Young Onset Breast Cancer by Professor Zoe Winters. Part 1

Part 1, describes causes and risk factors on young onset breast cancer.

Young onset breast cancer is uncommon with 20 % of all breast cancers occurring under 50 years of age. Young age is defined as less than and equal to 45 years, but also includes women under 50 years of age. In the USA, 10-11% of women are diagnosed under 45 years of age, which is comparable to the UK. The greatest risks relate to women diagnosed under 40 years. More African American women are diagnosed before 50 years of age compared to Caucasian women. YOBC comprises only 6-10 % of all breast cancers in the developed world, compared to 20% in developing countries such as: East Asia, Middle East, North Africa and South America. Death rates vary from 7% in developed countries, to 14 % in developing countries. 

Young onset breast cancer in women is associated with special survivorship issues: fertility, contraception, early treatment induced menopause and pregnancy.

Women with young onset breast cancer are usually diagnosed with a clinical lump, and have more advanced clinical stages at diagnosis. The types of breast cancer are also more aggressive: such as triple negative (22%) and HER-2 positive (9%). These characteristics are assessed by taking a tissue biopsy of the cancer under image guidance (usually ultrasound). The tissue is analysed by the pathologist under the microscope to assess the type of breast cancer, histological grade or the appearance of the cells, the oestrogen receptor (ER), progesterone receptor (PR) and the HER-2 protein, plus cellular proliferation or ki67. These types of cancer (triple negative and HER-2 positive) present typically in women under 40 years of age. Generally, young onset cancers present with the following features: High histological grade (HG), which means they look more aggressive under the microscope, and they have a higher percentage of growing or dividing breast cancer cells measured as a snap-shot in time called a proliferation index (ki67). They harbour higher levels of the protein or oncogene called HER-2 or Epidermal Growth Factor-2 called HER-2 positive (HER-2 turns on the growth of cancer cells and is treated using drugs that block and turn off the HER-2 gene). Young onset cancers are also more likely to comprise triple negative cancers (TN), are oestrogen receptor (ER) negative (ER 0-3/8), progesterone receptor negative (PR) and HER2 negative on tissue staining under the microscope). The basal types of breast cancer express specific markers within the triple negative (TN) group: Epidermal growth factor receptor and markers called cytokeratins within the milk duct wall. This group is strongly associated with the BRCA 1 gene mutation. 

A large UK study called POSH in over 2000 women under 40 years of age; who were tested for, and shown to carry the BRCA gene, did better clinically in the short term up to 5 years, compared to the non-BRCA carriers. This may relate to being able to combine drugs that target the BRCA gene defect and enhance cancer cell killing (called PARP2 inhibitors), when combined with chemotherapy. The PARP2 drugs target and sensitize the cancer cells to be optimally killed by chemotherapy drugs, as they further reduce the ability of cancer cells to repair their DNA damage caused by chemotherapy. This pathway is already defective in BRCA gene mutated breast cancers. Beyond 5 years, the clinical outcomes were the same in women with or without a BRCA gene mutation over 8 years.

Of concern, are the increasing numbers of young women with luminal A types of breast cancer, which means that they grow under strong hormonal influence with strongly positive expressions of the oestrogen (ER), and the progesterone receptors (PR). The ER positive cancers are more likely in the BRCA 2 gene carriers in young women. The mechanisms underlying the development of these cancers is generally poorly understood with 90% showing no individual gene mutation, like BRCA1/2. Luminal B types are typically positive for the ER, but either positive or negative for the PR, and either positive or negative for the HER2 oncogene. These are more aggressive than the Luminal A types with higher cell proliferation and growth (ki67). Up to 20% of the Luminal B cancers are associated with HER2 positivity, which is responsible for these cancers being more aggressive. However, current new dual blocking drugs can turn off the HER2 growth pathway, and optimally kill cancer cells with excellent clinical outcomes.

What are the biological causes?

Germline or single gene changes (faulty gene in either the sperm or egg, that is transmitted to children) gene testing:

Mutations of genes can relate to specific inherited single genes that are passed on at the time of conception, either from one’s mother, father or both parents. Germline changes refer to the DNA you have in every cell you are born with.

This is called a hereditary germline gene pathway and is responsible for 10-20 % of young onset breast cancer. Clinical guidelines recommend genetic assessment for all patients with first-and second-degree relatives diagnosed with breast cancer younger than 50 years. 

