Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study.

BACKGROUND: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. METHODS: Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05. RESULTS: Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS. CONCLUSIONS: In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.

Locoregional recurrence in triple negative breast cancer: past, present, and future.

INTRODUCTION: Triple negative breast cancer (TNBC) is a rare but aggressive biological subtype of breast cancer associated with higher locoregional and distant recurrence rates and lower overall survival despite advancements in diagnostic and treatment strategies. AREAS COVERED: This review explores the evolving landscape of locoregional recurrence (LRR) in TNBC with improved surgical and radiation therapy delivery techniques including salvage breast conserving surgery (SBCS), re-irradiation, and thermo-radiation. We review current retrospective and prospective, albeit limited, clinical data highlighting the optimal management of locoregionally recurrent TNBC. We also discuss tumor genomic profiling and transcriptome analysis and review potential investigational directions. EXPERT OPINION: Significant progress has been made in the prevention of LRR but rates remain suboptimal, particularly in the TNBC population, and outcomes following LRR are poor. Further prospective studies are needed to identify the most effective and safest systemic therapy regimens and to whom it should be offered. There has been growing interest in the role of molecular markers, genomic signatures, and tumor microenvironment in predicting outcomes and guiding LRR treatment. Transcriptome analyses and biomarker-driven investigations are currently being studied and represent a promising era of development in the management of LRR.

Toxicity Profile of Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapies in Multiple Myeloma: Pathogenesis, Prevention and Management.

Multiple myeloma is the second-most common hematologic malignancy in adults worldwide. Despite ongoing advancement in therapeutic modalities, it remains an incurable disease with a 5-year survival rate of approximately 50%. The recent development and introduction of anti-BCMA immunotherapies into clinical practice, including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific antibodies, has radically shifted the treatment paradigm. However, despite the promising potential of these therapies for broader application, frequent and significant adverse effects have been reported, both in short- and in long-term settings, requiring increasing awareness and vigilance in the treating team, close monitoring, and prompt interventions with a multidisciplinary approach. In this review, we will discuss the toxicities associated with CAR-T cell and bispecific antibody therapies, focusing on results from major clinical studies and real-world observations. In addition, we will emphasize on effective strategies for prevention, monitoring and management, and provide expert recommendations.

Immunotherapy response in patients with cutaneous squamous cell carcinoma of head and neck with cranial nerve involvement.

BACKGROUND: Metastatic or locally advanced cutaneous squamous cell carcinoma (cSCC) can be treated with immunotherapy (IO). Cranial nerve involvement (CNI) is uncommon in cSCC and is a poor prognostic factor. Our aim is to describe how patients with CNI respond to IO monotherapy and/or as an adjunct to RT. METHODS: Under an IRB approved protocol, patients with histologically proven cSCC of the head and neck with CNI treated with IO were retrospectively reviewed. RESULTS: Twelve patients were included and received cemiplimab or pembrolizumab. Eight patients had CNI at diagnosis, and 4 at time of recurrence after non-IO therapy. Best responses were complete response (1), partial response (7), stable disease (1), progressive disease (2), and pending response (1). Nine patients are alive, 6 of which remain on IO. CONCLUSIONS: In this cohort, IO showed clinical response in 83% of patients, indicating IO can be an effective monotherapy, reserving RT for instances of local failure after IO.

Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium.

PURPOSE: Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. METHODS: This retrospective study included PWH treated with anti-PD-1- or anti-PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). RESULTS: Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti-PD-1/anti-PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load <400 copies/mL. Twenty percent (79/390) had any grade immune-related adverse events (irAEs) and 7.7% (30/390) had grade ≥3 irAEs. ORRs were 69% (nonmelanoma skin cancer), 31% (NSCLC), 16% (HCC), and 11% (HNSCC). In the matched mNSCLC cohort (61 PWH v 110 PWOH), 20% (12/61) PWH and 22% (24/110) PWOH had irAEs. Adjusted 42-month RMST difference was -0.06 months (95% CI, -5.49 to 5.37; P = .98) for PFS and 2.23 months (95% CI, -4.02 to 8.48; P = .48) for OS. CONCLUSION: Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

Comparison of real-world outcomes following immunotherapy in recurrent or metastatic head and neck squamous cell carcinoma with outcomes of randomized controlled trials.

