germ cell tumor diagnosis :: Article CreatorManaging Germline Mutations In Hereditary Breast Cancer Risk
Hereditary breast cancer, which accounts for 5% to 10% of all cases of breast cancer,1 is the direct result of a genetic predisposition to a higher lifetime risk of breast cancer due to its inherent inherited nature compared with the general population, and it can significantly affect family health outcomes. This risk is inherited at conception and stems from germline mutations that exist in the germ cells that develop into reproductive cells and become eggs in female individuals and sperm in male individuals and are passed from parent to child.2 Each germ cell contains half of the chromosomes necessary for development, and mutations from them exist in every cell of an individual.3
Kate Baker, MD, MMHCImage Credit: © Tennessee Oncology
"Nonhereditary breast cancer, also known as sporadic breast cancer, occurs when gene mutations develop over a person's life due to factors like aging, environmental exposure, or lifestyle choices. In contrast, hereditary breast cancer is caused by mutations inherited from one or both parents," explained Kate Baker, MD, MMHC, medical director of value-based care and medical oncologist, Tennessee Oncology, in an interview with The American Journal of Managed Care® (AJMC®). "The mutations typically affect specific genes responsible for regulating how cells grow, divide, or repair damaged DNA, and disruption of these key processes is what leads to the development of breast cancer."
Understanding the genetic factors involved in hereditary breast cancer is crucial for early detection, risk assessment, and informed decision-making about preventive measures. By identifying individuals at high risk, there is greater ability to provide targeted treatment interventions that are also effective, thereby significantly improving patient outcomes and ultimately offering more personalized treatment options and preventive strategies for those affected by hereditary breast cancer.
Genes Implicated in Hereditary Breast Cancer
The genes that are most often implicated in hereditary breast cancer, and perhaps that are the most well known for that reason, are BRCA1 and BRCA2. Women found to have these genes can have a 55% to 58% greater risk of developing breast cancer in their lifetime compared with 12.5% among the general population, explained Samyukta Mullangi, MD, MBA, medical director at Thyme Care and medical oncologist with Tennessee Oncology. This hereditary risk can be even higher if a first-degree relative has received a breast cancer diagnosis, she added, or if there is a family history of "related" cancers that include ovarian, pancreatic, or prostate cancer.
Samyukta Mullangi, MD, MBAImage Credit: © Tennessee Oncology
When these DNA repair genes are not damaged, or mutated, they help to prevent harmful mutations from accumulating in our genomes and keep cells healthy across different tissues, explained Baker. However, these 2 genes also are known to give rise to other cancers in both women and men when damaged copies of them are present—because although it is less common, men can also develop breast cancer—which makes identifying them all the more important. Among female individuals, beyond breast cancer, there is a known higher risk for developing ovarian cancer, and among male individuals, there are established associations between the inheritance of BRCA1 and BRCA2 and the development of prostate cancer.4
"Genes can be passed equal to male or female [individuals]," explained Karen Kostroff, MD, chief of breast surgery at Northwell Health, who specializes in the diagnosis and treatment of hereditary breast cancer among women, to AJMC. "They are not tied to sex. But men still have a lesser chance of getting breast cancer."
Karen Kostroff, MDImage Credit: © Northwell Health
Beyond the risk contributions from the well-known BRCA1 and BRCA2, there are several less common inherited genes that are to blame for a greater risk of developing hereditary breast cancer, as well as other cancers, according to Mullangi. These genes are TP53, PTEN, PALB2, CHEK2, and ATM, she told AJMC, and they are all tumor suppressor genes.
The function of tumor suppressor genes is to regulate uncontrolled cell proliferation. Therefore, when they are mutated, cells can grow and proliferate unencumbered, "and this unchecked cell growth can lead to the formation of cancer as the body loses its ability to regulate cell activity," Baker added.