High penetration genes (the penetrance of a disease-causing mutation is the proportion of individuals with the mutation that exhibit clinical symptoms among all individuals with such a mutation). Examples of these genes are: BRCA1, BRCA2 that are involved in repairing damaged DNA or genetic material. Only 10% of young onset breast cancer are shown to carry a BRCA1/2 mutation. In the UK POSH study, 12 % of women under 40 years of age were shown to carry a BRCA gene mutation. That said, BRCA 1 and 2 account for 50% of gene mutations in early onset breast cancer (they are referred to as the DNA repair genes). In addition, tumour suppressor genes that stop cancers from developing are: TP53, PTEN, STK11, and CDH1. These genes are responsible for 20% of hereditary risks. Ashkenazi Jews have a 10-fold increased risk of carrying a BRCA 1 or 2 mutation, and should undergo routine testing.

Moderate penetration genes are responsible for 5% of hereditary risks such as:

PALB2, BRIP1, ATM, CHEK2, RAD51C.

The above is responsible for only half of genetic risks, with the other half currently unknown. 

Therefore, it is recommended that the following 12 genes are tested in young onset breast cancers.

High-Penetrance Genes

• BRCA1 and BRCA2: Found in 28.1% and 4.1% of very young patients (≤30 years), respectively. These genes confer high lifetime risks of breast, ovarian, and other cancers. Updated guidelines recommend testing all breast cancer patients ≤65 years.
• TP53: Second most prevalent gene (4.5%) in patients ≤30 years, even without family history (74.8% of carriers lacked familial cancer history). Associated with Li-Fraumeni syndrome, warranting early inclusion in testing panels for this population.

Additional High- and Moderate-Penetrance Genes

Testing should extend to:

• CHEK2, ATM, PALB2: Moderate-risk genes linked to increased breast cancer risk.
• PTEN, CDH1, STK11: High-penetrance genes for syndromes like Cowden (PTEN) and hereditary diffuse gastric cancer (CDH1).
• RAD51C, RAD51D, BARD1: Implicated in homologous recombination repair defects

Therefore, a blood or oral buccal mucosa (inner cheek scrape) test for assessing germline genes should be repeated every 6-8 years based on the American Society of Clinical Oncology (ASCO) guidelines. 

Currently, the NHS only tests 5 genes: BRCA1/2; PALB2; ATM and CHECK2, and potentially RAD51C and D where there is a history of ovarian cancer. 

Somatic mutations (faulty gene in the bodies normally functioning genes; these faults occur after conception and are not transmitted to one’s children): 

Somatic mutations are seen in cancer cells and cannot be inherited unless they are related to your germline. 80% of young onset breast cancer occur in-non carriers of a germline gene mutation.

Whole genome (DNA, specific gene code) or exome (the gene codes for and produces a message to produce a functioning protein) sequencing means reading abnormalities in the gene or the protein that detects abnormal gene and protein expressions that predisposes a cancer cell to develop. The earliest form of breast cancer develops from a normal breast duct epithelial cell: cells that line the wall of a microscopic breast milk duct, and is called ductal cancer in situ or DCIS. This mechanism for DCIS development involves deregulation of multiple gene and protein pathways that result in a cancer developing and growing, such as DCIS. 

The Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database showed high mutations in the CDH1 gene, that is responsible for encoding a key protein called E-Cadherin, that allows cells to adhere/stick to each other, and to the surrounding tissue called the extra-cellular matrix (tissue that surrounds the microscopic breast ducts). Cell to cell adhesion is reduced when a cancer develops. When these pathways are abnormal, E-cadherin levels go down, and cancer cells spread/detach or metastasize, leading to a poor prognosis. An e.g., of a particular type of cancer that results from this CDH1 gene mutation is the invasive lobular cancer or ILC, that spreads in a single microscopic file along the breast milk ducts. This is referred to by your surgeon as a ‘single file pattern’.

Other important genes:

GATA3 is important in developing the breast gland tissue, and in maturing the immune cells, called T cells. T cells are part of the immune system and develop from stem/originator cells in the bone marrow. They help protect the body from infection and may help fight cancer. They are also called T lymphocytes. Cancers that are defective in GATA3 have poorer outcomes, with shorter overall survival.

CTNNB1 is a gene that encodes Beta-catenin that also controls cell to cell adhesion (how cells stick together). If these genes don’t function and the levels of catenin drop, then cancer cells spread and don’t respond to anti-oestrogen hormone blockers like tamoxifen or letrozole.

