CIC Mutation as a Molecular Mechanism of Acquired Resistance to Combined BRAF‐MEK Inhibition in Extramedullary Multiple Myeloma with Central Nervous System Involvement

22 hours 14 minutes ago
AbstractCombined MEK‐BRAF inhibition is a well‐established treatment strategy in BRAF‐mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF‐MEK inhibitor treatment are unavailable.Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high‐risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient.Key Points.BRAF mutations constitute an attractive druggable target in multiple myeloma. This is the first genomic dissection of the central nervous system involvement in a multiple myeloma patient harboring a druggable BRAFV600E mutation. Deep genomic characterization of the extramedullary lesion prompted a personalized therapeutic approach.Acquisition of CIC mutation confers a mechanism of BRAF‐MEK inhibitor drug resistance in multiple myeloma.The in silico interrogation of the CoMMpass clinical study revealed 10 patients with somatic mutations of CIC and its downregulation at gene expression level in multiple myeloma. CIC gene silencing decreases the sensitivity of multiple myeloma cells to BRAF‐MEK inhibition in vitro. The correlation between CIC downregulation and ETV4/5 nuclear factor expression in multiple myeloma BRAF‐mutant cells is shown for the first time. CIC mutation, its downregulation, and the related downstream effect on MMP24 support disseminative potential providing new clues in the extramedullary biology definition.
Matteo Claudio Da Via, Antonio Giovanni Solimando, Andoni Garitano-Troȷaola, Santiago Barrio, Umair Munawar, Susanne Strifler, Larissa Haertle, Nadine Rhodes, Eva Teufel, Cornelia Vogt, Constantin Lapa, Andreas Beilhack, Leo Rasche, Hermann…

Contextualizing the Use of Moxetumomab Pasudotox in the Treatment of Relapsed or Refractory Hairy Cell Leukemia

22 hours 14 minutes ago
AbstractHairy cell leukemia (HCL) is an indolent B‐cell malignancy characterized by high initial sensitivity to purine analog chemotherapy, minimal residual disease (MRD) frequently accompanying complete remission (CR), and relapses requiring additional treatment. Repeat chemotherapy shows decreasing efficacy and increasing toxicity with each course. Newer therapies targeting BRAF/MEK or Bruton's tyrosine kinase are effective but generally leave MRD. Rituximab has modest activity as a single agent and can achieve MRD‐negative CR in combination with purine analogs, but there is significant toxicity from the chemotherapy. Moxetumomab pasudotox‐tdfk (Moxe) is a biologic containing an antibody fragment (Fv) binding to CD22, attached to a portion of Pseudomonas exotoxin A. Binding to CD22 enables the toxin to enter and kill cells. Moxe is administered by 30‐minute infusions on days 1, 3, and 5 of up to six cycles spaced 4 weeks apart. In phase I testing, 64% of 33 patients at the highest dose level achieved CR, most without MRD. Lack of MRD correlated with prolonged CR duration; of 11 MRD‐negative CRs, 10 were still in CR after a median of 42 months of observation. In pivotal testing, 75% of 80 patients had a hematologic response, 41% with CR; 82% (27/33) of CRs were MRD‐negative, and only 4 of the 27 MRD‐negative patients relapsed during the follow‐up period. Hemolytic uremic syndrome and capillary leak syndrome were each observed in 9% of patients, all reversible. In September 2018, the U.S. Food and Drug Administration approved Moxe for the treatment of relapsed/refractory HCL after ≥2 prior therapies. Moxe is undergoing further development in combination with rituximab.Implications for Practice.Hairy cell leukemia (HCL) has effective treatments including purine analogs with and without rituximab, and oral inhibitors of BRAF, MEK and Bruton's tyrosine kinase (BTK). Despite these therapies, relapse occurs, and moxetumomab pasudotox has an important role in relapsed and refractory HCL because of its ability to achieve high rates of complete remissions (CRs) without chemotherapy; most of these CRs are without minimal residual disease (MRD). CR duration is enhanced in patients who achieve eradication of MRD. To improve the efficacy of this recombinant immunotoxin, a phase I trial is underway in combination with rituximab to reduce tumor burden and decrease immunogenicity.
Robert J. Kreitman, Ira Pastan

Treatment of Pediatric Glioblastoma with Combination Olaparib and Temozolomide Demonstrates 2‐Year Durable Response