Mullangi elaborated on the specific cancers linked to each of these gene mutations, emphasizing their varying degrees of risk and the broad spectrum of malignancies they influence, including rare and aggressive cancers:
Mutated TP53 has been associated with the rare genetic autosomal dominant disorder Li-Fraumeni syndrome, which is associated with a 90% chance of developing 1 or more cancers over a lifetime and a 50% chance before age 30; these cancers include osteosarcoma, gliomas, leukemia, and breast cancer.5 Mutated PTEN is linked with Cowden syndrome, another rare inherited disorder, which confers a higher risk of melanoma, thyroid, endometrium, and breast cancers.6 PALB2 is a partner to BRCA2, Mullangi explained, and is involved in DNA damage repair; when this gene is mutated, women have a 35% greater risk of developing breast cancer before age 70,7 and there are higher risks of ovarian, prostate, and pancreatic cancers.8 CHEK2 mutations increase breast cancer risk in both women and men—although this varies according to the mutation—as well as confer a greater risk of prostate cancer.9 A mutated ATM gene can cause ataxia-telangiectasia, which is inherited from both parents, and disrupts the nervous and immune systems; however, just 1 inherited mutation is sufficient to increase risks for cancers that include breast, pancreatic prostate, and ovarian cancers.10 Genetic Testing for Hereditary Breast Cancer
In order to test for genes that increase the risk of developing hereditary breast cancer, germline testing, also known as biomarker testing, is necessary, and it is performed on cells that do not have cancer. These tests most often utilize blood samples,11 but can also use saliva and tissue, Mullangi explained, and they help to detect harmful pathogenic or likely pathogenic variants12—not all pathogenic variants lead to disease; identified variants can also be classified as benign, likely benign, or a variant of uncertain significance.13
Genetic testing is crucial for those meeting certain criteria, explained Kostroff.
However, many patients who could benefit from knowing their genetic risk for developing hereditary cancer do not even undergo germline testing, with restrictive germline genetic testing guidelines being to blame.14-16 Cost can also be a significant factor, with genetic tests often having high prices—from less than $100 to $2000 and above17—that are unaffordable for many and may not be covered by insurance for others, limiting access for certain populations. Research shows that rates for genetic testing remain far below the recommended levels from practice guidelines.11
So, what are the guideline recommendations for who should undergo germline genetic testing for hereditary breast cancer?
As a baseline, all women should under a breast cancer risk assessment by age 25, according to the American College of Radiology, especially those considered high risk, who include Black and Ashkenazi Jewish women. Black women are 40% more likely to die from breast cancer and BRCA1 and BRCA2 mutations are much more common in Ashkenazi Jewish women compared with the general population.18
Receiving a cancer diagnosis at a young age—which is usually considered to be younger than 50 years, highlighted Mullangi—is another important criterion. So, too, is having a personal and/or family history of the same cancer or a related cancer, she added, and with which Kostroff concurred. Cancers covered under this umbrella include triple-negative, metastatic, and male breast cancer; ovarian, pancreatic, and metastatic prostate cancers; medullary thyroid carcinoma; and pheochromocytoma or paraganglioma.11,19 Germline testing rates for several of these cancers remain at suboptimal levels; for example, just 26% of women with breast cancer have undergone germline testing.11
Baker elaborated on this guidance, noting, "The National Comprehensive Cancer Network recommends genetic testing for genes that cause hereditary breast cancer for anyone that has a close blood relative with breast cancer diagnosed earlier than age 50 or a male relative with breast cancer. Additionally, genetic testing is recommended when a patient has more than 3 blood relatives on the same side of the family with a diagnosis of breast cancer."
Many experts would like to see universal germline testing, as that can widen access to necessary targeted treatments and clinical trial enrollment.14 However, some insurance companies will only cover the cost of testing if a patient is considered high risk, Kostroff explained, such as in the case of patients diagnosed with triple-negative disease.
Meanwhile, there are patients who opt to foot the bill for genetic testing, "even though on paper they have zero risk factors. These patients want to know everything about their body," she added.
The experts interviewed for this article agreed that risk reduction strategies, coupled with screening, should be individualized per patient based on their genetic risk and personal preferences.
