Cancer Management: Breast Cancer

What is Breast Cancer?

With an estimated 2.26 million new cancer cases and 685 000 deaths in women, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death in 2020, representing approximately 11.7% of diagnosed cancers and 6.9% of deaths1. Men are susceptible to breast cancer, although at a far lower rate than women 2.

With modern advancements in early detection and treatment options, breast cancer mortality rates have shown improvements over the years. However, it still represents a significant cause of cancer-related deaths, particularly in low- and middle-income countries with limited access to healthcare resources 3.

By 2040, the burden from breast cancer is predicted to increase to over 3 million new cases (an increase of 40%) and 1 million deaths (an increase of 50%) every year because of population growth and ageing alone4.

Breast cancer is usually classified by the following5:

  • The kind of tissue in which cancer starts
  • The extent of the cancer’s spread
  • The type of tumor receptors on the cancer cells
 

Most breast cancers are carcinomas, which are tumors that start in the epithelial cells that line organs and tissues throughout the body.

The most common types of breast cancers are usually a more specific type called adenocarcinoma, which are classified according to the tissue of origin namely:

  • Ductal carcinoma: Cancer that start from the ducts which are small canals that come out from the lobules that carry milk to the nipple (most common, 90% of all breast cancers).
 
  • Lobular carcinoma: Cancers that start from the lobules which are glands that make breast milk.

The type of breast cancer can also refer to whether the cancer has spread or not. There are:

  • In situ breast cancer (Ductal Carcinoma In Situ or DCIS) which is a pre-cancer where abnormal cells have been found in the lining of the breast milk duct and have not spread outside the ducts into the rest of the breast tissue. DCIS is very early cancer that is highly treatable, however if left untreated or undetected, it may spread into the surrounding breast tissue.
 
  • Invasive breast cancer which is used to describe any type of breast cancer that has spread into the surrounding breast tissue. The two most common invasive breast cancers are:
 
  • Invasive ductal carcinoma (IDC) – About 8 in 10 invasive breast cancers are IDC (most common)
  • Invasive lobular carcinoma (ILC) – About 1 in 10 invasive breast cancers is an ILC
 

There are less common invasive breast cancers, and each typically makes up fewer than 5% of all breast cancers.

There are other types of breast cancers that start to grow in other types of cells in the breast. These cancers are much less common, and sometimes need different types of treatment:

  • Paget disease of the breast: Cancers involving the skin of the nipple and the areola. Paget disease usually affects only one breast. In 80-90% of cases, it is usually found along with either ductal carcinoma DCIS or invasive breast cancer
  • Phyllodes tumor: Cancers that start from the connective (stromal) tissue which is the tissue surrounding the ducts and lobules that help keep them in place. Most phyllodes tumors are benign and only a small number are malignant
  • Angiosarcoma: Rare cancers that start in the lining of the blood vessels and lymph vessels that are found in the breast.
 

Some breast cancers are sensitive to body’s naturally occurring female hormones and can be fueled by the natural hormones: estrogen or progesterone. These breast cancer cells have receptors on the outside of their walls that can catch these specific hormones that are circulating through the body. Knowing if the cancer is hormone-sensitive breast cancers can help doctors plan the course of treatment for their patients.

The hormone status of breast cancers is as below:

  • Estrogen receptor (ER) positive – This type of breast cancer cells has receptors that allow them to grow by using the hormone estrogen. Hence, treatment with anti-estrogen hormone (endocrine) therapy can block the growth of the cancer cells. About 80% of all breast cancers are “ER-positive.”
 
  • Progesterone receptor (PR) positive – This type of breast cancer cell has receptors that allow them to grow by using the hormone progesterone. Hence, treatment with anti- progesterone hormone (endocrine) therapy can block the growth of the cancer cells. About 65% of all breast cancers are “PR-positive.”
 
  • Hormone receptor (HR) negative – This type of breast cancer does not have hormone receptors (both ER and PR), hence endocrine treatments aimed at blocking hormones in the body would not be effective.
 

Breast cancer can also be classified as HER2-positive breast cancer. It is when breast cancer cells are making too much of a growth-promoting protein called HER2, which makes up about 20% of breast cancers. These cancers tend to be aggressive and fast-growing. HER2-positive breast cancer is important to identify as there is currently targeted therapies available that could shut down the HER2, hence slowing the growth and killing of these cancer cells.  

When breast cancer lacks hormone receptors and does not overexpress HER2 growth-promoting protein, they are categorized as triple-negative breast cancer (TNBC). This group makes up to between 10-20% of breast cancer; and both endocrine and HER2-targeted therapies would not be effective treatment. The number of treatment options available for TNBC is significantly less than that of other forms of breast cancer due to the lack of known actionable biomarker targets.

 

 

What is Biomarker Testing?

Breast cancer is a diverse disease with different types of breast cancers.  Biomarker testing helps identify which biomarkers (including genetic mutations, which are gene changes) the patient might have in order to determine their breast cancer subtype. This can be a critical part of identifying each patient’s breast cancer, particularly as knowing the subtype has the potential to help the patient and healthcare professional team make informed decisions about the patient’s care. The best mode of treatment will depend on the breast cancer subtype, but can include chemotherapy, radiation, surgery, targeted therapies, or a combined approach.  