2 days 21 hours ago
AbstractFor pediatric patients with high‐grade gliomas, standard‐of‐care treatment includes surgery, chemotherapy, and radiation therapy; however, most patients ultimately succumb to their disease. With advances in genomic characterization of pediatric high‐grade gliomas, the use of targeted therapies in combination with current treatment modalities offer the potential to improve survival in this patient population. In this report, we present the case of a 3‐year‐old girl with glioblastoma who continues to experience an exceptional and durable response (>2 years) to the poly (ADP‐ribose) polymerase (PARP) inhibitor olaparib. Our patient presented with persistent and progressive seizure activity that upon workup was the result of a large heterogeneously enhancing, mixed cystic and solid mass in the left frontal‐parietal‐temporal region. Histopathologic analysis of resected tumor tissue confirmed the diagnosis of glioblastoma, and comprehensive genomic profiling demonstrated absence of any BRAF or H3F3A mutations. Genomic profiling, however, did reveal a probable germline heterozygous BRCA2 Lys3326Ter (K3226*) nonsense variant. After debulking surgery, the patient received standard‐of‐care treatment with radiation and temozolomide. Nine months later the PARP inhibitor olaparib was administered in combination with temozolomide for 16 cycles. This regimen was well tolerated by the patient and serial imaging showed reduction in tumor size. Since completion of the regimen, the patient remains neurologically intact with no evidence of tumor recurrence. To our knowledge, this represents the first case of a pediatric glioblastoma that maintains a durable response to a therapeutic strategy that included the PARP inhibitor olaparib and more generally highlights the potential clinical utility of incorporating these agents into the treatment of pediatric high‐grade gliomas.Key Points.Germline mutations detected in pediatric gliomas may represent a cancer predisposition syndrome.Integrating molecular testing into routine clinical care for pediatric patients with glioma is critical to identify therapeutic targets and patients with a cancer predisposition syndrome.Patients with glioma with defects in DNA repair pathway components (e.g., BRCA1/2) may show increased responsiveness to poly (ADP‐ribose) polymerase (PARP) inhibitors.Combining PARP inhibitors with temozolomide (standard‐of‐care treatment) revealed no adverse events or toxicities over the course of 18 months.
Andge Valiakhmetova, Sergey Gorelyshev, Alexander Konovalov, Yuri Trunin, Alexander Savateev, David E. Kram, Eric Severson, Amanda Hemmerich, Claire Edgerly, Daniel Duncan, Nicholas Britt, Richard S.P. Huang, Julia Elvin, Vincent Miller, Jeffrey S. Ross,…

Real‐World Adherence in Patients with Metastatic Colorectal Cancer Treated with Trifluridine plus Tipiracil or Regorafenib

2 days 22 hours ago
AbstractBackground.Trifluridine and tipiracil (FTD + TPI) and regorafenib (REG) are approved treatments for the treatment of refractory metastatic colorectal cancer (mCRC). This study assesses adherence and duration of therapy with FTD + TPI versus REG and explores the effect of sequencing on adherence.Materials and Methods.Adults diagnosed with mCRC were identified in the IQVIA Real‐World Data Adjudicated Claims: U.S. database (October 2014–July 2017). The observation period spanned from the index date (first dispensing of FTD + TPI or REG) to the earliest of a switch to another mCRC agent, the end of continuous enrollment, or the end of data availability. Medication possession ratio (MPR), proportion of days covered (PDC), and persistence and time to discontinuation (gap ≥45 days) were compared between FTD + TPI and REG users and among switchers (FTD + TPI‐to‐REG vs. REG‐to‐FTD + TPI).Results.A total of 469 FTD + TPI and 311 REG users were identified. FTD + TPI users had higher compliance with an MPR ≥80% (odds ratio [OR], 2.47; p < .001) and PDC ≥80% (OR, 2.77; p < .001). FTD + TPI users had better persistence (82.8% vs. 68.0%; p < .001) and lower risk of discontinuation (hazard ratio [HR], 0.76; p = .006). Among switchers (96 FTD + TPI‐to‐REG; 83 REG‐to‐FTD + TPI), those switching from FTD + TPI to REG were more likely to have an MPR ≥80% (OR, 2.91; p < .001) and PDC ≥80% (OR, 4.60; p < .001) compared with REG‐to‐FTD + TPI switchers while treated with these drugs. Additionally, FTD + TPI‐to‐REG switchers had a lower risk of first treatment discontinuation (HR, 0.66; p = .009).Conclusion.FTD + TPI users had significantly higher adherence and persistence, and patients who were treated with FTD + TPI before switching to REG also had higher adherence and persistence outcomes.Implications for Practice.Trifluridine plus tipiracil (FTD + TPI) and regorafenib (REG) prolong survival in refractory metastatic colorectal cancer (mCRC) but have different tolerability profiles. This study assessed real‐world adherence to treatment with FTD + TPI versus REG and compared outcomes among patients who switched from FTD + TPI to REG and vice versa. FTD + TPI was associated with significantly higher medication adherence and longer time to discontinuation than REG. Patients treated with FTD + TPI prior to switching to REG also showed higher adherence outcomes. Findings could help inform decision making regarding the choice and sequencing of treatment with FTD + TPI versus REG in patients with mCRC.
Anu&#x0237; K. Patel, Victoria Barghout, Mihran A. Yenikomshian, Guillaume Germain, Philippe Jacques, Francois Laliberte, Mei S. Duh

The European Medicines Agency Review of Kymriah (Tisagenlecleucel) for the Treatment of Acute Lymphoblastic Leukemia and Diffuse Large B‐Cell Lymphoma

