Developing anti-HER2 vaccines: Breast cancer experience.

Breast cancer accounts for more than one million new cases annually and is the leading cause of death in women globally. HER2 overexpression induces cellular and humoral immune responses against the HER2 protein and is associated with higher tumor proliferation rates. Trastuzumab-based therapies are effectively and widely used as standard of care in HER2-amplified/overexpressed breast cancer patients; one cited mechanism of action is the induction of passive immunity and antibody-dependent cellular cytotoxicity against malignant breast cancer cells. These findings drove the efforts to generate antigen-specific immunotherapy to trigger the patient's immune system to target HER2-overexpressing tumor cells, which led to the development of various vaccines against the HER2 antigen. This article discusses the various anti-HER2 vaccine formulations and strategies and their potential role in the metastatic and adjuvant settings.

Prognostic Factors in Patients with Metastatic Breast Cancer with Bone-Only Metastases.

BACKGROUND: Patients with metastatic breast cancer with bone-only metastases (BOM) are a unique patient population without consensus regarding high-risk characteristics, which we sought to establish. METHODS: We identified 1,445 patients with BOM followed for at least 6 months at MD Anderson Cancer Center from January 1, 1997, to December 31, 2015. RESULTS: Seventy-one percent (n = 936) of the 1,325 patients with BOM with available pain characterization were symptomatic at time of BOM diagnosis. Pain was more common in patients with lytic compared with blastic or sclerotic metastases (odds ratio [OR], 1.79; 95% confidence interval [CI,] 1.26-2.53) and multiple versus single bone metastases (OR, 1.37; 95% CI, 1.03-1.83). Poorer overall survival (OS) was also noted in patients with multiple bone metastases (median OS, 4.80 years; 95% CI, 4.49-5.07) compared with single bone metastasis (median OS, 7.54 years; 95% CI, 6.28-10.10) and in patients with metastases in both the axial and appendicular skeleton (median OS, 4.58 years; 95% CI, 4.23-4.96) compared with appendicular-only (median OS, 6.78 years; 95% CI, 5.26-7.96) or axial-only metastases (median OS, 5.62 years; 95% CI, 4.81-6.69). Black/non-Hispanic patients had poorer outcomes, and patients aged 40-49 years at time of breast cancer diagnosis had significantly better OS compared with both younger and older patient groups. CONCLUSION: Overall, several risk features for decreased OS were identified, including multiple bone metastases and both axial and appendicular skeleton involvement. Multiple bone metastases and lytic bone metastases were associated with increased pain. IMPLICATIONS FOR PRACTICE: Patients with metastatic breast cancer and bone-only metastases (BOM) represent a poorly characterized patient subset. The ability to identify unique patient characteristics at time of BOM diagnosis associated with increased morbidity or mortality would allow for recognition of patients who would benefit from more aggressive therapy. In this study, the largest sample of patients with BOM thus far reported is characterized, highlighting several higher-risk BOM groups, including those with multiple bone metastases and bone metastases in both the axial and appendicular skeleton at time of BOM diagnosis. In addition to tailoring current practices for these high-risk patients, ongoing studies of these patients are indicated.

Long-Lasting Complete Remission in a Patient With Metastatic Metaplastic Breast Cancer Treated With Immune Checkpoint Inhibitor and Chemotherapy: A Case Report and a Review of the Literature.

Metaplastic breast cancer (MpBC) is a rare form of breast cancer known for suboptimal response to chemotherapy, high recurrence rate, poor prognosis, and limited treatment options. Recent studies have reported that MpBC has high expression of programmed death ligand 1 and tumor-infiltrating lymphocytes, indicating the potential effectiveness of immunotherapy (IO) in MpBC. In addition, several reports have demonstrated the activity of IO in MpBC. In this case report, we present a case of recurrent MpBC that achieved durable, rapid, complete remission with atezolizumab (anti-PD-L1) and nab-paclitaxel with a continued response even after discontinued therapy.

Retention in the endoplasmic reticulum is the underlying mechanism of some hereditary haemorrhagic telangiectasia type 2 ALK1 missense mutations.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterised by vascular dysplasia and increased bleeding that affect 1 in 5,000 people world-wide. Pathology is linked to mutations in genes encoding components of the heteromeric transforming growth factor-beta receptor (TGF-beta) and SMAD signalling pathway. Indeed HHT1 and HHT2 result from mutations in the genes encoding endoglin and activin-like kinase 1 (ALK1), TGF-beta receptor components. However, the fundamental cellular defects underlying HHT is poorly understood. Previously using confocal microscopy and N-glycosylation analysis, we found evidence that defective trafficking of endoglin from the endoplasmic reticulum (ER) to the plasma membrane is a mechanism underlying HHT1 in some patients. In this study, we used confocal microscopy to investigate whether a similar mechanism contributes to HHT2 pathology. To do this we expressed wild-type ALK1 and a number of HHT2 patient mutant variants as C-terminally tagged EGFP fusion proteins and tested their localisation in HeLa cells. We found that wild-type ALK1-EGFP was targeted predominantly to the plasma membrane, as evidenced by its colocalisation with the co-expressed HA-tagged endoglin. However, we found that in the majority of cases analysed the HHT2 patient mutant protein was retained within the ER as indicated by their colocalisation with the ER resident marker (calnexin) and lack of colocalisation with cell surface associated HA-endoglin. We conclude that defective trafficking and retention in the ER of mutant ALK1 protein is a possible mechanism of HHT2 in some patients.

Breast Cancer in the Arabian Gulf Countries.