OBJECTIVES: Evaluate outcomes of patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy (IO). METHODS: Among patients with R/M HNSCC treated with IO in this retrospective single-institution cohort, Cox regression was used to compare overall survival (OS) for those with platinum-refractory disease and those treated in the first-line setting with OS from KEYNOTE-040/048, respectively. Multivariable Cox regression was used to identify predictors of OS. RESULTS: There was no significant OS difference for those treated in the platinum-refractory setting when compared to patients on KEYNOTE-040 (HR = 1.22, p = 0.27), nor for the first-line setting compared to KEYNOTE-048 (HR = 1.23, p = 0.19). ECOG-PS 1 (HR = 2.00, p = 0.02) and ECOG-PS 2 (HR = 3.13, p < 0.01) were associated with worse OS. Higher absolute lymphocyte count (ALC) was associated with improved OS (HR = 0.93 per 100 cells/µL, p = 0.03). CONCLUSIONS: Real-world outcomes of IO in R/M HNSCC are similar to outcomes in randomized control trials, with performance status and ALC correlating with OS.

EGFR-mutated advanced lung cancer. Data from a single institution, the Hospital of Leon, in Spain.

INTRODUCTION: 10-16% of non-small cell lung cancer (NSCLC) cases have the epidermal growth factor receptor (EGFR) amplified and/or mutated. Studies show that EGFR tyrosine kinase inhibitors (TKIs) significantly prolong progression-free survival (PFS) in patients with advanced NSCLC compared to those treated with platinum-based chemotherapy (CT) doublets. Our aim is to perform a real-world survival analysis of patients treated with TKI as first-line therapy at the Hospital of Leon (CAULE) in Spain. The impact on global survival rates and responses to clinical and histopathological factors were also analyzed. MATERIAL AND METHODS: We retrospectively reviewed patients diagnosed with EGFR-mutated NSCLC who received treatment with EGFR-TKI in the Department of Oncology at the University of Leon Health Center complex between March 2011 and June 2018. Data was analyzed with Kaplan-Meier and Cox regression models to show overall survival (OS), progression-free survival (PFS), and the associated variables. RESULTS: 53 patients were included in the study, 50% (n = 27) were treated with gefitinib, 32% (n = 18) with erlotinib and 10% (n = 6) with afatinib. The median OS and PFS were 27.7 months (95% CI: 21-33.8 months) and 18 months (95% CI 14.25-21.89 months), respectively. The variables associated with OS and with PFS were exon19 deletion as a protective factor and presence of extrathoracic metastasis as a risk factor. The most frequent adverse effects were rash, diarrhea, asthenia, and conjunctivitis. CONCLUSIONS: Real-world analysis of this data confirms that treatment with TKI is beneficial for patients diagnosed with EGFR-mutated NSCLC. Our OS outcomes were similar to those reported in clinical trials.

Discovery, Significance, and Utility of JAK2 Mutation in Squamous Cell Carcinoma of the Lung.

Lung cancer continues to be the leading cause of cancer-related deaths worldwide. Many studies show lung cancer is a histologically and molecularly heterogeneous group, even within the same histological subtype. Liquid biopsies are a new tool that can identify targetable genomic mutations and impact management. JAK2 p.V617F is a mutation commonly found in myeloproliferative neoplasms but rarely identified in non-small cell lung cancer (NSCLCs). The significance of Janus Kinase (JAK2) mutation in lung cancer is not clearly understood. However, it is thought that it may have a role in treating solid tumors, such as lung cancer. We present two cases of patients diagnosed with NSCLC who were discovered to have JAK2 V617F mutation on liquid biopsy.

Atrial fibrillation in older adults with cancer.

Cancer and atrial fibrillation (AF) are common co-morbid conditions in older adults. Both cancer and cancer treatment increase the risk of developing new AF which increases morbidity and mortality. Heart rate and rhythm control along with anticoagulation therapy remain the mainstay of treatment of AF in older adults with both cancer and AF. Adjustments to the treatment may be necessary because of drug interactions with concurrent chemotherapy. Cancer and old age increase the risk of both, thromboembolism and bleeding. The risk of these complications is further enhanced by concomitant cancer therapy, frailty, poor nutrition status and, coexisting geriatric syndromes. Therefore, careful attention needs to be given to the risks and benefits of using anticoagulant medications. This review focuses on the management of AF in older patients with cancer, including at the end-of-life care.

Hercules and Cancer: A Metaphorical Attempt to Beat Mortality.