2 days 23 hours ago
AbstractChimeric antigen receptor (CAR)–engineered T‐cell therapy is becoming one of the most promising approaches in the treatment of cancer. On June 28, 2018, the Committee for Advanced Therapies (CAT) and the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kymriah for pediatric and young adult patients up to 25 years of age with B‐cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse after transplant, or in second or later relapse and for adult patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL) after two or more lines of systemic therapy. Kymriah became one of the first European Union–approved CAR T therapies. The active substance of Kymriah is tisagenlecleucel, an autologous, immunocellular cancer therapy that involves reprogramming the patient's own T cells to identify and eliminate CD19‐expressing cells. This is achieved by addition of a transgene encoding a CAR. The benefit of Kymriah was its ability to achieve remission with a significant duration in patients with ALL and an objective response with a significant duration in patients with DLBCL. The most common hematological toxicity was cytopenia in both patients with ALL and those with DLBCL. Nonhematological side effects in patients with ALL were cytokine release syndrome (CRS), infections, secondary hypogammaglobulinemia due to B‐cell aplasia, pyrexia, and decreased appetite. The most common nonhematological side effects in patients with DLBCL were CRS, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. Kymriah also received an orphan designation on April 29, 2014, following a positive recommendation by the Committee for Orphan Medicinal Products (COMP). Maintenance of the orphan designation was recommended at the time of marketing authorization as the COMP considered the product was of significant benefit for patients with both conditions.Implications for Practice.Chimeric antigen receptor (CAR)–engineered T‐cell therapy is becoming the most promising approach in cancer treatment, involving reprogramming the patient's own T cells with a CAR‐encoding transgene to identify and eliminate cancer‐specific surface antigen–expressing cells. On June 28, 2018, Kymriah became one of the first EMA approved CAR T therapies. CAR T technology seems highly promising for diseases with single genetic/protein alterations; however, for more complex diseases there will be challenges to target clonal variability within the tumor type or clonal evolution during disease progression. Products with a lesser toxicity profile or more risk‐minimization tools are also anticipated.
Sahra Ali, Rune K&#x0237;eken, Christiane Niederlaender, Greg Markey, Therese S. Saunders, Mona Opsata, Kristine Moltu, B&#x0237;orn Bremnes, Eirik Gronevik, Martine Muusse, Gro D. Hakonsen, Venke Skibeli, Maria Elisabeth Kalland, Ingrid Wang, Ingeb&…

Eosinophilic Fasciitis Following Checkpoint Inhibitor Therapy: Four Cases and a Review of Literature

3 days 22 hours ago
AbstractBackground.Checkpoint inhibitor therapy is widely known to cause a number of immune‐related adverse events. One rare adverse effect that is emerging is eosinophilic fasciitis, a fibrosing disorder causing inflammatory infiltration of subcutaneous fascia. It is characterized clinically by edema and subsequent induration and tightening of the skin and subcutaneous tissues. The condition is rare, yet at our institutions we have seen four cases in the past 3 years. We describe our 4 cases and review 11 other cases reported in the literature.Case Presentation.We present four cases of eosinophilic fasciitis following treatment with programmed cell death protein 1 or programmed cell death‐ligand 1 blockade. All patients had extremity involvement with characteristic skin changes ranging from peripheral edema to induration, tightening, and joint limitation. The patients had varying degrees of peripheral eosinophilia. In two of our patients, the diagnosis was made by full‐thickness skin biopsy showing lymphocytic infiltration of the subcutaneous fascia, with CD4+ T cells predominating in one case and CD8+ T cells in the other. In the other two cases, the diagnosis was made on the basis of characteristic imaging findings in the context of clinical features consistent with the diagnosis. All four patients were treated with glucocorticoids with varying degrees of success; immunotherapy had to be discontinued in all four. Patients with advanced melanoma who experienced this adverse effect had either a partial response or a complete response to therapy.Conclusion.Eosinophilic fasciitis can occur as a result of checkpoint inhibitor therapy. Although a tissue diagnosis is the gold standard, imaging studies may facilitate the diagnosis in the presence of consistent clinical features, but a degree of suspicion is key to recognizing the condition early. Therapy requires a collaborative approach by oncology, rheumatology, and dermatology; physical therapy is an important adjunct in treatment. For advanced melanoma, it may be a good prognostic indicator.Implications for Practice.It is important for clinicians to recognize that eosinophilic fasciitis is a potential immune‐related adverse event (irAE) as a consequence of immune checkpoint inhibitor therapy. The presentation is quite stereotypical; the diagnosis can be made by imaging in the absence of a full‐thickness skin biopsy. Early intervention is important to limit morbidity. This irAE may be a good prognostic sign among patients with melanoma.
Karmela Kim Chan, Cynthia Magro, Alexander Shoushtari, Charles Rudin, Veronica Rotemberg, Anthony Rossi, Cecilia Lezcano, John Carrino, David Fernandez, Michael A. Postow, Arlyn Apollo, Mario E. Lacouture, Anne R. Bass

Effects of High Anxiety Scores on Surgical and Overall Treatment Plan in Patients with Breast Cancer Treated with Neoadjuvant Therapy

