcoma patients: Results from a survivorship study in the Netherlands.

e23553 Background: Sarcoma patients are hypothesised to experience long intervals to cancer diagnosis, due to the rarity of the disease, heterogeneous presentation, and complexity of histological diagnosis. Comprehensive assessment of patient interval (time between first symptom and presentation to a doctor), diagnostic interval (time between presentation to a doctor and diagnosis ), and their associated factors is needed to improve referral pathways and outcomes for sarcoma patients. We investigated patient and diagnostic intervals and identified factors associated with prolonged intervals in order to identify risk groups. Methods: We conducted a cross-sectional cohort study among adult sarcoma survivors, diagnosed between 2008-2016. After informed consent, patient-reported interval length was collected via (online) questionnaires. This data was linked to the Netherlands Cancer Registry, which collects clinical data from patients at diagnosis. Descriptive statistics were used to describe interval lengths. Logistic regression analyses were conducted to investigate associations of patient and tumour characteristics (gender, age at diagnosis, time since diagnosis, histology, presence of metastases, grade, and localisation), with patient and diagnostic interval length. Results: 1099 survivors completed questionnaires (response rate 58%); 53% had a patient interval ≥1 month. Risk factors for a patient interval ≥1 month were bone or breast sarcoma, and being young(18-39 years). An interval ≥3 months (33%) was associated with dermatofibrosarcoma protuberans, bone sarcoma, low grade, and location in skin or pelvis. Diagnostic interval length was ≥1 month in 53%; risk groups were bone sarcomas, females, and young (18-39) or middle-aged (40-69) patients. In 27% the diagnostic interval lasted ≥3 months; risk groups were synovial sarcoma, chordoma, bone sarcomas in general, females, and being young (18-39) or middle aged (40-69). Conclusions: Over half of sarcoma survivors had a patient interval ≥1 month; a third ≥3 months. More than half of them reported a diagnostic interval ≥1 month; a quarter ≥3 months. Females and young patients were more at risk for a long diagnostic interval. Although limited by its retrospective nature, this study is the largest that studied the interval in a sarcoma survivorship group. Our current QUEST study (NTR-7253) will study the diagnostic trajectory prospectively to confirm these findings and find reasons for these results.

Pectoralis muscle wasting during chemotherapy.

e24069 Background: Chemotherapy is often followed by muscle mass loss which has been associated with frailty. We explored factors associated with change in pectoralis muscle mass after chemotherapy. We hypothesized greater muscle loss with time would be associated with poorer overall survival. Methods: We identified individuals with breast cancer (N = 221), sarcoma (N = 115), and lymphoma (N = 216) who received chemotherapy at the University of Minnesota MHealth Fairview and had CT scans before and after chemotherapy. Right pectoralis muscle area was measured using CORESLICER and indexed to body surface (right pectoralis muscle area [cm2] / body surface [m2]). We calculated quartiles of the indexed pectoralis measure. We restricted our analyses to participants who received a follow-up CT within two years after starting chemotherapy. In a multivariate linear regression, we explored associations of sex, age, BMI, ever-smoking, time since start of chemotherapy, indexed baseline muscle area, stage, type of diagnosis, and cumulative anthracycline dose with relative (%) change in muscle area. In a Cox regression we tested the association of relative muscle change with overall mortality. We used cubic splines to test for nonlinear effects. Results: Of 477 participants (66% female; mean age 61.3 (10.1) years), 366 received anthracyclines, 61 Trastuzumab, and 60 both. The average loss in right pectoral muscle area was -10% for women and -12% for men. We detected nonlinear effects of indexed baseline muscle area, P = 0.03. In a model using quartiles of indexed baseline muscle area, significant predictors of muscle loss included sex (women vs. men, -9.0%, 95% confidence interval (CI) -14.2- -3.7%, P = 0.0008), larger indexed baseline muscle area (quartiles 2, 3, 4 compared with quartile 1, change range -7 - -24%, 95% CI range, -2 - -30%, P-range &lt; 0.0001 – 0.006), smoking (ever vs. never, -4.1%, 95% CI -7.6 - -0.7%, P = 0.02), and diagnosis (sarcoma vs breast cancer, -5.7%, 95% CI -11.1 - -0.3%, P = 0.04). There was no significant association between muscle change and overall survival (median follow-up time 4.1). Conclusions: Being female, larger baseline muscle mass (per m2 body surface), ever-smoking, and a sarcoma diagnosis were associated with greater relative muscle loss after chemotherapy. More data is needed to understand the course of sarcopenia in terms of recovery and survivorship. [Table: see text]