TP53 (cancer suppressor gene that detects DNA/cell damage) and PIK3CA (growth factor pathway on the cancer cell surface) mutations are seen in up to 40% of cancers.     

Family history of Young Onset Breast Cancer:

Clinical guidelines recommend genetic testing for all women with first- and second-degree relatives with young onset breast cancer, occurring younger than 50 years of age.

A risk prediction tool called CanRisk is advised to estimate the predicted risk of a patient carrying a disease producing gene for either breast and/or ovarian cancer. If this estimate is 10%, a referral should be made for genetic testing. There is no consensus to support the recommendation of one risk prediction model only. Most tools predict 5- and 10-year risks of developing breast cancer, but not how young this will occur. 

This is called testing for a possible inheritable germline gene inheritance. A germline gene refers to a gene present in reproductive cells (sperm or eggs) that can be passed down to offspring, meaning any changes or mutations in these genes can be inherited by future generations. Living relatives with index cancers should be tested first using an appropriately large/extended gene panel to reflect their cancer and other cancer types that may link to breast in family members. Each sibling in a high-risk family should be tested as the potential risk of inheritance is 50/50. This approach to initial blood testing should always be discussed with a recognised genetic counsellor within a recognised genetics centre of excellence.

Presently, studies provide evidence to support the risk-reducing benefit of offering risk-reducing surgery (breasts and/or ovaries) in all patients shown to have mutations in: BRCA1, BRCA2, PTEN, and P53. Regarding all other gene mutations, the patient’s individual risks should be considered by using an evidence-based algorithm called CanRisk (https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/canrisk/). It is important to refer each patient for a consultation with a geneticist. It is important to select the appropriate and most extended gene panel (which means increasing the number of genes tested). Each patient needs to understand the numbers of genes that have been tested and that the results may need to be reassessed 6 yearly, as the scientists discover new genes. 

Single nucleotide polymorphisms (SNPs) and polygenic risk scores (PRS) explained:

The body’s genetic code is contained within one’s DNA that comprises a helix or twisted ladder containing multiple rungs comprising sugar base pairs represented by pairing sugars. When there is a single base or sugar letter change in a rung of the ladder, this is called a single nucleotide polymorphism (SNP), that on its own can cause a very small increased risk of developing a disease. However, when multiple SNPs and their individual risks are combined, there is an increased cancer polygenic risk score (PRS) risk for breast cancer. Therefore, the genetic team needs to test for a single germline gene and polygenic risk scores (PGRS).

The breast cancer risk prediction tool that uses polygenic risk scores (PRS) is BOADICEA, which is accessible through the CanRisk webtool. Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) incorporates PRS alongside other genetic and non-genetic factors, such as family history, mammographic density, and lifestyle factors, to provide comprehensive risk assessments for breast and ovarian cancer.

BOADICEA’s inclusion of PRS enhances its predictive accuracy and ability to stratify individuals into different risk categories for personalized prevention and screening strategies.

Risk Assessment tools: 

Current recommendations are to identify women at risk of familial cancer syndromes based on a detailed family history. Validated tools were developed to assess the risks of carrying a BRCA 1 or 2 mutation, such as BOADICEA/CanRisk or IBIS. Guidelines for genetic testing recommend testing no earlier than 18 years of age. 

The CanRisk breast cancer prediction tool includes BOADICEA. BOADICEA stands for Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, which serves as the foundational model for CanRisk. It integrates genetic factors, family history, lifestyle, hormonal/reproductive factors, polygenic risk scores, and mammographic density to estimate breast and ovarian cancer risks.

Validated models are used to assess estimated cancer risks at 5 and 10 years, including lifetime risk of breast cancer, such as the Breast Cancer Surveillance Consortium (BCSC). 

These are not necessarily specific to assess the risk of early onset or premenopausal breast cancer. The choice of tool depends on individual patient characteristics and clinical needs.

1. BOADICEA/CanRisk (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm)

• Incorporates genetic factors (e.g., BRCA mutations), family history, and polygenic risk scores (PRS).
• Available through the CanRisk webtool, it is highly accurate for both breast and ovarian cancer risk estimation.

2. IBIS (Tyrer-Cuzick Model, women older than 20 years) 

• Combines genetic information, family history, lifestyle factors, and hormonal data.
• Recently updated to include PRS for enhanced predictive accuracy.

3. Breast Cancer Surveillance Consortium (BCSC) Risk Calculator (women older than 35 years)

• Includes mammographic density alongside personal and family health history to estimate risk.
• Particularly useful for integrating radiographic factors into risk prediction.

