Sunitinib in Patients With Breast Cancer With FGFR1 or FGFR2 Amplifications or Mutations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results from cohorts of patients with metastatic breast cancer (BC) with FGFR1 and FGFR2 alterations treated with sunitinib are reported. METHODS: Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease of at least 16 weeks duration (SD16+) according to RECIST v1.1. Secondary end points included OR, progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Forty patients with BC with FGFR1 (N = 30; amplification only n = 26, mutation only n = 1, both n = 3) or FGFR2 (N = 10; amplification only n = 2, mutation only n = 6, both n = 2) alterations were enrolled. Three patients in the FGFR1 cohort were not evaluable for efficacy; all patients in the FGFR2 cohort were evaluable. For the FGFR1 cohort, two patients with partial response and four with SD16+ were observed for DC and OR rates of 27% (90% CI, 13 to 100) and 7% (95% CI, 1 to 24), respectively. The null hypothesis of 15% DC rate was not rejected (P = .169). No patients achieved DC in the FGFR2 cohort (P = 1.00). Thirteen of the 40 total patients across both cohorts had at least one grade 3-4 adverse event or serious adverse event at least possibly related to sunitinib. CONCLUSION: Sunitinib did not meet prespecified criteria to declare a signal of antitumor activity in patients with BC with either FGFR1 or FGFR2 alterations. Other treatments and clinical trials should be considered for these patient populations.

NCCN Guidelines® Insights: Breast Cancer, Version 4.2023.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer address all aspects of management for breast cancer. The treatment landscape of metastatic breast cancer is evolving constantly. The therapeutic strategy takes into consideration tumor biology, biomarkers, and other clinical factors. Due to the growing number of treatment options, if one option fails, there is usually another line of therapy available, providing meaningful improvements in survival. This NCCN Guidelines Insights report focuses on recent updates specific to systemic therapy recommendations for patients with stage IV (M1) disease.

Genomic Complexity Predicts Resistance to Endocrine Therapy and CDK4/6 Inhibition in Hormone Receptor-Positive (HR+)/HER2-Negative Metastatic Breast Cancer.

PURPOSE: Clinical biomarkers to identify patients unlikely to benefit from CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy (ET) are lacking. We implemented a comprehensive circulating tumor DNA (ctDNA) analysis to identify genomic features for predicting and monitoring treatment resistance. EXPERIMENTAL DESIGN: ctDNA was isolated from 216 plasma samples collected from 51 patients with hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) on a phase II trial of palbociclib combined with letrozole or fulvestrant (NCT03007979). Boosted whole-exome sequencing (WES) was performed at baseline and clinical progression to evaluate genomic alterations, mutational signatures, and blood tumor mutational burden (bTMB). Low-pass whole-genome sequencing was performed at baseline and serial timepoints to assess blood copy-number burden (bCNB). RESULTS: High bTMB and bCNB were associated with lack of clinical benefit and significantly shorter progression-free survival (PFS) compared with patients with low bTMB or low bCNB (all P < 0.05). Dominant APOBEC signatures were detected at baseline exclusively in cases with high bTMB (5/13, 38.5%) versus low bTMB (0/37, 0%; P = 0.0006). Alterations in ESR1 were enriched in samples with high bTMB (P = 0.0005). There was a high correlation between bTMB determined by WES and bTMB determined using a 600-gene panel (R = 0.98). During serial monitoring, an increase in bCNB score preceded radiographic progression in 12 of 18 (66.7%) patients. CONCLUSIONS: Genomic complexity detected by noninvasive profiling of bTMB and bCNB predicted poor outcomes in patients treated with ET and CDK4/6i and identified early disease progression before imaging. Novel treatment strategies including immunotherapy-based combinations should be investigated in this population.

Breast Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. These NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of ductal carcinoma in situ and the workup and locoregional management of early stage invasive breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.

A phase II trial of an alternative schedule of palbociclib and embedded serum TK1 analysis.