3 days 22 hours ago
AbstractBackground.Patients with newly diagnosed breast cancer and high levels of anxiety often pursue more aggressive surgical interventions. The neoadjuvant treatment (NAT) setting could provide a window of opportunity to address patients’ anxiety. However, the impact of anxiety on surgical decisions in the setting of NAT for breast cancer has not been previously studied.Materials and Methods.A prospective database of patients with breast cancer treated with NAT at BC Cancer was used to identify patients treated with NAT and subsequent surgical resection. Patients with bilateral breast cancer or BRCA mutations or those referred to the hereditary cancer program were excluded. An anxiety score of 0–3 was assigned based on responses to the Edmonton Symptom Assessment System and Psychosocial Screen for Cancer. Clinicopathological information and treatment data were retrieved and cross‐referenced between the low‐anxiety (scores 0–1) and high‐anxiety (scores 2–3) cohorts.Results.From 2012 to 2016, 203 patients met eligibility criteria. Of these, 93 patients (45.8%) had low anxiety and 110 patients (54.2%) had high anxiety. Overall, 161 patients (79.3%) had locally advanced cancers; no differences in stage, grade, or biomarkers were found between the low‐ and high‐anxiety cohorts. Patients with high self‐reported anxiety at initial consultation were younger (mean 56 years vs. 60 years; p = .011) and more likely to undergo mastectomy for breast‐conserving surgery–eligible disease and bilateral mastectomy for unilateral disease compared with those with low anxiety (37.3% vs. 18.3%; likelihood ratio 9.15; p = .002). No significant differences in treatment timelines were identified between the two cohorts.Conclusion.Patients with high anxiety at initial consultation were nine times more likely to undergo aggressive surgery compared with patients with low anxiety. These findings underscore the need for early identification of patients who may benefit from tailored supportive and educational services to address sources of anxiety and knowledge gaps.Implications for Practice.The prevalence of anxiety among women with newly diagnosed breast cancer is being increasingly acknowledged. However, health care providers have not fully appreciated the impact of anxiety on the surgical management of patients with early‐stage breast cancer. This study highlights the importance of self‐reported anxiety on surgical management. The preoperative period provides a unique window of opportunity to address sources of anxiety and provide targeted educational materials over a period of 4–6 months, which may ultimately lead to less aggressive surgery when it is not needed.
Nathalie LeVasseur, Huaqi Li, Winson Cheung, Paula Myers, Elaine Mckevitt, Rebecca Warburton, Kaylie-Anne Willemsma, Adam Deruchie Tan, Stephen Chia, Christine Simmons

Guillain‐Barré Syndrome During Platinum‐Based Chemotherapy: A Case Series and Review of the Literature

3 days 22 hours ago
AbstractPlatinum‐based chemotherapy is commonly associated with toxic sensory neuropathies, but also, although rarely, with Guillain‐Barré syndrome (GBS). We describe five patients who developed GBS while receiving platinum‐based chemotherapy for a solid tumor and report the five cases published so far. Most patients had received cumulative platinum doses below known neurotoxic levels, and all of them had an optimal outcome after platinum discontinuation, associated in most cases with administration of intravenous immunoglobulin. Clinical presentation, electroneuromyography, and cerebrospinal fluid analysis help clinicians to differentiate GBS from toxic neuropathy. Platinum compounds are the only chemotherapeutic agents used for solid tumors that have been associated to GBS. Thus, we propose that GBS may constitute a non–dose‐dependent side effect of platinum drugs and that awareness needs to be raised among oncologists on this rare but potentially life‐threatening complication of platinum chemotherapy.Implications for Practice.Many patients on platinum‐based chemotherapy for solid tumors develop sensory neuropathy, a common dose‐dependent side effect. The authors propose that Guillain‐Barré syndrome may constitute an immune‐mediated, non‐dose‐related side effect of platinum‐based chemotherapy. Prompt diagnosis of Guillain‐Barré syndrome and distinction from classical toxic neuropathy are crucial for optimal treatment. Platinum discontinuation, associated if needed to intravenous immunoglobulin administration, radically changes the course of the disease and minimizes neurological sequelae.
Evangelia Pappa, Giulia Berzero, Bastien Herlin, Damien Ricard, Camille Tafani, Perrine Devic, Denis Maillet, Alaina Borden, Karine Viala, Thierry Maisonobe, Timothee Lenglet, Nicolas Weiss, Dimitri Psimaras

Acupuncture for Chemotherapy‐Induced Peripheral Neuropathy in Breast Cancer Survivors: A Randomized Controlled Pilot Trial