Table 1: Risk factors included in CanRisk estimates

If a woman’s estimated lifetime risk of developing breast cancer is 20% or more, one is regarded as high risk. This merits early breast screening from 30 years of age. The USA National Comprehensive Cancer Network recommends starting yearly mammograms at 30 years, and yearly breast MRI at 25 years.

Other predisposing risk factors:

Dense breasts: The fibro glandular breast duct tissue appears white or brighter on the mammogram compared to darker fatty tissue. Dense breasts are present in the majority of younger women under 46 years of age. This is a subjective assessment about how much fibro glandular tissue there is. The highest density raises the risk of breast cancer 4-6-fold. However, most of this data comes from women older than 50 years of age.

High density on mammograms lowers their sensitivity (reduced ability to detect a cancer) to 62%, from 88%. This can result in more interval cancers, that means a cancer develops in between recommended screening intervals, after reporting a normal mammogram. Interval cancers are increased 2-fold in dense breasts and have a worse prognosis, based on their larger size, and higher lymph node positivity. 

Decisions recommending additional screening using ultrasound, should consider additional risk factors, and are indicated, where individual risk is above average.

Proliferative Breast disease: We list benign breast changes that have either increased risk of being associated with DCIS (Ductal Cancer in Situ), which means microscopic breast cancer cells that are contained within microscopic breast ducts, or predict increased risks of invasive breast cancer developing. 

1. 1. Atypical ductal hyperplasia (ADH): carries a 20% risk of associated DCIS or invasive cancer. This lesion requires diagnostic excision
   2. Radial scar: carries at 8-15% risk of associated DCIS or invasive cancer. This lesion requires diagnostic excision 
   3. Atypical lobular hyperplasia (ALH) or ADH: carries a 4-fold increased lifetime risk of breast cancer 

• Lobular carcinoma in situ (LCIS): increases the lifetime risk of breast cancer over 10 years to 7%

1. Pleomorphic LCIS: further increases the lifetime risk of breast cancer, and is an aggressive form of LCIS. It requires surgical excision

These lesions predict higher breast cancer risks and should be discussed with a Consultant Breast Specialist. Although data is lacking, increased breast screening is advised.

1. Yearly mammograms and tomosynthesis 
2. Yearly breast MRIs
3. Clinical examination yearly 

Hormonal contraception:

Current oral contraceptive use poses small increased risks of breast cancer (1 extra cancer per 7700 women). The oral contraceptive pill significantly reduces risks of uterine and ovarian cancer. There are no specific breast screening guidelines in this context.  Intrauterine or injectable progesterone poses no increased risks.

Fertility Treatments:

There is no conclusive evidence that fertility drugs are associated with increased risks of breast cancer. The American Society of Reproductive Medicine states that there is “fair evidence that fertility drugs are not associated with increased risk of breast cancer”. Therefore, routine breast screening is recommended in the absence of other risk factors.

History of radiation exposure:

Radiation treatment to the chest wall before 30 years of age is a high-risk factor for EOBC. These treatments may comprise “mantle radiotherapy” for Hodgkin’s lymphoma, with the greatest risks in women treated with 40 Gy or more. However, lower or moderate dose chest radiation of greater than 20 Gy also increases risks. The risks are equivalent to having a BRCA 1 or 2 mutation, comprising a 13-20% risk of EOBC by 40-45 years. These women should be offered high risk breast screening.

Prior Breast or Ovarian cancer: 

Among young onset breast cancer survivors, the risks of a second early onset breast cancer are unknown, unless there is a high-risk gene mutation, like BRCA 1 or 2. There is no data for the risk of early onset breast cancer in women with early onset ovarian cancer. Yearly mammograms are recommended at 6-12 months after completion of treatment.

Other links to related blogs by Professor Zoe Winters.

1. Personalised genetic testing in breast cancer patients and what it means.
2. Breast density 
3. Breast feeding 

References:

1. Chelmow D et al. Executive summary of early onset breast cancer evidence review committee. Obstetrics and Gynaecology 2020, 135 (6): 1457-78.
2. Gao Y et al. Non-BRCA early onset breast cancer in young women. Radiographics 2022; 42: 5-22
3. Copson ER et al. Germline BRCA mutation in young onset breast cancer (POSH): a prospective cohort study. Lancet Oncology 2018;19:169-80.

London Genetic Centre: https://www.thelondongeneticscentre.com/