Palbociclib 3-weeks-on/1-week-off, combined with hormonal therapy, is approved for hormone receptor positive (HR+)/HER2-negative (HER2-) advanced/metastatic breast cancer (MBC). Neutropenia is the most frequent adverse event (AE). We aim to determine whether an alternative 5-days-on/2-days-off weekly schedule reduces grade 3 and above neutropenia (G3 + ANC) incidence. In this single-arm phase II trial, patients with HR+/HER2- MBC received palbociclib 125 mg, 5-days-on/2-days-off, plus letrozole or fulvestrant per physician, on a 28-day cycle (C), as their first- or second-line treatment. The primary endpoint was G3 + ANC in the first 29 days (C1). Secondary endpoints included AEs, efficacy, and serum thymidine kinase 1 (sTK1) activity. At data-cutoff, fifty-four patients received a median of 13 cycles (range 2.6-43.5). The rate of G3 + ANC was 21.3% (95% CI: 11.2-36.1%) without G4 in C1, and 40.7% (95% CI: 27.9-54.9%), including 38.9% G3 and 1.8% G4, in all cycles. The clinical benefit rate was 80.4% (95% CI: 66.5-89.7%). The median progression-free survival (mPFS) (95% CI) was 19.75 (12.11-34.89), 33.5 (17.25-not reached [NR]), and 11.96 (10.43-NR) months, in the overall, endocrine sensitive or resistant population, respectively. High sTK1 at baseline, C1 day 15 (C1D15), and C2D1 were independently prognostic for shorter PFS (p = 9.91 × 10-4, 0.001, 0.007, respectively). sTK1 decreased on C1D15 (p = 4.03 × 10-7), indicating target inhibition. Rise in sTK1 predicted progression, with the median lead time of 59.5 (inter-quartile range: -206.25-0) days. Palbociclib, 5-days-on/2-days-off weekly, met its primary endpoint with reduced G3 + ANC, without compromising efficacy. sTK1 is prognostic and shows promise in monitoring the palbociclib response. ClinicalTrials.gov#: NCT3007979.

NCCN Guidelines® Insights: Breast Cancer, Version 4.2021.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer-focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor-positive, HER2-negative breast cancer.

Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

Targeting the Sanctuary Site: Options when Breast Cancer Metastasizes to the Brain.

Brain metastasis is a poor prognostic factor in breast cancer progression, and traditional treatment options have shown minimal response with overall low median survival rates. The incidence of brain metastasis has been increasing despite and, in part, due to advancements in treatment as a result of prolongation of survival. Targeted therapy such anti-HER2 agents have a lower efficacy in this setting compared to metastases elsewhere; however, novel therapies are emerging in this regard. In this comprehensive review, we discuss risk per subtype, special considerations for therapy selection, current focal and systemic treatments, and recent advancements and potential future targets for success. We present our treatment paradigm and multidisciplinary approach to brain metastases arising from breast cancer based on the available evidence, incorporating molecular characteristics.

Identification and Management of Lymphedema in Patients With Breast Cancer.

Breast cancer-related lymphedema (BCRL) is a potentially debilitating and often irreversible complication of breast cancer treatment. Risk of BCRL is proportional to the extent of axillary surgery and radiation. Other risk factors include obesity and infections. Given the 5-year survival rate of 90% and its potential impact on the quality of life of survivors of breast cancer, BCRL has become a significant financial burden on the health care system. Minimizing axillary surgery and radiation has been proven to reduce the risk of BCRL. Comprehensive multidisciplinary assessment at the time of initial diagnosis; early referral to physical therapy after surgery; and patient education regarding weight loss, skin, and nail care are cornerstones of the management of early-stage lymphedema. End-stage lymphedema may benefit from referral to a plastic surgeon specializing in lymphedema surgery. In this review, we attempt to review the incidence, risk factors, staging, prevention, and management of this complication of breast cancer treatment. We also describe our multidisciplinary approach for the prevention of this complication at the time of initial diagnosis.

