HER2 Positive Breast Cancer

Revolutionize Care in HER2 Positive Breast Cancer Market with DiseaseLandscape Insights

Breast cancer stands as the most prevalent form of cancer among women in the United States, with approximately 20% of diagnoses attributed to HER2-positive breast cancer. Additionally, HER2-low breast cancers, characterized by lower HER2 expression levels, contribute to ~55 % of all breast cancer cases.

Historically, HER2-positive breast cancer, known for its aggressive and rapid growth, was linked to poorer outcomes and higher mortality rates compared to other subtypes of breast cancer. However, the advent of HER2-targeted therapies has transformed it into a manageable condition, significantly improving patient outcomes.

It was demonstrated by two separate teams, one under the direction of Dr. Dennis J. Slamon and the other by Dr. Stuart Aaronson, a former BCRF scientist, that the HER2 gene and its protein product, HER2 protein, could cause normal cells to expand uncontrolled like cancer cells. Moreover, according to Dr. Slamon and his associates, 25–30% of breast tumors have overexpressed HER2 protein.

Presently, early diagnosis and the application of chemotherapy alongside dual antibody therapy have propelled survival rates beyond 90 % for HER2-positive breast cancer. Nonetheless, five-year survival rates vary based on hormone receptor (HR) status and cancer's initial location, showcasing superior outcomes for localized (confined to the breast) in contrast to regional (near the breast) or distant (metastatic) HER2-positive breast cancer cases.

According to cancer registry data, breast cancer is the most frequent cancer among Indian women living in urban areas. There is a dearth of information on the percentage of Indian breast cancer patients who test positive for human epidermal growth factor receptor-2 (HER2). In the Western literature, it has been reported that HER2 overexpression occurs in about 25–30% of all breast cancer cases.

Furthermore, the HER2 protein aids in the proper development and maintenance of breast cells. However, in certain instances, the HER2 gene malfunctions and instructs breast cells to proliferate. Tumor formation results from this uncontrollably growing tissue. Genes that overexpress themselves by making an excessive number of copies of HER2 receptors (overexpression) or of themselves (gene amplification) may affect the gene's normal function. Amplification of the HER2 gene and consequent overexpression of HER2 receptors is also be brought on by a mutation in the gene. Breast cells that express more of the HER2 gene, overexpress more of the protein, or both result in HER2-positive breast cancer. However, it should be noted that HER2-negative breast tumors with IHC 1+ and 2+ without amplification are not fully devoid of HER2, which simply does not have sufficient receptors to respond to current targeted therapies for the treatment of HER2. Recent clinical trials evaluating a novel HER2-targeted therapy have led to the identification of a subset of breast cancers known as HER2-low. Among the four primary subtypes of female breast cancer, these HER2-low breast cancers have been recognized as a distinct category, with prevalence rankings as follows.

• HR+/HER2-
• HR-/HER2-
• HR+/HER2+
• HR-/HER2+

According to the National Cancer Institute the most prevalent subtype of breast cancer, HR+/HER2-, exhibits an age-adjusted rate of 87.2 new cases per 100,000 women, as indicated by data from 2016 to 2020.

Diagnosis and Testing–

Multiple diagnostic tests are available for the detection of HER2- breast cancer. It is crucial to ascertain the presence and quantity of HER2 in breast cancer tissue, as this information significantly influences the treatment strategy selected by the healthcare provider to address the cancer effectively.

HER2 testing results are crucial in guiding optimal treatment decisions in collaboration with the cancer care team. While the comparative accuracy of tests is unclear, it's notable that FISH, though more expensive and time-consuming, is an option, with IHC often being the initial choice.

Interpreting IHC results:

IHC result of 0 indicates HER2-negative status, suggesting resistance to HER2-targeted treatments.

IHC result of 1+ is considered HER2-negative, with limited responsiveness to HER2-targeted drugs, though recent research suggests potential benefits in certain cases.

IHC result of 2+ signifies an equivocal HER2 status, necessitating FISH testing for clarification.

IHC result of 3+ designates HER2-positive status, warranting treatment with HER2-targeted drugs.

Some breast cancers with IHC results of 1+ or 2+ along with a negative FISH test are termed HER2-low cancers. Ongoing research indicates potential benefits from specific HER2-targeted drugs for these cases.