Art offers a visual document of ancestral suffering, as such mythological images in the arts can provide cathartic relief in our patients with existential anxiety. The image of Hercules fighting Hydra and Cancer may serve as an example on how art can help attaining that goal. One example of such an attempt is reflected in the story of Hercules who had to defeat Hydra and Cancer as part of his twelve labors to become immortal. The same way Hercules fought against Cancer to become immortal, humans fight against cancer to defeat death. Cancer is a constant threat to mankind; oftentimes feeling as if it belongs to an alternate reality; a different reality we cannot comprehend, but that will unavoidably reach and impact us all.

Fallopian tube cancer- challenging to diagnose but not as infrequent as originally thought.

Background: Primary fallopian tube carcinoma (PFTC) is a rare gynecological malignancy though its prevalence may be underestimated given that most 'ovarian' serous cancers originate in the fallopian tube. Its diagnosis is challenging due to its vague signs and symptoms on presentation and it is frequently under-diagnosed pre-operatively. Case Presentation: We present a case of a pre-menopausal woman who presented with vaginal bleeding. Her laboratory testing and physical examination were grossly unremarkable. Gynecologic ultrasound demonstrated multiple uterine fibroids and a double layer endometrium measuring 4.5 mm. More importantly, the left ovary was seen with a complex cyst with mildly echogenic fluid and a solid excerscence. These findings were suspicious for malignancy. The clinical and radiological findings with elevated CA-125 were consistent with a malignant process. Patient subsequently underwent a diagnostic laparoscopy, which required conversion to exploratory laparotomy, supracervical hysterectomy, bilateral salpingo-oophorectomy, right ureteral lysis, right para-aortic and right pelvic lymph node debulking and omentectomy. Biopsy of left fallopian tube and ovary revealed invasive high-grade serous carcinoma of fallopian tube, with involvement of lymphovascular spaces and with surface involvement. Peritoneal washings were negative for malignancy. She was diagnosed with a high-grade serous carcinoma of the fallopian tube after undergoing an endometrial biopsy, multiple imaging tests and finally surgical intervention that yielded the diagnosis. She was started on chemotherapy with carboplatin and paclitaxel. Conclusion: Our aim is to highlight the importance of having PFTC among the differential diagnosis when women present with vaginal bleeding or abdominal pain, as the clinical presentation of PFTC tends to be non-specific, and is often under-diagnosed; reviewing the diagnosis and management, and characterizing the similarities and differences of PFTC with other gynecological malignancies such as ovarian cancer.

Intracranial bleeding following soccer-related head trauma in a young student with occult factor VII deficiency.

It is important to obtain coagulation tests to assess bleeding risk in trauma patients undergoing emergency surgery when a bleeding disorder may be obscured. Identifying specific clotting factor defects is critical in successful patient management.

Bile Cast Nephropathy Secondary to Hemophagocytic Lymphohistiocytosis With Liver Failure.

Acute kidney injury (AKI) is a common complication seen in patients with hemophagocytic lymphohistiocytosis (HLH). More than half of patients with HLH require renal replacement therapy (RRT). There are four main causes of kidney dysfunction in HLH, which include acute tubular necrosis (ATN), hypoperfusion, tumor lysis syndrome (TLS), and HLH-related glomerulopathies. Bile cast nephropathy (BCN) is a known cause of kidney injury in patients with liver failure and hyperbilirubinemia. We present the case of a 58-year-old man who presented to the hospital with painless jaundice, choluria, acholia, and generalized malaise and was found to have hyperbilirubinemia and kidney injury in the setting of HLH, who underwent a renal biopsy showing bile salt casts with degenerating tubular lining cells consistent with BCN. This case highlights the importance of considering BCN as a cause of kidney injury when a patient with HLH presents with liver failure and elevated bilirubin levels.

Tumor Lysis Syndrome Caused by Unrecognized Richter's Transformation of Chronic Lymphocytic Leukemia: Treatment With Venetoclax for Suspected Disease Progression.