Retrospective Analysis of Treatment Patterns and Effectiveness of Palbociclib and Subsequent Regimens in Metastatic Breast Cancer.

Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors are now the standard of care for hormone receptor-positive (HR+), HER2-negative (HER-) metastatic breast cancer (MBC). However, guidelines are lacking regarding their optimal sequencing with other available agents. This study examines physician practice patterns and treatment outcomes of palbociclib and subsequent therapies in a real-world setting. Methods: A retrospective chart review was conducted for consecutive patients with MBC who received palbociclib between February 2015 and August 2017 at the Alvin J. Siteman Cancer Center. Kaplan-Meier method was used to generate time-to-event curves and estimate median progression-free survival (mPFS). Log-rank test was used to compare differences. Results: A total of 200 patients, with a median age of 59.4 years and a follow-up of 19.5 months, were included. Palbociclib was most frequently combined with letrozole (73.5%), followed by fulvestrant (25%), anastrozole (1%), and tamoxifen (0.5%). Most patients received palbociclib in the endocrine-resistant setting (n=42, n=50, and n=108 in the first-, second-, and subsequent-line settings, respectively), and the fraction of patients receiving palbociclib as first- or second-line therapy increased in recent months (P=.0428). mPFS was 20.7, 12.8, and 4.0 months with palbociclib administered in the first-, second-, and subsequent-line settings, respectively (P<.0001). Incidences of grade 3/4 neutropenia (41.5%) and dose reductions (29%) were comparable to reports in the literature. Among patients whose disease progressed on palbociclib (n=104), the most frequent next-line treatment was capecitabine (n=21), followed by eribulin (n=16), nab-paclitaxel (n=15), and exemestane + everolimus (n=12). mPFS with hormone therapy alone or in combination with targeted agents (n=32) after first-, second-, and subsequent-line palbociclib was 17.0, 9.3, and 4.2 months, respectively (P=.04). mPFS with chemotherapy (n=70) was not reached, 4.7, and 4.1 months after first-, second-, and subsequent-line palbociclib, respectively (P=.56). Conclusions: Palbociclib is effective for HR+/HER2- MBC in real-world practice. Hormone therapy alone or in combination with targeted agents remains an effective option after palbociclib progression.

Type 2M Von Willebrand Disease: A Case Report.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is divided into three types, namely type 1, type 2 (2A, 2B, 2M, 2N), and type 3. We report a case of a 24-year-old Caucasian woman with a rare variety of type 2M VWD. Her von Willebrand factor versus antigen ratio was 0.44 (normal ratio is greater than 0.7) . She was asymptomatic and hence not treated but followed up regularly. VWD is not life-threatening when treated timely.

Upper Limb Phlegmasia Cerulea Dolens Secondary to Heparin-induced Thrombocytopenia Leading to Gangrene.

We present a case of a dialysis-dependent end-stage renal disease patient who originally presented with sepsis and later developed heparin-induced thrombocytopenia-related upper extremity deep venous thrombosis that rapidly progressed to phlegmasia. Argatroban, a direct thrombin inhibitor, was initiated without delay. Argatroban restored the venous patency completely but did not reverse his two gangrenous fingers. The patient finally underwent digital amputation. The management of this uncommon, but life-threatening, situation of upper limb phlegmasia cerulea dolens secondary to heparin-induced thrombocytopenia leading to gangrene is discussed in this case report.

A prognostic scoring model for survival after locoregional therapy in de novo stage IV breast cancer.