4 days 23 hours ago
AbstractBackground.Chemotherapy‐induced peripheral neuropathy (CIPN) is one of the most debilitating long‐term side effects in breast cancer survivors. We conducted a randomized controlled pilot trial to assess the feasibility, safety, and effects of an acupuncture intervention on CIPN in this population.Patients and Methods.Women with stage I–III breast cancer with grade 1 or higher CIPN after taxane‐containing adjuvant chemotherapy were randomized 1:1 to an immediate acupuncture (IA) arm or to a waitlist control group (CG). Participants in the IA arm received 18 sessions of acupuncture over 8 weeks, then received no additional acupuncture. Patients in the CG arm received usual care over 8 weeks, followed by nine sessions of acupuncture over 8 weeks. Measures including Patient Neurotoxicity Questionnaire (PNQ), Functional Assessment of Cancer Therapy—Neurotoxicity subscale (FACT‐NTX), and Brief Pain Inventory—short form (BPI‐SF) were collected at baseline and at 4, 8, and 16 weeks after enrollment.Results.Forty women (median age, 54) were enrolled (20 to IA and 20 to CG), with median time between completion of chemotherapy and enrollment of 14 months (range 1–92). At 8 weeks, participants in the IA arm experienced significant improvements in PNQ sensory score (−1.0 ± 0.9 vs. −0.3 ± 0.6; p = .01), FACT‐NTX summary score (8.7 ± 8.9 vs. 1.2 ± 5.4; p = .002), and BPI‐SF pain severity score (−1.1 ± 1.7 vs. 0.3 ± 1.5; p = .03), compared with those in the CG arm. No serious side effects were observed.Conclusion.Women with CIPN after adjuvant taxane therapy for breast cancer experienced significant improvements in neuropathic symptoms from an 8‐week acupuncture treatment regimen. Additional larger studies are needed to confirm these findings.Implications for Practice.Chemotherapy‐induced peripheral neuropathy (CIPN) is a toxicity that often persists for months to years after the completion of adjuvant chemotherapy for early breast cancer. In a randomized pilot trial of 40 breast cancer survivors with CIPN, an 8‐week acupuncture intervention (vs. usual care) led to a statistically and clinically significant improvement in subjective sensory symptoms including neuropathic pain and paresthesia. Given the lack of effective therapies and established safety profile of acupuncture, clinicians may consider acupuncture as a treatment option for mild to moderate CIPN in practice.
Weidong Lu, Anita Giobbie-Hurder, Rachel A. Freedman, Im Hee Shin, Nancy U. Lin, Ann H. Partridge, David S. Rosenthal, Jennifer A. Ligibel

Lenvatinib in Management of Solid Tumors

4 days 23 hours ago
AbstractLenvatinib is a type I tyrosine kinase inhibitor exhibiting powerful antiangiogenic activity in cancer therapy. Displaying activity in multiple solid tumors, it has been approved in differentiated thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma as single agent or in combination. In addition, lenvatinib has shown promise in several other tumor types including medullary, anaplastic thyroid, adenoid cystic, and endometrial cancer. Exploring synergy between angiogenic and immune checkpoint inhibitors, the lenvatinib/pembrolizumab combination is poised to become the next pair of active drugs in endometrial, lung, and gastrointestinal malignancies. Despite robust activity, the drug can be difficult to tolerate. Optimization of dose and biomarkers for prediction of efficacy and toxicities will be of great help.Implications for Practice.Readers will be presented with an update on U.S. Food and Drug Administration approval of lenvatinib and suggestions for off‐label use in thyroid cancer and adenoid cystic carcinomas. They will become familiarized with the common side effects, frequency, and predicators of response. In addition, they will learn that different strengths of lenvatinib are prescribed and why. Finally, readers are pointed to the latest efforts to combine lenvatinib and pembrolizumab, as well as to unresolved issues such as long‐term side effects/toxicities of this drug.
Zhonglin Hao, Peng Wang

Lymph Node Imaging in Patients with Primary Breast Cancer: Concurrent Diagnostic Tools

4 days 23 hours ago
AbstractThe detection of lymph node metastasis affects the management of patients with primary breast cancer significantly in terms of staging, treatment, and prognosis. The main goal for the radiologist is to determine and detect the presence of metastatic disease in nonpalpable axillary lymph nodes with a positive predictive value that is high enough to initially select patients for upfront axillary lymph node dissection. Features that are suggestive of axillary adenopathy may be seen with different imaging modalities, but ultrasound is the method of choice for evaluating axillary lymph nodes and for performing image‐guided lymph node interventions. This review aims to provide a comprehensive overview of the available imaging modalities for lymph node assessment in patients diagnosed with primary breast cancer.Implications for Practice.The detection of lymph node metastasis affects the management of patients with primary breast cancer. The main goal for the radiologist is to detect lymph node metastasis in patients to allow for the selection of patients who should undergo upfront axillary lymph node dissection. Features that are suggestive of axillary adenopathy may be seen with mammography, computed tomography, and magnetic resonance imaging, but ultrasonography is the imaging modality of choice for evaluating axillary lymph nodes. A normal axillary lymph node is characterized by a reniform shape, a maximal cortical thickness of 3 mm without focal bulging, smooth margins, and, depending on size, a discernable central fatty hilum.
Maria Adele Marino, Daly Avendano, Pedro Zapata, Christopher C. Riedl, Katja Pinker

De Novo Versus Recurrent HER2‐Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from the SystHERs Registry