Breast cancer stands as the prevailing malignancy across all six Gulf Cooperation Council (GCC) nations. In this literature review, we highlighted the incidence and trend of breast cancer in the GCC. Most of the studies reported a consistent increase in breast cancer incidence over the past decades, which was particularly attributed to the adoption of a Westernized lifestyle in the region and the implications of emerging risk factors and other environmental and societal factors, the increase in screening uptake, as well as the improvement in data collection and reporting in the GCC. The data on breast cancer risk factors in the GCC were limited. In this geographic region, breast cancer frequently manifests with distinctive characteristics, including an early onset, typically occurring before the age of 50; an advanced stage at presentation; and a higher pathological grade. Additionally, it often exhibits more aggressive features such as human epidermal growth factor receptor 2 (HER2) positivity or the presence of triple-negative (TN) attributes, particularly among younger patients. Despite the growing body of literature on breast cancer in the GCC, data pertaining to survival rates are, regrettably, meager. Reports on breast cancer survival rates emanating from the GCC region are largely confined to Saudi Arabia and the United Arab Emirates (UAE). In the UAE, predictive modeling reveals 2-year and 5-year survival rates of 97% and 89%, respectively, for the same period under scrutiny. These rates, when compared to Western counterparts such as Australia (89.5%) and Canada (88.2%), fall within the expected range. Conversely, Saudi Arabia reports a notably lower 5-year survival rate, standing at 72%. This disparity in survival rates underscores the need for further research directed toward elucidating risk factors and barriers that hinder early detection and screening. Additionally, there is a pressing need for expanded data reporting on survival outcomes within the GCC. In sum, a more comprehensive and nuanced understanding of breast cancer dynamics in this region is imperative to inform effective strategies for prevention, early detection, and improved patient outcomes.

Defective cellular trafficking of missense NPR-B mutants is the major mechanism underlying acromesomelic dysplasia-type Maroteaux.

Natriuretic peptides (NPs) comprise a family of structurally related but genetically distinct hormones that regulate a variety of physiological processes such as cardiac growth, blood pressure, axonal pathfinding and endochondral ossification leading to the formation of vertebrae and long bones. The biological actions of NPs are mediated by natriuretic peptide receptors (NPRs) A, B and C that are located on the cell surface. Mutations in NPR-B have been shown to cause acromesomelic dysplasia-type Maroteaux (AMDM), a growth disorder in humans and severe dwarfism in mice. We hypothesized that missense mutations of NPR-B associated with AMDM primarily affect NPR-B function by the arrest of receptor trafficking at the endoplasmic reticulum (ER), due to conformational change, rather than an impairment of ligand binding, transmission of signal through the membrane or catalytic activity. Twelve missense mutations found in AMDM patients and cn/cn mice were generated by site-directed mutagenesis and transiently overexpressed in HeLa cells. Confocal microscopy revealed that 11 out of 12 mutants were retained in the ER. Determination of the ligand-dependent cGMP response confirmed that ER-retained NPR-B mutants are non-functional. Meanwhile, the only cell surface-targeted NPR-B missense mutant (D176E) displayed greatly reduced enzymatic activity due to impaired ligand binding. Thus, in the majority of cases of AMDM associated with missense NPR-B mutation, disease appears to result from defects in the targeting of the ER receptor to the plasma membrane.

The State of Cancer Care in the United Arab Emirates in 2020: Challenges and Recommendations, A report by the United Arab Emirates Oncology Task Force.

With cancer being the third leading cause of mortality in the United Arab Emirates (UAE), there has been significant investment from the government and private health care providers to enhance the quality of cancer care in the UAE. The UAE is a developing country with solid economic resources that can be utilized to improve cancer care across the country. There is limited data regarding the incidence, survival, and potential risk factors for cancer in the UAE. The UAE Oncology Task Force was established in 2019 by cancer care providers from across the UAE under the auspices of Emirates Oncology Society. In this paper we summarize the history of cancer care in the UAE, report the national cancer incidence, and outline current challenges and opportunities to enhance and standardize cancer care. We provide recommendations for policymakers and the UAE Oncology community for the delivery of high-quality cancer care. These recommendations are aligned with the UAE government's vision to reduce cancer mortality and provide high quality healthcare for its citizens.

Characterization of bone only metastasis patients with respect to tumor subtypes.

Metastatic breast cancer (MBC) patients with bone only metastasis (BOM) are a unique population with limited characterization. We identified patients followed at MD Anderson Cancer Center from 01/01/1997 to 12/31/2015 for at least 6 months with a BOM diagnosis as first site of metastasis. Tumor subtype (TS) was assessed by initial breast biopsy immunohistochemistry using hormonal receptor (HR) and HER2 status, with four subtypes identified: HR+/HER2-, HR+/HER2+, HR-/HER2-, HR-/HER2+. HR+ was defined as estrogen receptor or progesterone receptor ≥1%. We identified 1445 patients with BOM, 1048 with TS data available. Among these patients, the majority were HR+/HER2- (78%). Median time from breast cancer diagnosis to first bone metastasis was 2.3 years (95% CI 2.1, 2.5) and varied significantly by TS, with longer time to distant disease in HR+/HER2- patients relative to all other TS (p < .0001). Median overall survival (OS) from breast cancer diagnosis was 8.7 years (95% CI 8.0, 9.7) and varied significantly by TS with poorer OS for HR-/HER2- and HR-/HER2+ patients relative to HR+/HER2- TS (p < .0001). The 442 patients with de novo BOM disease, defined as bone metastasis diagnosis within 4 months of breast cancer diagnosis, had significantly shorter OS (p < .0001). Overall, several higher risk BOM subsets were identified in this analysis, most notably HR-/HER2+ and HR-/HER2- TS and de novo BOM patients.