BACKGROUND: The role of locoregional treatment (LRT) remains controversial in de novo stage IV breast cancer (BC). We sought to analyze the role of LRT and prognostic factors of overall survival (OS) in de novo stage IV BC patients treated with LRT utilizing the National Cancer Data Base (NCDB). The objective of the current study is to create and internally validate a prognostic scoring model to predict the long-term OS for de novo stage IV BC patients treated with LRT. METHODS: We included de novo stage IV BC patients reported to NCDB between 2004 and 2015. Patients were divided into LRT and no-LRT subsets. We randomized LRT subset to training and validation cohorts. In the training cohort, a seventeen-point prognostic scoring system was developed based on the hazard ratios calculated using Cox-proportional method. We stratified both training and validation cohorts into two "groups" [group 1 (0-7 points) and group 2 (7-17 points)]. Kaplan-Meier method and log-rank test were used to compare OS between the two groups. Our prognostic score was validated internally by comparing the OS between the respective groups in both the training and validation cohorts. RESULTS: Among 67,978 patients, LRT subset (21,200) had better median OS as compared to that of no-LRT (45 vs. 24 months; p < 0.0001). The group 1 and group 2 in the training cohort showed a significant difference in the 3-year OS (p < 0.0001) (68 vs. 26%). On internal validation, comparable OS was seen between the respective groups in each cohort (p = 0.77). CONCLUSIONS: Our prognostic scoring system will help oncologists to predict the prognosis in de novo stage IV BC patients treated with LRT. Although firm treatment-related conclusions cannot be made due to the retrospective nature of the study, LRT appears to be associated with a better OS in specific subgroups.

Clinicopathologic characteristics and management trends of cutaneous invasive and in situ melanoma in older patients: a retrospective analysis of the National Cancer Data Base.

BACKGROUND: The incidence of melanoma in older patients is on the rise. Prior studies have shown disparities in surgical management and poor survival of older patients with melanoma. METHODS: This is a retrospective study of adult patients diagnosed with cutaneous invasive and in situ melanoma between 2000 and 2011 in the National Cancer Data Base. Characteristics and management of older patients (≥60 years) were compared with younger patients (20-59 years) using χ(2) testing. RESULTS: Of 476,623 total cases, 54% (n = 258,153) were diagnosed among older patients. The reported cases in the older patients increased by 1.74-fold between 2000 and 2011. The majority were white (96%), men (65%), with early-stage disease (76% stage 0-II), and superficial spreading melanoma histology (39%). Older patients, compared with younger patients, were more likely to be men (65% versus 49%, p < 0.0001), and have in situ melanoma (28% versus 21%, p < 0.0001); less likely to have nodal metastases (7% versus 9%, p < 0.0001), receive care in academic centers (30% versus 35%, p < 0.0001), undergo wide excision or major amputation for stage I-III disease (68% versus 72%, p < 0.0001) and systemic therapy for stage III (18% versus 45%, p < 0.0001) and IV disease (30% versus 50%, p < 0.0001). CONCLUSION: Older patients with melanoma are less likely to receive care in academic centers, undergo wide excision for stage I-III disease and receive systemic therapy for stage III-IV disease. Particularly, the utilization of systemic therapy is markedly low. This disparity is particularly important with the availability of less intense more effective therapies.

Undifferentiated Embryonal Sarcoma of Liver.

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare malignant hepatic tumor. A 47 year old male presented with symptoms of sour taste in his mouth, occasional nausea, indigestion and 15-pound weight loss over two months. He had an unremarkable upper gastrointestinal endoscopy. Imaging showed a large liver mass in the left hepatic lobe that was resected and then reported as UESL. He went on to develop lung metastases and was initially treated with doxorubicin and ifosfamide followed by switching of therapy to gemcitabine and docetaxel due to progression of disease. He had a good response after two cycles and went on to receive four more cycles, achieving stable disease. We can therefore conclude that the combination of gemcitabine and docetaxel is a potential therapeutic option for patients with UESL.

Risk factors, therapy and survival outcomes of small cell and large cell neuroendocrine carcinoma of urinary bladder.

