Breast and ovarian cancer

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Breast and ovarian cancer
Adenocarcinoma of the breast metastatic to the ovary - low mag.jpg
Metastasis of breast cancer to ovary.
Specialty Oncology
MeSH D001943

Breast and ovarian cancer does not necessarily imply that both cancers occur at the same time, but rather that getting one cancer would lead to the development of the other within a few years. Women with a history of breast cancer have a higher chance of developing ovarian cancer, [1] vice versa.

Contents

Breast cancer refers to the uncontrolled division of breast cells. It is possible for both males and females to get breast cancer. Breast cancer is the most common cancer women face.

Ovarian cancer is a type of cancer which begins in the ovaries. Anyone with ovaries can get it, including women, trans men, non-binary people and intersex people. [2] Although ovarian cancer is much less frequent, it is the deadliest among gynecologic cancers. [3]

Early signs of possible breast cancer Early signs of breast cancer hariadhi svg.svg
Early signs of possible breast cancer

Symptoms

Breast cancer

People can experience different symptoms for breast cancer while others may be asymptomatic.

Common symptoms include: [4] [5]

Ovarian cancer

There may be no clear signs or symptoms at the early stages of ovarian cancer, especially in benign conditions. Symptoms are more likely to emerge after metastasis, a process where cancer cells spread from the site of origin to different organs through blood and lymphatic vessels and form a new tumor.

Ovarian cancer tumours in both ovaries Bilateral ovarian serous carcinomas, gross pathology.jpg
Ovarian cancer tumours in both ovaries

Common symptoms include: [6] [7]

Risk Factor

Hereditary breast and ovarian cancer (HBOC)

HBOC is an inherited cancer syndrome which produces more breast cancer and ovarian cancer in genetically related families. Mutations in BReast CAncer 1 (BRCA1) and BReast CAncer 2 (BRCA2) are significantly related. The lifetime risk of a female developing breast and/or ovarian cancer increases if she inherits a harmful mutation of BRCA1 or BRCA2, but the severity depends on the type of mutation. [8] Each year, about 3% of breast cancers and 10% of ovarian cancers result from inherited mutations in the BRCA1 and BRCA2 genes. [9]

Lifetime risk of having breast or ovarian cancer with and without BRCA1 and BRCA2 mutations. BRCA1 and BRCA2 mutations and absolute cancer risk (Updated-2023).jpg
Lifetime risk of having breast or ovarian cancer with and without BRCA1 and BRCA2 mutations.
BOC reoccurring commonly in a family. PedigreechartC.png
BOC reoccurring commonly in a family.

However, most BOC are non-inherited, so most women who have BOC do not have HBOC. It is estimated that less than 1% of the general population has a mutation in the BRCA1 or BRCA2 genes. Mutations in other tumor suppressor genes like TP53, PTEN, CDH1, ATM, CHEK2 and PALB2, and oncogenes like KRAS, BRAF and ERBB2 have also been linked with an increased risk of HBOC. [14] [15]

HBOC is considered when multiple cases of breast cancer, ovarian cancer, prostate cancer, and/or pancreatic cancer occur in the same family. In families with 4 or more cases of breast cancer diagnosed before age 60, the chance of having HBOC is about 80%. The risk would be even higher for women who have close blood relatives with breast cancer. Women with a first-degree female relative(FDR) who has been diagnosed with breast cancer would have a risk that is two times higher than the general population, particularly if the FDR was diagnosed early in life. They also show 32% higher risk when they have five or more third-degree relatives. A similar trend is seen in ovarian cancer, where women with FDRs diagnosed with ovarian cancer shows a risk three times higher than the general population. [16] [17]

Families of Ashkenazi Jewish ancestry backgrounds have an increased risk of HBOC. Mutations in BRCA1 and BRCA2 are 10 times more common in Ashkenazi Jewish individuals. [18] 2.5% of individuals of Ashkenazi Jewish ancestry have such mutations. [14]

Genetic testing is available for testing mutations in BRCA1 and BRCA2. Methods include sequence analysis and gene-targeted deletion/duplication analysis. [10] However, most BOC occur by chance without a known cause, so genetic testing is only recommended for people with family history suggesting HBOC. [14]