Triple-negative breast tumors lack significant HER2 expression and lack Estrogen and progesterone receptors (ER-, PR-). Hormone therapy and HER2-targeted drugs are not effective in treating these cancers.

In contrast, triple-positive breast tumors are characterized by HER2-positive, ER-positive, and PR-positive status. These cancers are managed with both hormone drugs and HER2-targeted treatments.

• IHC testing-

IHC (Immunohistochemistry) is employed to assess the quantity of HER2 protein in breast tissue. The HER2 cell surface proteins undergo chemical staining and are quantified on a scale ranging from 0 to 3+. A score of 3+ indicates a HER2-positive status. In cases where IHC results are inconclusive, termed equivocal (2+), an additional test may be conducted to conclusively determine whether the cancer is HER2 positive or negative.

Around 80% of new invasive breast cancer cases undergo HER2 testing through IHC (Immunohistochemistry), while the remaining 20% are tested using FISH (Fluorescence in Situ Hybridization). Numerous testing kits commercially available have obtained FDA approval for evaluating HER2 status. While standardized assays for IHC and ISH are employed, the current methods for HER2 testing exhibit inaccuracies in approximately 20% of cases.

• FISH testing-

FISH (Fluorescence in Situ Hybridization) is a more precise method compared to IHC (Immunohistochemistry) as it specifically targets and screens for genes or gene segments within the DNA of tumor cells. Cancer cells often exhibit abnormal amplification of certain genes. In the context of breast cancer, FISH is employed to quantify the number of copies of the HER2 gene in the cancerous tissue.

INFORM HER2 Dual ISH test.

The INFORM HER2 Dual ISH test, akin to FISH testing and IHC, employs an alternative technology for screening the HER2 gene in breast cancer tissue. This method allows for the visualization of results using a light microscope.

Imaging Tests-

Breast cancer is typically detected through a routine "screening" mammogram, often before any noticeable lumps or changes occur in the breast.

A mammogram involves a very low-dose X-ray of the breast. During the procedure, the breast tissue is compressed to decrease thickness, ensuring accurate detection of abnormalities. Each breast is compressed and x-rayed from two directions, top-down and side-to-side, for comprehensive examination. Mammograms are currently regarded as the most effective screening method for identifying breast cancer. Some mammograms use digital imaging, providing improved clarity, and image adjustment capabilities, and reducing the likelihood of requiring repeat pictures on a different day.

3D tomosynthesis, an advanced form of digital mammogram, captures multiple images of the breast while it is compressed in both directions. This technology allows radiologists to review numerous pictures of each breast, aiding in the detection of abnormalities hidden by overlapping tissue. Moreover, the finer detail revealed by 3D tomosynthesis is valuable in distinguishing between benign lumps and those requiring further investigation with additional images.

Ultrasound employs sound waves to generate images of internal structures within the body. It is utilized to ascertain whether a recently discovered breast lump is a solid mass or a cyst filled with fluid.

Treatment Analysis -

The life expectancy of individuals with HER2-positive breast cancer is influenced by various factors, including the stage of diagnosis and the chosen treatment approach. Multiple effective treatments are available for HER2-positive breast cancer, and the selection is tailored by the doctor based on several considerations, such as hormone receptor status.

The primary treatment for HER2-positive breast cancer often involves targeted therapies, which are medications designed to specifically inhibit the HER2 protein, preventing the growth of cancer cells. Additionally, patients undergo a combination of treatments, including surgery, radiation, chemotherapy, and targeted or hormonal therapies (in cases where the tumor is hormone receptor-positive). The drugs administered for HER2-positive breast cancer patients encompass a range of therapeutic options.

The treatment approach for HER2-positive breast cancer is determined by the size of the tumor. If the tumor is smaller than 2 centimeters and no lymph nodes are involved, the initial step involves surgical intervention. Subsequently, patients undergo chemotherapy, coupled with administering a singular antibody that targets the HER2 protein, identified as Trastuzumab (Herceptin).