References
1. What causes hereditary breast and ovarian cancers. CDC. August 28, 2024. Accessed October 5, 2024. Https://www.Cdc.Gov/breast-ovarian-cancer-hereditary/causes/index.Html#:~:text=to%20fighting%20cancer.-,Hereditary%20breast%20and%20ovarian%20cancer,from%20your%20mother%20or%20father
2. Germ cell. National Cancer Institute. Accessed October 5, 2024. Https://www.Cancer.Gov/publications/dictionaries/cancer-terms/def/germ-cell
3. Germline mutation. National Cancer Institute. Accessed October 5, 2024. Https://www.Cancer.Gov/publications/dictionaries/cancer-terms/def/germline-mutation
4. Inherited cancer risk: BRCA mutation. Johns Hopkins Medicine. Accessed October 5, 2024. Https://www.Hopkinsmedicine.Org/health/conditions-and-diseases/breast-cancer/inherited-cancer-risk-brca-mutation#:~:text=Inheriting%20damaged%20copies%20of%20the,as%20well%20as%20other%20cancers
5. Li-Fraumeni syndrome. Cleveland Clinic. Accessed October 5, 2024. Https://my.Clevelandclinic.Org/health/diseases/22073-li-fraumeni-syndrome
6. Cowden syndrome. National Cancer Institute. Accessed October 5, 2024. Https://www.Cancer.Gov/publications/dictionaries/cancer-terms/def/cowden-syndrome
7. Antoniou AC, Casadei S, Keikkinen T, et a. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497-506. Doi:10.1056/NEJMoa1400382
8. Liu D. PALB2. City of Hope. Updated December 1, 2022. Accessed October 5, 2024. Https://www.Cancercenter.Com/cancer-types/breast-cancer/risk-factors/palb2#:~:text=PALB2%20gene%20mutation?-,What%20is%20PALB2?,its%20connection%20to%20breast%20cancer
9. CHEK2 gene mutations: cancer risk. Facing Our Risk of Cancer Empowered. Accessed October 5, 2024. Https://www.Facingourrisk.Org/info/hereditary-cancer-and-genetic-testing/hereditary-cancer-genes-and-risk/genes-by-name/chek2/cancer-risk
10. About mutations in the ATM gene. Memorial Sloan Kettering Cancer Center. Updated July 17, 2023. Accessed October 5, 2024. Https://www.Mskcc.Org/cancer-care/patient-education/about-mutations-atm-gene
11. McGrath D. Few people with cancer undergo testing for inherited gene mutations. National Cancer Institute. August 1, 2023. Accessed October 6, 2024. Https://www.Cancer.Gov/news-events/cancer-currents-blog/2023/germline-testing-for-cancer-underused
12. Most "pathogenic" genetic variants have a low risk of causing disease. News release. Mount Sinai. January 25, 2022. Accessed October 6, 2024. Https://www.Mountsinai.Org/about/newsroom/2022/most-pathogenic-genetic-variants-have-a-low-risk-of-causing-disease
13. Do all gene variants affect health and development? MedlinePlus. Updated March 25, 2021. Accessed October 6, 2024. Https://medlineplus.Gov/genetics/understanding/mutationsanddisorders/neutralmutations/#:~:text=Pathogenic:%20The%20variant%20is%20responsible,the%20research%20may%20be%20conflicting
14. WhitworthPW, Beitsch PD, Patel R, et al. Clinical utility of universal germline genetic testing for patients with breast cancer. JAMA Netw Open. 2022;5(9):e2232787. Doi:10.1001/jamanetworkopen.2022.32787
15. Beitsch PD, Whitworth PW, Hughes K, et al. Underdiagnosis of hereditary breast cancer: are genetic testing guidelines a tool or an obstacle? J Clin Oncol. 2018;37(6):453-460. Doi:10.1200/JCO.18.01631
16. Kurian AW, Abrahamse P, Furgal A, et al. Germline genetic testing after cancer diagnosis. JAMA. 2023;330(1):43-51. Doi:10.1001/jama.2023.9526
17. DePolo J. Genetic testing for breast cancer. Breastcancer.Org. Accessed October 6, 2024. Https://www.Breastcancer.Org/genetic-testing
18. DePolo J. New ACR guidelines say all women should have breast cancer risk assessment by age 25. Breastcancer.Org. May 9, 2023. Accessed October 7, 2024. Https://www.Breastcancer.Org/research-news/acr-2023-screening-guidelines
19. Indications for germline testing in cancer patients. The Jackson Laboratory. Updated October 2021. Accessed October 7, 2024. Https://www.Jax.Org/education-and-learning/clinical-and-continuing-education/clinical-topics/tumor-testing/germlinetest#
NJ State Senator, Teen Share Childhood Cancer Challenges With Nation
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Decoding Ovarian Cancer
