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Hemangiosarcoma – Developing New Treatment Options

August 12, 2020

Current Approach and Prognosis

Hemangiosarcoma is a common malignant cancer of dogs and carries a prognosis that is universally understood to be poor. Hemangiosarcoma’s poor prognosis is due to its rapid onset of metastasis (spreading to other organs) and the high propensity for hemangiosarcoma tumors to spontaneously rupture, resulting in life-threatening internal hemorrhage (a condition known as hemoperitoneum when this bleeding occurs in the abdomen). Hemangiosarcoma can arise in just about any organ, however most cases originate from the spleen in dogs. The primary treatment for hemoperitoneum secondary to a bleeding splenic tumor is splenectomy (surgical removal of the entire spleen and its associated tumor). For dogs diagnosed with hemangiosarcoma, this is then followed by chemotherapy.

Even with this aggressive treatment approach, the reported survival times for dogs with splenic hemangiosarcoma is only around 4-6 months, whereas dogs with benign splenic tumors are often cured with surgery alone.

Splenic hemangiosarcoma is challenging to diagnose as dogs often only show symptoms of disease in later and more progressed stages. Most dogs aren’t diagnosed until they have a rupture of their splenic tumor (causing hemoperitoneum), meaning that the cancer itself was diagnosed incidentally as a consequence of the severe internal bleeding and is often already in advanced stages. Currently no screening tests for early diagnosis of hemangiosarcoma exist. The fact that most dogs already have advanced stages of disease at the time of diagnosis may in part contribute to the reported poor prognosis for canine hemangiosarcoma, making new diagnostic tests capable of earlier detection a much-needed area of research.

Current Method of Diagnosis

The current gold standard method to diagnose hemangiosarcoma is to send a sample of the tumor to a diagnostic lab where it will undergo histopathologic (microscopic) analysis. Once submitted, the average turnaround time for this analysis is 3-5 days. In most cases this means that the decision to go to surgery to remove the spleen for dogs with hemoperitoneum must be made without knowledge of whether the mass is benign (cured with surgery) or malignant (often hemangiosarcoma). Previous retrospective studies report the incidence of hemangiosarcoma in dogs with hemoperitoneum due to a bleeding splenic tumor to be as high as 96%. This uncertainty around the preoperative diagnosis and the knowledge of the possible poor prognosis for dogs with hemangiosarcoma can often lead many owners to considering euthanasia rather than pursuing surgery. This choice can be even further complicated by the stress and confusion that most owners experience secondary to the unexpected and abrupt nature of hemoperitoneum.

There is concern that the decision to euthanize could result in some dogs with benign tumors, which could be cured with surgery alone, being put to sleep.

New Hope

Ethos Discovery recently completed one of the first prospective, nationwide studies in canine hemoperitoneum. This study showed an incidence of hemangiosarcoma to be 62% in dogs with hemoperitoneum, which is significantly lower than the previous reports of 96%. This study suggests that a larger proportion of dogs have benign causes to their hemoperitoneum than previously thought. Most dogs with hemoperitoneum present in critical condition and so another goal of the study was to evaluate mortality associated with splenectomy and factors that may predict higher risk cases. The study revealed that 95% of patients survived and were discharged from the hospital in under 40 hours. These findings bring hope to the owners of dogs with hemoperitoneum when they are faced with the need to decide whether to pursue surgical treatment. Furthermore, there are numerous prospective clinical trials open around the country that seek to improve the long-term outcomes in dogs with hemangiosarcoma. This provides further hope to the owners of dogs with hemangiosarcoma, as the results of these studies may not only benefit their own dog, but will also provide valuable data towards developing a cure for this disease.

Improving Treatment Options Through Early Diagnosis

The ability to detect hemangiosarcoma sooner could alter the way hemangiosarcoma is treated and perceived. In patients that present emergently with hemoperitoneum, a rapid diagnostics could allow for a diagnosis to be made preoperatively, meaning that owners would no longer have to make the decision for surgery without knowing what their dog’s diagnosis or long-term prognosis is. Additionally, an earlier diagnostic test for hemangiosarcoma could result in the cancer being diagnosed before tumor rupture occurs, allowing the pet owner and their family more time to consider options and treatment decisions in a non-emergent setting. Furthermore, having the ability to make an earlier diagnosis may result in improved patient responses to the current treatment options available for hemangiosarcoma, and could even allow for novel approaches to how we care for these patients.