Richter's transformation (RT) is defined as the transition of chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) into an aggressive lymphoma. The conversion generally leads to diffuse large B-cell lymphoma (DLBCL), but more aggressive forms such as Hodgkin lymphoma (HL) can also occur. RT is a rare complication of CLL. RT can be confused with CLL progression. Its identification is crucial because the management of lymphoma and CLL differ from each other. Furthermore, the use of certain agents for CLL such as venetoclax increases the risk of tumor lysis syndrome (TLS) in neoplasms with rapid replication such as DLBCL or CLL with hyperleukocytosis (blast crisis). We present the case of a 76-year-old man with a history of CLL on chemotherapy who developed fatigue, malaise, night sweats, chills, and unintentional weight loss for which he was started on treatment with venetoclax due to suspected clinical progression of his disease. The patient developed TLS, requiring hospitalization, and he was found to have an acute blast crisis. Also, his CLL was found to have been transformed into an aggressive DLBCL. This case highlights the importance of differentiating a true progression of CLL from RT into an aggressive lymphoma given that treatment would be different for the two and the prognosis with the transformation is worse.

Leukocytoclastic Vasculitis: An Early Skin Biopsy Makes a Difference.

Leukocytoclastic vasculitis (LCV) is an uncommon condition with a broad differential diagnosis. Although the clinical history, physical examination, and laboratory workup are pivotal when formulating a differential diagnosis of LCV, a skin biopsy is required in most cases to elucidate the cause. The diagnostic yield of a skin biopsy increases within the first 24 to 48 hours of the lesion onset indicating the importance of obtaining a prompt skin sample. We present the case of a 60-year-old man who presented to the emergency department with a three-day history of fevers, headaches, and a painful skin rash. He endorsed rhinorrhea and sore throat a week ago. Physical examination was notable for an erythematous papular rash with palpable violaceous purpura located mainly at the distal right leg and thigh. He also complained of painful bilateral hand edema. His complete blood count and chemistries were unremarkable. His C-reactive protein was 147 mg/L (normal value <8 mg/L), and sedimentation rate was 51 mm (normal value <15 mm). Immunoglobulin A was 509 mg/dL (normal value 82-460 mg/dL). Further workup including viral hepatitis serologies, antinuclear antibodies, complements, antineutrophil cytoplasmic antibodies, cryoglobulins, rheumatoid factor, and blood cultures yielded negative results. Therefore, it was believed that his rash was likely associated with his recent upper respiratory infection. A skin biopsy done on the first day of admission was positive for LCV without immunoglobulin A deposition. He was managed with prednisone and anti-inflammatory medications with improvement of his rash.

Primary central nervous system marginal zone B-cell lymphoma arising from the dural meninges: A case report and review of literature.

Primary central nervous system (CNS) marginal zone B-cell lymphoma (MZBCL) arising from the dural meninges is a rare but indolent disease. This malignancy can present in various ways, hence making it difficult to diagnose. Biopsy results dictate an appropriate treatment plan, which commonly consists of a combination of surgical resection, whole brain radiotherapy and systemic therapy.

Breast Cancer Metastasis Masquerading as Primary Colon and Gastric Cancer: A Case Report.

BACKGROUND Breast cancer is the most common malignancy in women worldwide. Despite treatment, recurrence and metastasis are common. Lobular breast cancer most commonly metastasizes to the lungs, liver, lymph nodes, and sites in the brain. Metastasis to the gastrointestinal tract is rare, with few cases reported to date. CASE REPORT This report describes a patient with late colon and gastric metastases from lobular breast cancer mimicking primary colon and gastric cancers. CONCLUSIONS Immunohistochemical methods can help differentiate metastatic breast disease to the gastrointestinal tract from primary gastrointestinal malignancy.

Hyperprogression in PDL1 Expressive, Recurrent Gastroesophageal-junction Adenocarcinoma After Pembrolizumab.

Hyperprogression is a pattern of accelerated tumor growth noted uncommonly after the use of immune checkpoint inhibitors in some patients. We present a 56-year-old female with gastroesophageal junction (GEJ) adenocarcinoma who was initially treated with neoadjuvant radiation and chemotherapy with carboplatin and paclitaxel, followed by esophagogastrectomy and postoperative FOLFOX chemotherapy. After a stable two-year course, she was noted to have recurrence at the GEJ which was biopsy confirmed. She was started on pembrolizumab, after which she developed several new metastases noted on the PET/CT. Lesions were noted in iliac bones, spine, retroperitoneal lymph nodes, hilar nodes, mediastinum, and lungs. Postdiscontinuation of the pembrolizumab, she received six cycles of paclitaxel with ramucirumab and showed remarkable improvement on the next imaging scan with resolution of osseous lesions, lung nodules and significant improvement in hilar, mediastinal, and retroperitoneal lymph nodes. We hope that this case report sheds further light on this uncommon complication of immune checkpoint inhibitors.