History of breast or ovarian cancer

Prior diagnosis of breast cancer is associated with a higher risk of ovarian cancer, particularly in women who are diagnosed at a young age and in those with estrogen receptor-negative breast cancer. [19]

Similarly, women with ovarian cancer have an increased risk of developing breast cancer. [19]

Old age

People encounter more environmental exposures and accumulate genetic mutations as they age. Therefore, most breast cancers are found in women aged 50 or older. Similarly, the risk of ovarian cancer is the greatest in female populations aged 75–79. [20]

HRT's effect on cancer risk Hormone replacement therapy (HRT) and cancer risk in the UK.svg
HRT's effect on cancer risk

Use of hormone replacement therapy

Hormone replacement therapy (HRT) includes both estrogen and progesterone. They are used for treating menopausal symptoms.

A woman exposed to estrogen either endogenously or exogenously for a long period of time has an increased risk of developing BOC. [21] Studies suggest that using HRT in postmenopausal women for more than five years increases the risk of breast cancer. [10] [15] It also increases the risk of ovarian cancer. 4% of ovarian cancers are linked to HRT use. [22]

Women with family histories of breast cancer show a higher risk of breast cancer when using HRT. [15] [23] Progestin-containing hormonal treatments after a bilateral risk-reducing oophorectomy may increase risk of breast cancer in BRCA mutation carriers. [24] [25]

Contraceptives

The use of oral contraceptives (OCs) by women with BRCA2 mutations shows 75% increased breast cancer risk, especially in long-term users. [16] [26]

Levonorgestrel-releasing intrauterine system (LNG-IUS) increases breast cancer risk in all women. [27]

Being overweight or obese

Women have a higher risk of getting breast cancer if they are not physically active. Being overweight or obese, especially after menopause, increase the risk of getting many types of cancer, including breast cancer and ovarian cancer. [18] [20]

Not having children or having children at a later age

Women who never have a full-term pregnancy, or have one after 30 years old, or did not breastfeed, are at a higher risk of BOC. [11] [20]

Mechanisms

HBOC

BRCA1 and BRCA2 mutations can increase the risk of developing HBOC. They are expressed in the epithelial cells of breast and ovarian tissues. They are involved in DNA repair, cell cycle checkpoints and DNA damage signalling pathways. Inherited mutations inactivate them. Such mutations include complete or partial gene deletions, large insertions, duplications, splicing, frameshifts, missense and nonsense mutations. This leads to abnormal gene structure and function. [21]

BRCA1 and BRCA2 are important DNA repair genes and tumor suppressor genes. They help repair double-strand breaks in DNA. If any mutations or damage occurs in BRCA1/BRCA2, DNA damage cannot be repaired properly. Chromosomal abnormalities, breaks, aneuploidy and centrosome amplification occurs. This increases the risk of developing HBOC. [21]

Besides, BRCA1 and BRCA2 are involved in the decision of cell fate. DNA replication introduces a lot of errors and mutations, resulting in DNA damage. Usually, if DNA damage is too excessive and cannot be repaired efficiently, the cell will be directed to be destroyed. But when BRCA1 and BRCA2 lose their functions, breast and ovarian cells with DNA damage are not destroyed. This causes genome instability and triggers cancer. [21] [28]

Hormones

Both breast cancer and ovarian cancer are hormone-dependent cancers, meaning they cannot grow without the presence of hormones. [29] These hormones include estrogen, progesterone and growth hormone. They promote the growth of cells through special hormone receptors, thus initiating cancer when the rate of cell growth is out of control. [21] They also promote metastasis. [29]

Estrogen

Estrogen causes BOC progression.