September 26, 2024 Introduction: As per GLOBOCAN 2022 data, cancer cases are raising with incidence being 14,13,316 cases/ 1,40,66,31,781 population in India. Ovarian Cancer is the third most common cancer in females both in incidence being 47,333 new cases (6.6%) and mortality cases being 32,978 cases (4.6%) after breast and cervical cancer cases. Ovarian Cancer usually got undetected and about 60% of ovarian cancer cases are diagnosed at stage 3. The average 5-year survival rate for stage 3 ovarian cancer drops down to 41%. But then the survival rates can vary depending on several factors, including the cancer spread, general health condition, and their response to the treatment. So, it is important to understand the symptoms of the ovarian cancer, for it to be detected early, reduce the mortality and thereby achieve an early cure. Etiology and pathophysiology: Ovarian cancers basically comprise of two types epithelial and non-epithelial ovarian malignancies. Epithelial ovarian cancer is the most prevalent type, accounting for more than 95%, while approximately 5% are non-epithelial ovarian cancers. Non-epithelial ovarian cancers like germ cell, sex-cord stromal, and small cell ovarian cancers. Epithelial ovarian malignancies cancer incidence increase with age and the highest incidence is seen in 55-65 years age group while certain types under germ cell (yolk sac, dysgerminoma) and sex-cord stromal malignancies (adult granulosa cell, sertoli cell tumor) under non-epithelial ovarian cancers can occur early at 20-30 years of age (Figure 1). Figure 1: Classification of Carcinoma Ovary Based on the Origin of Malignancy The risk of developing ovarian cancer is directly proportional to the time a woman spends ovulating and the number of ovulatory cycles. During ovulation, cells are stimulated to divide. If this division is abnormally regulated, tumors may form which can be malignant. Early menarche (first age of menstrual cycle) and late menopause, increase the number of ovulatory cycles a woman undergoes in her lifetime and thereby increases the risk of developing ovarian cancer. Since ovulation is suppressed during pregnancy (a protective factor), not having children also increases the risk of ovarian cancer. Therefore, women who have not borne children are at twice the risk of ovarian cancer than those who have. Both obesity and hormone replacement therapy also raise the risk. Postmenopausal hormone replacement therapy (HRT) with estrogen and endometriosis likely increases the risk of ovarian cancer. Non-genetic factors such as diabetes mellitus, high body mass index, and tobacco use are also risk factors for ovarian cancer. Certain reports suggests that application of talcum powder to the groin, pesticides, and herbicides increase the risk of ovarian cancer. Women with hereditary nonpolyposis colon cancer (Lynch syndrome), and those with BRCA-1 and BRCA-2 genetic abnormalities are at increased risk. Several rare genetic disorders are associated with specific subtypes of ovarian cancer. Peutz–Jeghers syndrome, a rare genetic disorder, also predisposes women to sex cord tumour with annular tubules. Ollier disease and Maffucci syndrome are associated with granulosa cell tumors in children and may also be associated with Sertoli-Leydig tumors. Women who have had fewer menstrual cycles/no menstrual cycles, breast feeding, take oral contraceptives, have multiple pregnancies, and have a pregnancy at an early age are all protective factors against ovarian cancer. The risk of developing ovarian cancer is reduced in women who have had tubal ligation or tubectomy, both ovaries removed, or hysterectomy (an operation in which the uterus is removed). Ovaries are located on either side of the uterus and it is situated in between bladder and rectum in the pelvis. The outer layer of the uterus and ovary is lined by the peritoneum. The peritoneum is the inner lining of the abdominal wall which lines abdominal cavity and The peritoneum is made of two layers, the parietal peritoneum and the visceral peritoneum, that are continuous with each other. The parietal peritoneum lines the abdominal and pelvic walls, while the visceral peritoneum wraps around the abdominal organs