In addition, biomarker testing (also known as mutation, genomic, or molecular testing) of tumor tissue allows us to look for abnormalities in the DNA and/or RNA and expression levels of specific proteins. Biomarker testing is critical to learning more about each patient’s tumour type and can be used to help determine treatment options.

By tailoring treatments based on a comprehensive understanding of cancer, we can improve the chances of successful outcomes. 

What type of biomarkers are used to determine the best treatment option for breast cancer patients?

Tumor molecular analysis is recommended by NCCN7 and is often used for the development of breast cancer patient’s treatment plan as it looks for large number of genetic alterations and levels of specific proteins. The result of comprehensive biomarker testing helps determine whether any of the approved treatments is right as part of the patient’s treatment plan. It is the first step in precision medicine, ensuring that a patient gets matched to the right treatment at the right time, based on the patient’s biomarker status. Furthermore, testing results will also provide information about biomarkers that identify patients who are eligible for current clinical trial recruitment.

Actionable biomarkers are defined as genetic alterations that are functional in driving malignancy and may be targeted by an approved treatment (Table 1). They can lead to oncogenic activation through several mechanisms, including point mutations insertions/deletions and rearrangements. These actionable biomarkers help determine whether a targeted therapy might be appropriate.

Genomic signatures such as MSI and TMB can be used to determine whether an immunotherapy drug might be appropriate. 

Expression level of proteins, such as HER2, ER or PD-L1 immunochemistry, in the patient’s tumor helps to determine whether targeted-, hormonal- or immuno- therapy might be appropriate.

 

Table 1: Biomarkers with current FDA or EMA approved treatment for Breast Cancer (As of June 2023)

Genes Biomarkers types Atlerations FDA-approved therapy EMA-approved therapy
BRCA1/2
Loss of function mutation
NA
Olapariba
Talazoparibb
Olapariba
Talazoparibb
PIK3CA
Activating mutation
NA
Alpelisib + Fulvestrantc
Alpelisib + Fulvestrantc
ESR1
Activating mutation
NA
Elacestrantd
None
BRAF
Activating mutation
V600E
Dabrafenib + Trametinibe
None
NTRK
Gene Fusion
None
Larotrectinibe, Entrectinibe
Larotrectinib, Entrectinib
RET
Rearrangement
None
Selpercatinibe
None
MSI
Genomic signature
Unstable
Pembrolizumab
None
TMB
Genomic signature
High
Pembrolizumabe
None
 
  • a Approved only for HER2-negative breast cancer
  • b Approved only for HER2-negative locally advanced or metastatic breast cancer
  • c Approved only for HR-positive, HER2-negative, locally* advanced, or metastatic breast cancer
  • d Approved only for ER-positive, HER2-negative, advanced, or metastatic breast cancer
  • e Under accelerated approval
  • *Only for EMA approval and not for FDA approval

How can OncoDEEP® test help oncologists with breast cancer treatment plan?

Genetic testing allows both clinicians and patients to make an informed decision when it comes to the treatment they receive.

Our OncoDEEP test is designed to detect all the biomarkers as mentioned in Table 1 (and more!). We understand the challenges in detecting large array of biomarkers from low quantity and poor-quality tumor genetic material; hence with a team of experts, we have developed, optimized and validated OncoDEEP test to be able to detect low level of biomarker in difficult to analyse tumor biopsy. Our test is sensitive enough to detect allelic frequency of 5%, and even down to 1% for FDA and EMA-approved biomarkers! Upon detecting any of the biomarkers that are associated with treatment options or recruiting clinical trials, a report will be generated to help oncologists work out the most suitable cancer treatment plan for their patients.  

  1. World Health Organization. Globocan 2020 Fact Sheet. Available at: https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf. Accessed June 2023. 
  2. Gucalp A, et al. Male breast cancer: a disease distinct from female breast cancer. Breast Cancer Res Treat. 2019;173(1):37-48.
  3. Wilkinson L, et al. Understanding breast cancer as a global health concern. Br J Radiol. 2022 Feb 1;95(1130):20211033.
  4. Arnold M, et al. Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast. 2022 Dec; 66:15-23
  5. Kohler BA, et al. Annual Report to the Nation on the Status of Cancer, 1975-2011, Featuring Incidence of Breast Cancer Subtypes by Race/Ethnicity, Poverty, and State. J Natl Cancer Inst. 2015 Mar 30;107(6)
  6. https://www.cancer.org/cancer/types/breast-cancer/about/types-of-breast-cancer.html
  7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Breast Cancer Version 4.2023 — March 23, 2023

 

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Scientific Application Note

Biliary Tract Cancer Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in Patients With Advanced Biliary Tract Cancers. Subgroup Analysis of a Phase 2 Nonrandomized Clinical Trial

Oliver Klein, MD1,2; Damien Kee, MD1,3; Adnan Nagrial, MD4; etalBen Markman, MD5,6; Craig Underhill, MD7; Michael Michael, MD3; Louise Jackett, MD8; Caroline Lum, MD5; Andreas Behren, PhD2,9; Jodie Palmer, PhD2,9; Niall C. Tebbutt, MD1,10; Matteo S. Carlino, PhD4; Jonathan Cebon, PhD1,2,9 Author Affiliations JAMA Oncol. Published online July 30, 2020. doi:10.1001/jamaoncol.2020.2814 Key Points Question:  Is combination immunotherapy with nivolumab and ipilimumab associated with positive outcomes in patients with advanced biliary tract cancers?...

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