Estrogen receptors(ER) are nuclear receptors found in the epithelium of the breast, ovaries and uterine tissues. They can be classified as ER alpha (α) and beta (β). [29] When estrogen binds to ERs in the cytoplasm, these receptors are activated and translocate into the nucleus to activate transcriptional responses. They dimerize in the nucleus and bind to the specific DNA sequences to induce gene expression. [30] This triggers cell division. Increased levels of estrogen promote the probability of having errors in DNA replication when cells divide more frequently. [21] Unrepaired DNA damage may cause cancer. More estrogen also enhances epithelial-mesenchymal transition in which cells lose polarity and cell adhesion, inducing metastasis. [29]

Progesterone

Progesterone promotes cancer progression and metastasis in breast cancer but inhibits the growth of ovarian cancer cells. [29] [31]

There are 2 types of progesterone receptors (PR): A (PRA) and B (PRB). They are found in the epithelium of breast and ovary tissues and are responsible for their normal development (PRA for ovarian; PRB for breast). [29] When progesterone binds to PR, there is a conformational change of the receptors, which results in the dimerization of two receptors. The dimerized receptors bind to specific DNA sequences, activating or inhibiting the transcription of target cancer-related genes. [30]

Growth hormone

Growth hormone is responsible for the development, progression, and metastasis of breast cancer.

Alteration of growth hormone signalling results in dysregulation of normal cell activities, thus leading to cancer. Breast cancers express growth hormone and growth hormone receptors. Breast cancers that have undergone metastasis express the highest levels of growth hormone. [32]

Treatment

Both cancers are treated depending on the stage and type of cancer, as well as age and health of patients. There are two major types of treatments: local or systemic. Local treatments, such as surgery and radiation therapy, treat the tumor without affecting other parts of the body. Systemic treatments rely on drug use to reach cancer cells in any body parts. It is given orally or via injections into the bloodstream. [33]

Mastectomy surgery removing the entire breast tissue Paget-Karzinom 05.jpg
Mastectomy surgery removing the entire breast tissue

Breast cancer

For breast cancer, more than one kind of treatment is involved typically, which can include both local and systemic treatments. Most women with breast cancer from stage I to III are treated with surgery, often followed by radiation to lower the chances of cancer recurrence. Two main types of surgery are lumpectomy (breast-conserving surgery) and mastectomy (removing the entire breast tissue). For cancer cells that exhibit large amounts of HER-2 protein, doctors might apply targeted drug therapy, such as using Trastuzumab, as a systemic treatment. [34]

Ovarian cancer

Ovarian cancer is typically treated with a combination of surgery and chemotherapy. In surgery, hysterectomy and bilateral salpingo-oophorectomy are often involved, where the uterus, both fallopian tubes and both ovaries are removed. Chemotherapy would be recommended when cancer reaches stage IC or above. [35]

Prevention

Breast examination procedures How to examine your breasts, extracted from Mammograms and breast cancer (1998).jpg
Breast examination procedures

Screening

A combination of regular clinical breast examination, regular mammograms and magnetic resonance imaging (MRI) can help detect early development of breast cancer. As for ovarian cancer, CA-125 blood tests can be carried out to monitor the antigen level in the body. Transvaginal ultrasound or clinical examinations beginning from age 35 are suggested for ovarian cancer prevention. [8]

Risk-reducing surgery

In females with BRCA1 or BRCA2 mutation, preventive mastectomy could reduce the risk of breast cancer by 90%. Prophylactic salpingo-oophorectomy could lower the risk of ovarian cancer by 85 to 90% and the risk of breast cancer by 40 to 70%. Ovary removal may also reduce the risk of breast cancer in premenopausal women by eliminating a source of hormones which can fuel the growth of some types of breast cancer. [1]

Chemoprevention

Chemoprevention refers to the use of medicines to reduce the risk of cancer. Chemopreventive drugs such as tamoxifen and raloxifene have been approved by the U.S. Food and Drug Administration (FDA). Tamoxifen may be able to reduce the risk of breast cancer in women with BRCA2 mutations [36] and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. [8]

Other protective factors

Having children or breastfeeding may also reduce the risk of developing ovarian cancer. This is likely because ovulation is stopped during pregnancy. The fewer times a woman ovulates in her lifetime, the lower her chance of getting ovarian cancer. [22]

Incidence rate and mortality

The incidence rate and mortality of BOC from a 2020 study. Findings on diagnosed age, incidence rate, intervals between two cancers, overall survival rates and mortality are summarised in Table 1: [37]