4 days 23 hours ago
AbstractBackground.Limited data exist describing real‐world treatment of de novo and recurrent HER2‐positive metastatic breast cancer (MBC).Materials and Methods.The Systemic Therapies for HER2‐Positive Metastatic Breast Cancer Study (SystHERs) was a fully enrolled (2012–2016), observational, prospective registry of patients with HER2‐positive MBC. Patients aged ≥18 years and ≤6 months from HER2‐positive MBC diagnosis were treated and assessed per their physician's standard practice. The primary endpoint was to characterize treatment patterns by de novo versus recurrent MBC status, compared descriptively. Secondary endpoints included patient characteristics, progression‐free and overall survival (PFS and OS, by Kaplan‐Meier method; hazard ratio [HR] and 95% confidence interval [CI] by Cox regression), and patient‐reported outcomes.Results.Among 977 eligible patients, 49.8% (n = 487) had de novo and 50.2% (n = 490) had recurrent disease. A higher proportion of de novo patients had hormone receptor–negative disease (34.9% vs. 24.9%), bone metastasis (57.1% vs. 45.9%), and/or liver metastasis (41.9% vs. 33.1%), and a lower proportion had central nervous system metastasis (4.3% vs. 13.5%). De novo patients received first‐line regimens containing chemotherapy (89.7%), trastuzumab (95.7%), and pertuzumab (77.8%) more commonly than recurrent patients (80.0%, 85.9%, and 68.6%, respectively). De novo patients had longer median PFS (17.7 vs. 11.9 months; HR, 0.69; 95% CI, 0.59–0.80; p < .0001) and OS (not estimable vs. 44.5 months; HR, 0.55; 95% CI, 0.44–0.69; p < .0001).Conclusion.Patients with de novo versus recurrent HER2‐positive MBC exhibit different disease characteristics and survival durations, suggesting these groups have distinct outcomes. These differences may affect future clinical trial design. Clinical trial identification number. NCT01615068 (clinicaltrials.gov).Implications for Practice.SystHERs was an observational registry of patients with HER2‐positive metastatic breast cancer (MBC), which is a large, modern, real‐world data set for this population and, thereby, provides a unique opportunity to study patients with de novo and recurrent HER2‐positive MBC. In SystHERs, patients with de novo disease had different baseline demographics and disease characteristics, had superior clinical outcomes, and more commonly received first‐line chemotherapy and/or trastuzumab versus those with recurrent disease. Data from this and other studies suggest that de novo and recurrent MBC have distinct outcomes, which may have implications for disease management strategies and future clinical study design.
Debu Tripathy, Adam Brufsky, Melody Cobleigh, Mohammad Jahanzeb, Peter A. Kaufman, Ginny Mason, Joyce O'Shaughnessy, Hope S. Rugo, Sandra M. Swain, Denise A. Yardley, Laura Chu, Haocheng Li, Vincent Antao, Sara A. Hurvitz

Use of High‐Cost Cancer Treatments in Academic and Nonacademic Practice

4 days 23 hours ago
AbstractBackground.Academic physicians, such as those affiliated with National Cancer Institute (NCI)–designated Comprehensive Cancer Centers, may have different practice patterns regarding the use of high‐cost cancer drugs than nonacademic physicians.Materials and Methods.For this cohort study, we linked cancer registry, administrative, and demographic data for patients with newly diagnosed cancer in North Carolina from 2004 to 2011. We selected cancer types with multiple U.S. Food and Drug Administration–approved, National Comprehensive Cancer Network–recommended treatment options and large differences in reimbursement between higher‐priced and lower‐priced options (stage IV colorectal, stage IV lung, and stage II–IV head‐and‐neck cancers). We assessed whether provider's practice setting—NCI‐designated Comprehensive Cancer Center (“NCI”) versus other location (“non‐NCI”)—was associated with use of higher‐cost treatment options. We used inverse probability of exposure weighting to control for patient characteristics.Results.Of 800 eligible patients, 79.6% were treated in non‐NCI settings. Patients treated in non‐NCI settings were more likely to receive high‐cost treatment than patients treated in NCI settings (36.0% vs. 23.2%), with an unadjusted prevalence difference of 12.7% (95% confidence interval [CI], 5.1%–20.0%). After controlling for potential confounding factors, non‐NCI patients remained more likely to receive high‐cost treatment, although the strength of association was attenuated (adjusted prevalence difference, 9.6%; 95% CI −0.1%–18.7%). Exploratory analyses suggested potential heterogeneity across cancer type and insurance status.Conclusion.Use of higher‐cost cancer treatments may be more common in non‐NCI than NCI settings. This may reflect differential implementation of clinical evidence, local practice variation, or possibly a response to the reimbursement incentives presented by chemotherapy billing.Implications for Practice.Oncology care delivery and practice patterns may vary between care settings. By comparing otherwise similar patients treated in National Cancer Institute (NCI)–designated Comprehensive Cancer Centers with those treated elsewhere, this study suggests that patients may be more likely to receive treatment with certain expensive cancer drugs if treated in the non‐NCI setting. These practice differences may result in differences in patient costs and outcomes as a result of where they receive treatment.
Aaron P. Mitchell, Alan C. Kinlaw, Sharon Peacock-Hinton, Stacie B. Dusetzina, Hanna K. Sanoff, Jennifer L. Lund

Urine Drug Testing in Cancer Pain Management

1 week ago
AbstractUrine drug test (UDT) is an effective tool used in chronic opioid therapy to ensure patient adherence to treatment and detect nonmedical opioid use. The two main types of UDT used in routine clinical practice are the screening tests or immunoassays and the confirmatory tests or laboratory‐based specific drug identification tests such as gas chromatography–mass spectrometry, liquid chromatography–mass spectrometry, or tandem mass spectrometry. UDT produces objective data on some nonmedical opioid use that may otherwise go undetected, such as the use of undisclosed medications, the nonuse of prescribed medications, and the use of illegal drugs. It allows clinicians to initiate an open and effective conversation about nonmedical opioid use with their patients. However, the test has certain limitations that sometimes compromise its use. Its interpretation can be challenging to clinicians because of the complexity of the opioid metabolic pathways. Clear guidelines or recommendations regarding the use of UDT in cancer pain is limited. As a result, UDT appears to be underused among patients with cancer pain receiving opioid therapy. More studies are needed to help standardize the integration and use of UDT in routine cancer pain management.Implications for Practice.Despite its potential benefits, urine drug testing (UDT) appears to be underused among patients with cancer pain receiving opioid therapy. This is partly because its interpretation can be challenging owing to the complexity of the opioid metabolic pathways. Information regarding the use of UDT in opioid therapy among patients with cancer is limited. This review article will improve clinician proficiency in UDT interpretation and assist oncologists in developing appropriate treatment plans during chronic opioid therapy.
Joseph A. Arthur