There are diverse treatment options available for addressing HER2-positive breast cancers, and the choice depends on the specific type and stage of the cancer. The doctor collaborates with the individual to formulate an appropriate treatment plan, which may encompass:

Surgical Interventions –

Surgical interventions are employed for acquiring tissue samples to verify a diagnosis, pinpoint a particular cancer, and assess the extent of the disease. Furthermore, surgery serves the purpose of extracting both malignant and non-malignant tumors, addressing solid tumors such as those located in the breast, colon, or lung, resolving issues causing discomfort or impairment, and facilitating other treatment methods, including the installation of IV access devices.

Radiation Therapy (RT)–

Radiation therapy (RT) has the potential to substantially enhance overall survival (OS) and breast cancer-specific survival (BCSS) among individuals with early-stage HER2-positive breast cancer following breast-conserving surgery (BCS). For those deemed high-risk, RT is a crucial element of comprehensive cancer treatment. Nevertheless, for HER2-positive early-stage patients with a low-risk profile, the exclusion of radiotherapy may be contemplated as a viable option.

Radiation therapy employs high-energy rays or particles to eliminate cancer cells, and it is often a necessary component of treatment for some women with breast cancer, complementing other therapeutic interventions.

The utilization of radiation therapy is contingent on various factors, including the stage of breast cancer. It is employed in the following scenarios:

• After Breast-Conserving Surgery (BCS):

Aimed at reducing the likelihood of cancer recurrence in the same breast or nearby lymph nodes following breast-conserving surgery.

• After Mastectomy:

Particularly recommended if the cancer is larger than 5 cm (about 2 inches), if cancer is detected in numerous lymph nodes, or if specific surgical margins, such as the skin or muscle, contain cancer cells.

• If Cancer Has Spread:

Radiation therapy is considered if breast cancer has metastasized to other parts of the body, such as the bones, spinal cord, or brain.

Types of Radiation Therapy-

• External Beam Radiation Therapy
• Internal Beam Radiation Therapy (Brachytherapy)
• Intraoperative Radiation Therapy

HER2-Targeted Therapies / Anti-HER2 Therapies

HER2-positive breast cancers exhibit an abundance of the HER2 protein on their cell surfaces, which significantly influences cell growth and survival. Therapies specifically targeting HER2 are intended for the treatment of HER2-positive breast cancers and do not play a role in the treatment of HER2-negative cancers. Anti-HER2 therapies, also known as HER2 inhibitors or HER2-targeted therapies, are a category of medications utilized to address HER2-positive breast cancer at all stages, as well as specific cases of HER2-low breast cancers.

Medications classified as anti-HER2 drugs attach to the HER2 receptor proteins found on the surface of breast cancer cells. These drugs are commonly referred to as "HER2-targeted therapies" due to their specific targeting of HER2 receptors. Other targeted therapies exist that focus on different receptors.

The mechanism of action of anti-HER2 drugs involves blocking HER2 receptors to prevent them from receiving growth signals in HER2-positive breast cancer. This interference with growth signals can effectively impede or halt the growth of both HER2-positive and HER2-low breast cancer. It's important to note that anti-HER2 drugs exclusively impact HER2-positive and HER2-low breast cancer and are not effective against HER2-negative breast cancer.

Various medications are designed to specifically target HER2 receptors found in breast cancer cells. HER2 inhibitors are often administered in combination with other treatments. Certain anti-HER2 medications, known as "antibody-drug conjugates," consist of HER2 inhibitors with additional medicines attached to them.

These anti-HER2 medicines not only target HER2-positive cancer cells but also deliver chemotherapy directly to them. This targeted approach helps minimize the toxic effects of chemotherapy on healthy cells.

Here are various medications designed to specifically target HER2 receptors.

Monoclonal Antibodies –

Monoclonal antibodies, synthesized in a laboratory, mimic the action of naturally produced antibodies in our immune systems. Apart from directly targeting HER2 receptors on breast cancer cells, these medications stimulate the immune system to recognize and eliminate cancer cells. This dual action has led to them being referred to as "immune-targeted therapies."

Most of these treatments are administered through intravenous infusion, wherein they are directly delivered into your bloodstream using either an IV or a port.