Table 1: Patients with breast/ovarian cancer who developed BOC
BOC patients who have ovarian cancer firstBOC patients who have breast cancer first
Median age at the first cancer diagnosis51.5 years old47.5 years old
Median age at the other cancer diagnosis56.5 years old56 years old
Patients diagnosed with the other cancer within 5 years65.6%41.5%
Patients diagnosed with the other cancer 10 years later34.4%35.4%
Average interval between two cancers79.4 months115.9 months
Median interval between two cancers37.5 months84 months
Range of intervals between two cancers0 – 336 months5 – 480 months
5-year overall survival rates 90.6%91.5%
10-year overall survival rates87.5%81.7%
MortalityDue to ovarian cancer: 30.7%

Due to breast cancer: 2.6%

See also

Related Research Articles

<span class="mw-page-title-main">Ovary</span> Female reproductive organ that produces egg cells

The ovary is a gonad in the female reproductive system that produces ova. When an ovum is released, this travels through the fallopian tube/oviduct into the uterus. There is an ovary found on the left and the right side of the body. The ovaries also secrete hormones that play a role in the menstrual cycle and fertility. The ovary progresses through many stages beginning in the prenatal period through menopause. It is also an endocrine gland because of the various hormones that it secretes.

<span class="mw-page-title-main">Breast cancer</span> Cancer that originates in mammary glands

Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a red or scaly patch of skin. In those with distant spread of the disease, there may be bone pain, swollen lymph nodes, shortness of breath, or yellow skin.

<span class="mw-page-title-main">Penetrance</span> Proportion of individuals that express the trait associated with an allele

Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation that exhibit clinical symptoms among all individuals with such mutation. For example: If a mutation in the gene responsible for a particular autosomal dominant disorder has 95% penetrance, then 95% of those with the mutation will go on to develop the disease, showing its phenotype, whereas 5% will not. 

Oophorectomy, historically also called ovariotomy, is the surgical removal of an ovary or ovaries. The surgery is also called ovariectomy, but this term is mostly used in reference to non-human animals, e.g. the surgical removal of ovaries from laboratory animals. Removal of the ovaries of females is the biological equivalent of castration of males; the term castration is only occasionally used in the medical literature to refer to oophorectomy of women. In veterinary medicine, the removal of ovaries and uterus is called ovariohysterectomy (spaying) and is a form of sterilization.

<span class="mw-page-title-main">BRCA1</span> Gene known for its role in breast cancer

Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the BRCA1 gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. BRCA1 is a human tumor suppressor gene and is responsible for repairing DNA.

<span class="mw-page-title-main">Endometrial cancer</span> Uterine cancer that is located in tissues lining the uterus

Endometrial cancer is a cancer that arises from the endometrium. It is the result of the abnormal growth of cells that have the ability to invade or spread to other parts of the body. The first sign is most often vaginal bleeding not associated with a menstrual period. Other symptoms include pain with urination, pain during sexual intercourse, or pelvic pain. Endometrial cancer occurs most commonly after menopause.

<span class="mw-page-title-main">Ovarian cancer</span> Cancer originating in or on the ovary

Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different cell types including epithelial cells, germ cells, and stromal cells. When these cells become abnormal, they have the ability to divide and form tumors. These cells can also invade or spread to other parts of the body. When this process begins, there may be no or only vague symptoms. Symptoms become more noticeable as the cancer progresses. These symptoms may include bloating, vaginal bleeding, pelvic pain, abdominal swelling, constipation, and loss of appetite, among others. Common areas to which the cancer may spread include the lining of the abdomen, lymph nodes, lungs, and liver.

<span class="mw-page-title-main">BRCA2</span> Gene known for its role in breast cancer

BRCA2 and BRCA2 are human genes and their protein products, respectively. The official symbol and the official name are maintained by the HUGO Gene Nomenclature Committee. One alternative symbol, FANCD1, recognizes its association with the FANC protein complex. Orthologs, styled Brca2 and Brca2, are common in other vertebrate species. BRCA2 is a human tumor suppressor gene, found in all humans; its protein, also called by the synonym breast cancer type 2 susceptibility protein, is responsible for repairing DNA.

