Therapeutic landscape of advanced HER2-positive breast cancer in 2022.

HER2-positive breast cancer is an aggressive subtype of breast cancer with five-year survival rates of 30% for the advanced stage. The development of anti-HER2 treatments has led to a paradigm shift in the management and clinical outcomes of advanced HER2-positive breast cancer patients. The standard first-line treatment consists of taxane-based chemotherapy plus dual anti-HER2 therapies with trastuzumab and pertuzumab. The antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) has been a second-line therapeutic standard, but the second-line treatment approach is rapidly evolving. Given a substantial advantage of another ADC, Fam-trastuzumab deruxtecan (T-DXd), compared to T-DM1 in a recent randomized trial in the second-line setting, T-DXd is currently the preferred second-line option. Optimal third-line treatment strategies are still not established, and multiple approaches have been used including combinations based on capecitabine, trastuzumab, or both with oral anti-HER2 tyrosine kinase inhibitors. Tucatinib plus capecitabine and trastuzumab, lapatinib plus trastuzumab, neratinib or lapatinib plus capecitabine are some of the FDA approved combinations. Another newer agent approved for third- or later-line therapy in the metastatic setting is margetuximab, an Fc-engineered anti-HER2 monoclonal antibody, in combination with chemotherapy. Other novel agents currently under clinical trials are the drugs that indirectly target HER2, including immune cell cycle inhibitors, PI3K/mTOR inhibitors, and immunotherapy agents.

NUT midline lung cancer: a rare case report with literature review.

Nuclear carcinoma of the testis (NUT) midline carcinoma are rare, poorly differentiated tumors resulting from t(15; 19) rearrangement, clinically characterized by aggressive and rapid progression to death. No optimal treatment regimen has been established for this rare malignancy. Surgery, chemotherapy, and radiation have been used for treatment alone or in combination, depending on location and staging of the disease, and may confer short periods of remission; however, re-emergence of the disease inevitably occurs. Targeted therapies such as bromodomain and extra-terminal domain protein (BET) inhibitors are currently in early phases of clinical trials. Here we describe a 49-year-old-male with no comorbidities who presented with acute worsening of chronic cough, new onset hemoptysis and left sided chest pain for 2 weeks. Workup revealed stage IIIB NUT midline carcinoma (NMC) of the lung with next-generation sequencing confirming the presence of a NUTM1-BRD4 fusion. The tumor was unresectable, and he began concurrent chemoradiation with weekly carboplatin and paclitaxel for 5 weeks. The follow-up CT scan showed partial response, so maintenance was continued with durvalumab. Two months later, he presented with metastasis to the posterior muscle compartment of the left arm, which was treated with local radiotherapy. Four months later he developed progression of lung disease with multiple pulmonary nodules. Durvalumab was discontinued and he was prescribed the BET inhibitor molibresib, 120 mg daily. After nearly 3 months of treatment with molibresib, he presented with brain metastasis for which he had a craniotomy with tumor resection and gamma knife radiation to solitary metastatic lesions. He was then prescribed chemo-immunotherapy with carboplatin plus pemetrexed and pembrolizumab. After two cycles of treatment his disease progressed, and he succumbed to it. Total survival was 18 months. In conclusion, NUT midline lung carcinoma is a rare but aggressive malignancy and patients have limited treatment options especially in advanced stages. Few targeted therapies have shown promising results in early clinical trials but more treatment options are awaited.

Coronavirus Disease 2019 and Cold Agglutinin Syndrome: An Interesting Case.

The coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality worldwide. While patients with COVID-19 most frequently present with pneumonia, respiratory failure and acute respiratory distress syndrome, increasing cases of immune-mediated disorders such as autoimmune thrombocytopenia, haemolytic anaemia and antiphospholipid syndrome have been reported. In this article we describe a rare case of cold agglutinin syndrome (CAS) in a patient with COVID-19. The patient was a 77-year-old man with a history of glucose-6-phosphate dehydrogenase (G6PD) deficiency who presented with COVID-19 infection and acute respiratory failure. Initially he was started on intravenous steroids, antibiotics and hydroxychloroquine. Laboratory analysis revealed haemolytic anaemia with a positive direct anti-globulin test (DAT) and high titres of cold agglutinins. Hydroxychloroquine was stopped due to suspicion of haemolysis due to G6PD deficiency but the haemolysis persisted. Unfortunately, the respiratory failure progressed and the patient died. In summary, this article describes a rare case of CAS associated with COVID-19. CAS is a heterogenous group of cold autoimmune haemolytic anaemias occurring secondary to infections or malignancies. No definite treatment for CAS in COVID-19 patients has been approved so far. LEARNING POINTS: Autoimmune haemolytic anaemia has been reported in COVID-19 patients.Cold agglutinin syndrome (CAS) can occur in patients with COVID-19.Efforts to determine the optimal management of CAS in COVID-19 patients must continue.

Effective Immunotherapy in Bone Marrow Metastatic Melanoma Presenting with Disseminated Intravascular Coagulopathy.

Malignant melanoma is responsible for the majority of skin cancer deaths and is increasing in prevalence. Bone marrow (BM) involvement by melanoma is rare in the absence of widespread visceral disease. Here, we report the case of a 30-year-old female who presented to the hospital with back pain, low-grade fever, and easy bruising. She was found to be bicytopenic and in disseminated intravascular coagulopathy (DIC). Surprisingly, BM biopsy showed extensive involvement by metastatic malignant melanoma in the absence of visceral or brain metastasis. The unique presentation of this case and the challenge of management of a potentially treatable cancer in a critically ill patient are discussed, alongside a review of published cases of metastatic melanoma in the BM and an exploration of currently available treatment options. The excellent response of our patient to combined immune checkpoint inhibitors has yet to be paralleled in the available literature.

Excellent Response with Ado-Trastuzumab Emtansine in a Patient with Relapsed Metastatic Breast Cancer Presenting with Pulmonary Lymphangitic Carcinomatosis.

In breast cancer, aggressive tumor biology and the corresponding poor prognosis is associated with amplification or overexpression of the human epidermal growth factor receptor 2 (HER2). Trastuzumab has significantly changed the natural history of HER2-positive breast cancer. However, resistance to trastuzumab remains a substantial clinical problem. Ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate, has demonstrated impressive results in second- or later-line treatment of HER2-positive breast cancer. We report a case of 43-year-old female with previously trastuzumab-treated HER2-positive breast cancer relapsed with pulmonary lymphangitis carcinomatosis that responded dramatically to T-DM1 therapy.

BCR-ABL Testing by Polymerase Chain Reaction in Patients With Neutrophilia: The William Beaumont Hospital Experience and the Case for Rational Laboratory Test Requests.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from the fusion of the BCR-ABL genes, forming the Philadelphia chromosome. The diagnosis is often suspected when there is leukocytosis with left shift and basophilia. Confirmation of the diagnosis requires a demonstration of BCR-ABL by polymerase chain reaction. Using data from the William Beaumont laboratory data registry, we conducted a retrospective review of all the orders for BCR-ABL tests sent to the clinical pathology laboratory between March 11, 2014 and September 12, 2014. We concluded that the presence of concurrent neutrophilia and basophilia has a sensitivity of 100% (95% CI, 69.15% to 100%) and specificity of 100% (95% CI, 93.15% to 100%) in the initial diagnosis of CML. Our results suggest that the presence of both neutrophilia and basophilia should be used as a threshold for the placement of orders for BCR-ABL in the initial diagnosis of CML in patients with leukocytosis with left shift and provide a basis for a reduction in health care spending. Restricting BCR-ABL tests to this population would save approximately $198 million annually in national health care spending.