Antibody-drug Conjugates-

Antibody-drug conjugates (ADCs) have demonstrated effectiveness even in cases where the target protein is expressed in minimal quantities. In the realm of HER2-positive breast cancer, the introduction of T-DM1 marked a groundbreaking advancement, and ongoing developments in ADCs aim to enhance treatment options. Notably, ADCs have exhibited promising outcomes in addressing brain metastases and HER2-low breast cancer. Presently, there are 14 FDA-approved ADCs for diverse cancers, each with variations in the target molecule, conjugated drugs, and/or linkers. Adverse events associated with ADCs constitute 10–15% of cases, with prevalent side effects including fatigue, neuropathies, leukopenia, thrombocytopenia, pneumonitis, interstitial lung disease, and nausea.

TKI’s –

Tyrosine kinase inhibitors (TKIs) constitute a group of small molecules that hinder the activity of protein tyrosine kinases, essential for regulating cellular, physiological, and biochemical processes through signal transduction. These inhibitors compete with ATP within the ATP binding domain of tyrosine kinase receptors, thereby impeding downstream signaling. Several TKIs designed to target the HER2 family have received approval for cancer treatment in combination with other therapies. Ongoing research in this field is motivated by the need to address resistance events that compromise their efficacy and off-target toxicity concerns.

Chemotherapy –

Human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer, which accounts for 25–30% of all breast cancers, was once considered an aggressive, dangerous, or even lethal subtype based on the characteristics of its biological behavior.1,2 However, the situation has now changed. With one-year adjuvant trastuzumab therapy combined with standard adjuvant chemotherapy, nearly 70% of early-stage HER2-positive breast cancer patients participating in the HERA clinical trial lived 10 years longer, without invasive disease. Neoadjuvant therapy has recently been greatly revolutionized.5 According to some neoadjuvant clinical trials, adding trastuzumab to conventional chemotherapies can nearly double the pathologic complete response (PCR) rate, up to 30–40%, as compared with monochemotherapies.

Her2 chemotherapy drugs may be used in combination with targeted therapies to further reduce tumor size and prevent metastasis.

Regulatory Framework –

The regulatory landscape for HER2-positive breast cancer is significantly enhanced by Disease Landscape Insights, which leverages data-driven analyses to inform regulatory norms across various countries. This comprehensive approach provides valuable insights guiding risk assessment, regulatory framework development, surveillance strategies, import/export regulations, research oversight, emergency response planning, and cross-border collaboration. By integrating DLI services into the regulatory framework, institutions and stakeholders can proactively prevent, control, and respond to HER2-positive breast cancer outbreaks. This ensures the safety and well-being of affected individuals while fostering a coordinated and effective response within the regulatory framework.

At the 2023 San Antonio Breast Cancer Symposium held from December 5 to 9 in Texas, experts from the FDA provided data and regulatory perspectives on significant advancements in treatments for metastatic breast cancer. The two medications discussed were trastuzumab deruxtecan (T-DXd, Enhertu; jointly developed by Daiichi-Sankyo and AstraZeneca) and elacestrant (Orserdu; developed by the Menarini Group).

Clinical Trials –

Numerous market participants actively engage in clinical trials for breast cancer, investigating novel drug candidates, combinations of therapies, and innovative treatment strategies. DiseaseLandscape Insights as a market research and consultancy firm provides information regarding clinical trials. Our experts also assist in the proper and successful completion of clinical trials. The below table lists the ongoing clinical trials along with the phases being conducted -

Conclusion –

DiseaseLandscape Insight services are essential for businesses, offering a thorough analysis of prevalence, diagnostics, treatments, regulatory updates, and advancements in HER2-positive breast cancer research. This targeted information empowers companies to strategically position themselves, develop precise marketing strategies, and invest in innovative solutions tailored to the unique landscape of HER2-positive breast cancer. By understanding disease patterns and treatment needs, businesses capitalize on growth opportunities, fostering expansion and success in the competitive market for HER2-positive breast cancer treatments.

DLI services act as a catalyst for efficient and successful drug launches leading to fruitful outcomes. DiseaseLandscape Insights Services offers a comprehensive suite of offerings that extend beyond disease prevalence and treatment patterns. This specialized service covers a spectrum of crucial areas, including clinical trials, regulatory insights, and drug discovery, providing businesses with a universal understanding of the healthcare landscape.