The early detection of cancer is defined as the ability to achieve a cancer diagnosis before the disease is altering the patient’s quality of life and prior to any local or distant spread (i.e. metastasis). In veterinary practice there are two requirements for the diagnosis of cancer:

1. Visualization of a tumor – This can include visually seeing or feeling a tumor on an animal or identifying it on diagnostic imaging (e.g. x-rays or ultrasound).
2. Confirmation of cancer cells – This involves obtaining a tissue sample from the tumor (fine-needle aspirate or biopsy), processing this tissue for evaluation, and then visually confirming the presence of cancer cells in the tissue.

While this process is standard practice and is highly accurate, it does have several disadvantages.

• For instance, dogs with large splenic tumors often require surgery to sample the tumor (via splenectomy) because preoperative sampling can result in tumor rupture and severe internal bleeding.
• Tumors can also be located in regions where sampling comes with a high chance of complication, such as tumors located near major blood vessels or deep within tissues.
• Even when a tumor sample is obtained, there is always the potential that the selected section of tumor that is submitted for histopathologic evaluation is not representative of majority of the tumor, and a misdiagnosis can be made.
• Finally, the standard turn-around-time for tissue samples submitted for histopathologic evaluation is 3-5 days, however these samples can sometimes require second opinions or special staining procedures to clarify a diagnosis, which can further delay the start of treatment.

Investigating Novel Diagnostic Approaches

Liquid Biopsy

Ethos Discovery is currently investigating the use of novel blood-based biomarkers for the diagnosis of hemangiosarcoma. A biomarker is a normal compound in the body that becomes elevated in times of illness or is a compound that is only present in the body when certain diseases exist (e.g. cancer). If these compounds are able to be accurately detected, they could provide reliable means to diagnose disease. Furthermore, blood-based biomarkers have the potential to be used to monitor therapeutic response more reliably than standard monitoring techniques (i.e. x-rays and ultrasound). In the area of early cancer detection, the use of circulating cell-free tumor DNA (cftDNA) has shown promise. cftDNA are small fragments of DNA from tumors that get released from the tumor and enter the bloodstream. Their detection in the blood indicates the tumor’s presence and could even have the potential to indicate the degree of cancer burden. This ability to detect cftDNA in the blood of dogs with cancer is a process known as liquid biopsy. Ethos Discovery seeks to develop a liquid biopsy that will be accurate at diagnosing hemangiosarcoma in dogs.

Specialized Test for the Assessment of Molecular Prognosis (STAMP)

Many cancers are highly complex, with numerous genomic subtypes of the same cancer. Hemangiosarcoma is one of these caners that is thought to have multiple subtypes. These subtypes often look the same under a microscope but can carry different prognoses. This means that histopathologic diagnosis of a cancer is not sufficient enough for predicting the course of disease in that patient and the ability to detect the specific cancer subtype would more accurately inform an owner about the long-term prognosis for their dog. These subtypes also present patient-specific drug targets that could be used to direct therapy.

The current gold standard chemotherapeutic treatment for canine hemangiosarcoma is a drug called doxorubicin. The response to doxorubicin is variable among dogs with hemangiosarcoma, and the presence of these various subtypes may be an explanation for the variable therapeutic responses. Cancer treatments often target the specific genomic alterations that led to the development of that cancer, therefore preventing or delaying its progression. With the ability to now easily perform genomic analysis of patient’s tumors, a new patient-specific approach can be taken by matching effective drugs with each patient’s tumor subtype. This is a transition away from the “one treatment fits all” approach and the adoption of a more tailored approach for each patient. This method of treatment is referred to as precision medicine.

Ethos Discovery has shown that canine hemangiosarcoma consists of at least four different subtypes and is now in the process of developing a precision medicine test that would be capable of detecting each of the subtypes. The test would also be able to provide prognostic information about that subtype of hemangiosarcoma. This test will be called the Ethos Hemangiosarcoma Specialized Test for the Assessment of Molecular Prognosis (STAMP).

Ethos Precision Medicine Umbrella Study for Hemangiosarcoma (Ethos-PUSH)

Ethos Discovery will also soon be launching a second prospective, multicenter, nationwide study called the Ethos Precision Medicine Umbrella Study for Hemangiosarcoma (Ethos-PUSH). In this study, 400 pet dogs with naturally ocurring hemangiosarcoma will have genomic profiling performed on their tumors to determine their genomic subtype. A precision medicine approach will then be used to match these dogs to the most effective treatments to determine if this results in improved long-term outcomes. You can read more about this study here. It is through this research that Ethos Discovery hopes to improve the outcome for dogs with hemangiosarcoma and take a similar path as to that of human childhood leukemia, which through significant research efforts went from a commonly fatal disease to a commonly cured disease.