<span class="mw-page-title-main">Hypothalamic–pituitary–gonadal axis</span> Concept of regarding the hypothalamus, pituitary gland and gonadal glands as a single entity

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

Primary ovarian insufficiency (POI), also called premature ovarian insufficiency, premature menopause, and premature ovarian failure, is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of follicular dysfunction or early loss of eggs. POI can be seen as part of a continuum of changes leading to menopause that differ from age-appropriate menopause in the age of onset, degree of symptoms, and sporadic return to normal ovarian function. POI affects approximately 1 in 10,000 women under age 20, 1 in 1,000 women under age 30, and 1 in 100 of those under age 40. A medical triad for the diagnosis is amenorrhea, hypergonadotropism, and hypoestrogenism.

<span class="mw-page-title-main">Hereditary breast–ovarian cancer syndrome</span> Medical condition

Hereditary breast–ovarian cancer syndromes (HBOC) are cancer syndromes that produce higher than normal levels of breast cancer, ovarian cancer and additional cancers in genetically related families. It accounts for 90% of the hereditary cancers. The hereditary factors may be proven or suspected to cause the pattern of breast and ovarian cancer occurrences in the family. The name HBOC may be misleading because it implies that this genetic susceptibility to cancer is mainly in women. In reality, both sexes have the same rates of gene mutations and HBOC can predispose to other cancers including prostate cancer and pancreatic cancer. For this reason, the term "King syndrome" has recently come into use. The new name references Mary-Claire King who identified the genes BRCA1 and BRCA2.

Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification. Triple-negative is sometimes used as a surrogate term for basal-like.

Risk factors for breast cancer may be divided into preventable and non-preventable. Their study belongs in the field of epidemiology. Breast cancer, like other forms of cancer, can result from multiple environmental and hereditary risk factors. The term environmental, as used by cancer researchers, means any risk factor that is not genetically inherited.

Antihormone therapy is a type of hormone therapy that suppresses selected hormones or their effects, in contrast with hormone replacement therapy, which encourages hormone activity.

TOX high mobility group box family member 3, also known as TOX3, is a human gene.

<span class="mw-page-title-main">Male breast cancer</span> Medical condition

Male breast cancer (MBC) is a cancer in males that originates in their breasts. Males account for less than 1% of new breast cancers with about 20,000 new cases being diagnosed worldwide every year. Its incidence rates in males vs. females are, respectively, 0.4 and 66.7 per 100,000 person-years. The worldwide incidences of male as well as female breast cancers have been increasing over the last few decades. Currently, one of every 800 men are estimated to develop this cancer during their lifetimes.

<i>BRCA</i> mutation Medical condition

A BRCA mutation is a mutation in either of the BRCA1 and BRCA2 genes, which are tumour suppressor genes. Hundreds of different types of mutations in these genes have been identified, some of which have been determined to be harmful, while others have no proven impact. Harmful mutations in these genes may produce a hereditary breast–ovarian cancer syndrome in affected persons. Only 5–10% of breast cancer cases in women are attributed to BRCA1 and BRCA2 mutations, but the impact on women with the gene mutation is more profound. Women with harmful mutations in either BRCA1 or BRCA2 have a risk of breast cancer that is about five times the normal risk, and a risk of ovarian cancer that is about ten to thirty times normal. The risk of breast and ovarian cancer is higher for women with a high-risk BRCA1 mutation than with a BRCA2 mutation. Having a high-risk mutation does not guarantee that the woman will develop any type of cancer, or imply that any cancer that appears was actually caused by the mutation, rather than some other factor.

GT198 is a human oncogene located within the BRCA1 locus at chromosome 17q21. It encodes protein product named GT198, Hop2 or TBPIP. The GT198 gene is found to be mutated with its protein overexpressed in human cancers including breast and ovarian cancers.

A hormone-sensitive cancer, or hormone-dependent cancer, is a type of cancer that is dependent on a hormone for growth and/or survival. Examples include breast cancer, which is dependent on estrogens like estradiol, and prostate cancer, which is dependent on androgens like testosterone.

Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However, resistance to this therapy can develop, leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.

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