like liver, stomach and intestines. The peritoneum folds below the stomach in two layers to form omentum.The peritoneum covers most of the intra-abdominal organs. The space between the parietal and visceral peritoneum is called the peritoneal cavity. The peritoneum supports the abdominal organs, insulates them, and helps hold them in place. It also secretes a lubricating fluid to reduce friction between the organs. This anatomical knowledge is essential as the carcinoma of the ovary apart from the lymph nodal spread, has got propensity to spread into the peritoneum layers as it lies in the peritoneal cavity (Figure 2). Figure 2: Anatomy and Peritoneal Spread Symptoms and Investigations: Early signs and symptoms of ovarian cancer is usually subtle. Therefore in most cases, symptoms exist for several months before being recognized and diagnosed. Symptoms can often be misdiagnosed as gastritis since the early stages of ovarian cancer tend to be painless which makes it difficult to detect it early on. The most typical symptoms of ovarian cancer include Bloating, abdominal or pelvic pain or discomfort, back pain. Irregular menstruation or postmenopausal vaginal bleeding, pain or bleeding after or during intercourse. Fatigue, diarrhoea, constipation, nausea, loss of appetite and frequent urination. Later symptoms of ovarian cancer are due to the growing mass causing pain by pressing on other abdominopelvic organs or from metastases. Most of the occasions, there might be peritoneal deposits (peritoneum is the inner lining of the abdominal wall) leading to abdominal distension (increase in the size of the abdomen). In India, this is the most common presentation since the early signs and symptoms are usually ignored by general population. Sometimes, the growing mass may cause pain if ovarian torsion develops. Patients having any of these symptoms might get evaluated after routine ultrasound of the abdomen to have an ovarian mass. Later would require to undergo routine laboratory workups with complete blood count (CBC), iron panel, renal function tests, liver function and coagulation tests. Pre-operative Serum CA- 125 is usually raised in all epithelial ovarian cancer. CA-125 is useful tumour marker, if elevated in pre-operative condition, can be used as a marker follow-up and to detect early recurrence. In non-epithelial ovarian cancer, based on the subtypes other blood serum markers like serum alpha-fetoprotein, neuron-specific enolase, and lactate dehydrogenase in young girls and adolescents with suspected ovarian tumors as younger women with malignant germ cell tumors. Serum inhibin A and inhibin B can indicate a granulosa cell tumor. In women in whom pregnancy is a possibility and choriocarcinoma is suspected, BHCG level can be measured during the diagnosis process. Baseline CT of the chest, abdomen, and pelvis with intravenous (IV) and oral contrast or PET-CT Scan is the preferred staging imaging study to assess local, regional and distant spread. Contrast MRI abdomen or pelvis alternatively can be done to assess the ovarian cancer status and its spread to the pelvic, para-aortic lymph nodes, peritoneum (peritoneal thickening/nodules), ascites, deposits in the diaphragm, liver surface and omentum (omental nodules). Based on the imaging, if the disease is involving uterus, ovary and confined to the pelvis, it would be considered upto FIGO Stage 2. If the disease involves para-aortic nodes, peritoneum, omentum and possibility of ascites (fluid accumulation in the abdomen), it would be considered FIGO Stage 3 and above (Figure 3 and 4). Above FIGO Stage 3, patient would require to undergo Neo-Adjuvant Chemotherapy/NACT (chemotherapy given prior to surgery) to reduce the disease status and surgical induced morbidity. For this, ultrasound guided ascitic fluid tapping or biopsy from the omental/peritoneal deposits is taken for the confirmation of the malignancy. Gene panel analysis for suspected genetic cause of BRCA and lynch syndrome. Immune-histochemistry analysis for PDL1 receptors. Figure 3: Stage 1 and 2 Spread Figure 4: Stage 3 and 4 Spread Treatment: Surgery forms the mainstay in the treatment of the ovarian