The risk factors, the optimal therapy and prognostic factors contributing to poor outcomes of neuroendocrine urinary bladder carcinoma are not fully elucidated because of its rarity. We reviewed the medical records of neuroendocrine bladder carcinoma patients treated at the University of Nebraska Medical Center between 1996 and 2011. Eighteen patients, 55% female with a median age of 77 years, had stage IV disease at diagnosis in 50% of cases. There was a high prevalence of smoking (78%), medical co-morbidities (94%), prior cancer history (22%) and family history of cancer (61%). Treatment modalities included surgery (72%), platinum-based chemotherapy (50%) and/or radiation (22%). Median overall survival was 18.5 months (95% confidence interval, 7-36 months). Patients with Stage II and III cancer who underwent radical surgery with or without neoadjuvant chemotherapy had a median survival of 37 months. In addition to smoking, for the first time, our study indicates that the personal or family history of cancer may increase risk to neuroendocrine bladder cancer. Advanced age and stage at diagnosis, and the presence of multiple co-morbidities contribute to poor overall survival. Patients with early-stage disease are likely to benefit from a combination of radical surgery and platinum-based neoadjuvant chemotherapy.

Reversible bone marrow aplasia induced by pegylated interferon-α-2a therapy in a patient with primary myelofibrosis.

Interferon has been widely used in the management of patients with hematological malignancies such as polycythemia vera, myelofibrosis, chronic myeloid leukemia and viral infections such as chronic hepatitis C. Hematological adverse effects such as cytopenias have been observed, particularly in patients who receive a combination of interferon-α-2a and ribavirin for hepatitis C. Mild myelosuppression can be seen with pegylated interferon; however, bone marrow aplasia in patients with myelofibrosis has not been reported. It is important to be aware of such a serious complication since persistent bone marrow aplasia can be fatal. We describe a case of pegylated interferon-induced reversible bone marrow aplasia in a patient with primary myelofibrosis.

Autoimmune cytopenias in chronic lymphocytic leukemia, facts and myths.

CLL has been defined as presence of more than 5000 small mature appearing monoclonal B lymphocytes with a specific immunophenotype in peripheral blood. It is a well-known fact that CLL is associated with autoimmune cytopenias. CLL cells are CD5(+) B lymphocytes, and usually are not the "guilty" cells which produce autoantibodies. T cell defect is another characteristic of CLL and the total number of T cells is increased, and there is inversion of the CD4/CD8 ratio. Autoimmune hemolytic anemia (AIHA) is the most common autoimmune complication of CLL and has been reported in 10-25% of CLL patients. However, the stage-adjusted estimated rate of AIHA in CLL is about 5%. Conversely, CLL is three times more common in patients who present with AIHA. Direct agglutinin test (DAT) is positive in 7-14% of CLL patients but AIHA may also occur in DAT negative patients. Autoimmune thrombocytopenia (AIT) is the second most common complication of CLL and has been reported in 2-3% of patients. DAT is positive in AIT but presence of antiplatelet antibodies is neither diagnostic nor reliable. Autoimmune neutropenia (AIN) and pure red cell aplasia (PRCA) are very rare complications of CLL and like other autoimmune complications of CLL may occur at any clinical stage. It is believed that most case reports of AIN and PRCA in CLL actually belong to large granular lymphocytic leukemia (LGL). Non-hematologic autoimmune complications of CLL including cold agglutinin disease (CAD), paraneoplastic pemphigus (PNP), acquired angioedema, and anti-myelin associated globulin are rare. Before starting any treatment, clinicians should distinguish between autoimmune cytopenias and massive bone marrow infiltration since autoimmune complications of CLL are not necessarily equal to advanced disease with poor prognosis. According to IWCLL guideline, steroids are the mainstay of treatment of simple autoimmunity. Intravenous immunoglobulin (IVIg), cyclosporine, and rituximab are used in complex, steroid refractory cases. Monotherapy with purine analogues and alkylating agents should be avoided as they may increase CLL associated autoimmune complications.