Premature Termination of a Randomized Controlled Trial on Image‐Guided Stereotactic Body Radiotherapy of Metastatic Spinal Cord Compression

1 week ago
AbstractLessons Learned.It is possible to plan and treat some patients with stereotactic body radiotherapy (SBRT) in a timely fashion in an acute setting.Advanced and, in some indications, already implemented technologies such as SBRT are difficult to test in a randomized trial.Background.Stereotactic body radiotherapy (SBRT) in metastatic spinal cord compression (MSCC) could be an alternative to decompressive surgery followed by fractionated radiotherapy.Methods.In a randomized, single‐institution, noninferiority trial, patients with MSCC were assigned to stereotactic body radiotherapy of 16 Gy in 1 fraction or decompression surgery followed by fractionated radiotherapy of 30 Gy in 10 fractions. Primary endpoint was ability to walk by EQ5D‐5L questionnaire. Based on power calculations, 130 patients had to be included to be 89% sure that a 15% difference between the treatment arm and the experimental arm could be detected.Results.Ten patients were accrued in 23 months, with six patients allocated to surgery and four patients to stereotactic body radiotherapy. The trial was closed prematurely because of poor accrual. One patient undergoing surgery and one patient undergoing stereotactic body radiotherapy were unable to walk at 6 weeks. Two patients were not evaluable at 6 weeks.Conclusion.A randomized, phase II, clinical trial comparing surgery followed by fractionated radiotherapy or image‐guided SBRT of MSCC was initiated. SBRT was shown to be feasible, with three out of four patients retaining walking function. The trial was determined futile as a result of low accrual.
Morten Hiul Suppli, Per Munck af Rosenschold, Benny Dahl, Anne Kiil Berthelsen, Svend Aage Engelholm, Helle Pappot

The Pan‐Cancer Landscape of Coamplification of the Tyrosine Kinases KIT, KDR, and PDGFRA

1 week ago
AbstractPurpose.Amplifications of receptor tyrosine kinases (RTKS) are therapeutic targets in multiple tumor types (e.g. HER2 in breast cancer), and amplification of the chromosome 4 segment harboring the three RTKs KIT, PDGFRA, and KDR (4q12amp) may be similarly targetable. The presence of 4q12amp has been sporadically reported in small tumor specific series but a large‐scale analysis is lacking. We assess the pan‐cancer landscape of 4q12amp and provide early clinical support for the feasibility of targeting this amplicon.Experimental Design.Tumor specimens from 132,872 patients with advanced cancer were assayed with hybrid capture based comprehensive genomic profiling which assays 186–315 genes for all classes of genomic alterations, including amplifications. Baseline demographic data were abstracted, and presence of 4q12amp was defined as 6 or more copies of KIT/KDR/PDGFRA. Concurrent alterations and treatment outcomes with matched therapies were explored in a subset of cases.Results.Overall 0.65% of cases harbored 4q12amp at a median copy number of 10 (range 6–344). Among cancers with >100 cases in this series, glioblastomas, angiosarcomas, and osteosarcomas were enriched for 4q12amp at 4.7%, 4.8%, and 6.4%, respectively (all p < 0.001), giving an overall sarcoma (n = 6,885) incidence of 1.9%. Among 99 pulmonary adenocarcinoma cases harboring 4q12amp, 50 (50%) lacked any other known driver of NSLCC. Four index cases plus a previously reported case on treatment with empirical TKIs monotherapy had stable disease on average exceeding 20 months.Conclusion.We define 4q12amp as a significant event across the pan‐cancer landscape, comparable to known pan‐cancer targets such as NTRK and microsatellite instability, with notable enrichment in several cancers such as osteosarcoma where standard treatment is limited. The responses to available TKIs observed in index cases strongly suggest 4q12amp is a druggable oncogenic target across cancers that warrants a focused drug development strategy.Implications for Practice.Coamplification of the receptor tyrosine kinases (rtks) KIT/KDR/PDGFRA (4q12amp) is present broadly across cancers (0.65%), with enrichment in osteosarcoma and gliomas. Evidence for this amplicon having an oncogenic role is the mutual exclusivity of 4q12amp to other known drivers in 50% of pulmonary adenocarcinoma cases. Furthermore, preliminary clinical evidence for driver status comes from four index cases of patients empirically treated with commercially available tyrosine kinase inhibitors with activity against KIT/KDR/PDGFRA who had stable disease for 20 months on average. The sum of these lines of evidence suggests further clinical and preclinical investigation of 4q12amp is warranted as the possible basis for a pan‐cancer drug development strategy.
Umut Disel, Russell Madison, Kumar Abhishek, Jon H. Chung, Sally E. Trabucco, Asli O. Matos, Garrett M. Frampton, Lee A. Albacker, Venkataprasanth Reddy, Nuri Karadurmus, Adam Benson, Jennifer Webster, Semra Paydas, Ruben Cabanillas, Chaitali Nangia, M.A…