cancer. Upto Stage 2 (the disease is restricted in the pelvis), patient can undergo staging laparotomy, Peritoneal Carcinomatosis Index (PCI) scoring and cytoreductive surgery/CRS (removal of uterus, both the ovaries, appendix, pelvic and para-aortic lymph nodes). But if it is stage 3 and beyond, 3 cycles NACT is given and then the patient is taken up for staging laparotomy, Peritoneal Carcinomatosis Index (PCI) scoring and cytoreductive surgery. This time apart from removal of uterus, both the ovaries, appendix, pelvic, para-aortic lymph nodes; total peritonectomy along with the resection of any visceral organs (colon, rectum etc.) is done. Combined with CRS if HIPEC (Hyperthermic intra-peritoneal chemo-therapy) is added, then the 5 year survival rate increases to 57%. HIPEC (Hyperthermic intra-peritoneal chemo-therapy) refers to continuous circulation of chemotherapy agent at higher temperatures of 43-450 for 60-90mins after performing optimal CRS, so that the microscopic tumour cells are destroyed. This is an advanced facility which is performed in limited centers which requires trained medical and surgical oncologist, ICU care (Figure 5). Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique delivering normothermic chemotherapy into the abdominal cavity as an aerosol under pressure, based on trials, there is a positive outcome by enhancing drug depth penetration with elevated tumoral interstitial fluid pressure (Figure 6). PIPAC is currently used for palliative setting in selected patients. Currently HIPEC and PIPAC facilities are available in few centres in Mangaluru. Figure 5: Hyperthermic Intra-Peritoneal Chemo-Therapy (HIPEC) Figure 6: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Chemotherapy is offered to all the patients post-operatively except for FIGO Stage 1 and as NACT for the FIGO Stage 3 patients. Current chemotherapy protocols are safe and has got minimal side effects. Immunotherapy has evolved in management of ovarian cancer especially with BRCA 1, IHC positive for Lynch syndrome, PDL1 receptors. Pembrolizumab, Dostarlimab, Bevacizumab and Poly ADP-ribose polymerase (PARP) inhibitors are few of immunotherapy, mono-clonal antibodies and targeted therapy agents respectively. These agents can prolong the disease progression time. Radiotherapy has very limited role in treatment of ovarian cancer. Precautions to avoid ovarian cancer: Anything that stops ovulation for a time, like birth control pills, pregnancy or breastfeeding, can lower the average woman's ovarian cancer risk. Taking oral contraceptives (birth control pill) for at least five years may lower the risk of ovarian cancer. Pregnancy and breastfeeding avoids ovulation for at least a year may lower the risk of ovarian cancer. But all these should be followed based on the guidance of the gynaecologist or a oncologist. Tubal ligation: Having a tubal ligation, which is a surgery to close both fallopian tubes, may lower the risk of ovarian cancer. Having both ovaries removed, both fallopian tubes removed, or a hysterectomy may lower the risk of ovarian cancer. Weight: Maintaining a healthy weight, following good diet habits and regular exercise may lower the risk of ovarian cancer. Quitting smoking may lower the risk of ovarian cancer. Genetic testing: Women with a family history of ovarian or breast cancer may want to consider genetic testing. Patients with BRCA positive genes have 90% risk to develop breast and ovarian cancer. After completion of the family, undergoing bilateral subcutaneous mastectomy (both the breasts) and bilateral salphingo-oopherectomy (both ovaries) can reduce the risk to 5%. Annual health check-up after age of 45 years in terms of getting ultrasound abdomen and blood investigations to detect and undergo screening Ovarian cancer survivors to be on regular follow-up with ultrasound/PET-CT scan and blood investigations. I have covered the ovarian cancer topic briefly and I hope this basic information is sufficient to guide you on ovarian cancer, you can approach me if there are any further queries. Thank you for patiently going through the article! Also read:
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