A Large, Multicenter, Retrospective Study on Efficacy and Safety Of Stereotactic Body Radiotherapy (SBRT) in Oligometastatic Ovarian Cancer (MITO RT1 Study): A Collaboration of MITO, AIRO GYN, and MaNGO Groups

1 week 1 day ago
AbstractBackground.Recent studies have reported improvement of outcomes (progression‐free survival, overall survival, and prolongation of androgen deprivation treatment‐free survival) with stereotactic body radiotherapy (SBRT) in non‐small cell lung cancer and prostate cancer. The aim of this retrospective, multicenter study (MITO RT‐01) was to define activity and safety of SBRT in a very large, real‐world data set of patients with metastatic, persistent, and recurrent ovarian cancer (MPR‐OC).Materials and Methods.The endpoints of the study were the rate of complete response (CR) to SBRT and the 24‐month actuarial local control (LC) rate on “per‐lesion” basis. The secondary endpoints were acute and late toxicities and the 24‐month actuarial late toxicity‐free survival. Objective response rate (ORR) included CR and partial response (PR). Clinical benefit (CB) included ORR and stable disease (SD). Toxicity was evaluated by the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) and Common Terminology Criteria for Adverse Events (CTCAE) scales, according to center policy. Logistic and Cox regression were used for the uni‐ and multivariate analysis of factors predicting clinical CR and actuarial outcomes.Results.CR, PR, and SD were observed in 291 (65.2%), 106 (23.8%), and 33 (7.4%) lesions, giving a rate of CB of 96.4%. Patient aged ≤60 years, planning target volume (PTV) ≤18 cm3, lymph node disease, and biologically effective dose α/β10 > 70 Gy were associated with higher chance of CR in the multivariate analysis. With a median follow‐up of 22 months (range, 3–120), the 24‐month actuarial LC rate was 81.9%. Achievement of CR and total dose >25 Gy were associated with better LC rate in the multivariate analysis. Mild toxicity was experienced in 54 (20.7%) patients; of 63 side effects, 48 were grade 1, and 15 were grade 2. The 24‐month late toxicity‐free survival rate was 95.1%.Conclusions.This study confirms the activity and safety of SBRT in patients with MPR‐OC and identifies clinical and treatment parameters able to predict CR and LC rate.Implications for Practice.This study aimed to define activity and safety of stereotactic body radiotherapy (SBRT) in a very large, real life data set of patients with metastatic, persistent, recurrent ovarian cancer (MPR‐OC). Patient age <60 years, PTV <18 cm3, lymph node disease, and biologically effective dose α/β10 >70 Gy were associated with higher chance of complete response (CR). Achievement of CR and total dose >25 Gy were associated with better local control (LC) rate. Mild toxicity was experienced in 20.7% of patients. In conclusion, this study confirms the activity and safety of SBRT in MPR‐OC patients and identifies clinical and treatment parameters able to predict CR and LC rate.
Gabriella Macchia, Roberta Lazzari, Nicoletta Colombo, Concetta Laliscia, Giovanni Capelli, Giuseppe Roberto D'Agostino, Francesco Deodato, Ernesto Maranzano, Edy Ippolito, Sara Ronchi, Fabiola Paiar, Marta Scorsetti, Savino Cilla, Rossana Ingargiola,…

Endocrine‐Related Adverse Events Related to Immune Checkpoint Inhibitors: Proposed Algorithms for Management

1 week 1 day ago
AbstractImmune checkpoint inhibitors have proven to be effective for various advanced neoplasia. Immune‐related adverse events (irAEs) as a result of increased T cell activation are unique and potentially life‐threating toxicities associated with the use of immune checkpoint inhibitors. Multiple endocrine irAEs, including primary hyperthyroidism and hypothyroidism, thyroiditis, primary adrenal insufficiency, type 1 diabetes mellitus, and hypophysitis, have been reported with the use of various immune checkpoint inhibitors. In some cases, these irAEs can lead to discontinuation of treatment. Here we propose for the general oncologist algorithms for managing endocrine irAEs to aid in the clinical care of patients receiving immunotherapy.Key Points.There is a relative high risk of endocrine immune‐related adverse events (irAEs) during therapy with checkpoint inhibitors, particularly when combination therapy is implemented.Patients treated with anti‐CTLA‐4 antibodies have an increased risk of hypophysitis, whereas patients treated with anti‐PD‐1/PD‐L1 antibodies have a higher risk of primary thyroid dysfunction.Rarely, patients develop T1DM and central diabetes insipidus, and hypoparathyroidism is a rare occurrence.A growing clinical understanding of endocrine irAEs has led to effective treatment strategies with hormone replacement.
Jaydira Del Rivero, Lisa M. Cordes, Joanna Klubo-Gwiezdzinska, Ravi A. Madan, Lynnette K. Nieman, James L. Gulley
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