Oncogenes, Tumor-Suppressor Genes andDNA Repair GenesWhen it comes to cancer and how things can go wrong in the cell cycle, three different genes are very important:An oncogene is a proto-oncogene that has been mutated. Proto-oncogenes stimulate the cell to grow, divide and move through each cell cycle checkpoint to be inspected. If a proto-oncocogene mutates, it becomes an oncogene and no longer stops at cell check-points to insure it is normal.Tumor-suppressor genes act to stop cell growthDNA repair genes fix errorsOncogenes: The bad guys, turn abnormal cell growth on (go/gas pedal)An oncogene is a proto-oncogene that has been mutated in a way that leads to signals that cause uncontrolled growth- i.e., cancer. This is like pushing down on the gas pedal - you now have a gene that is telling the cell, "go, go, go; don't pay attention to the check-point and stop". Not all genes can mutate and form oncogenes. Only "proto-oncogenes" can mutate to form an oncogene. There are about 70 proto-oncogenes in our DNA

Oncogenes are mutated genes whose PRESENCE can stimulate the development of can-cer.When oncogenes arise in normal cells, they can contribute to the development of cancer by telling cells to make proteins that stimulate excessive cell growth and division.

 

  

 

 

 

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 Section Index

●What We Know About Cancer How Cancer is Studied Drug Development

New Treatments Research Advocacy

 

 

 

  

   Oncogenes are "gain of function" genes. They gain the ability to drive non-stop growth. In spite of their dominant activities, a single mutated oncogene usually isn't enough to cause cancer all by itself because tumor-suppressor genes are acting to put the brakes on to keep cell growth from getting out of control.Oncogenes aren't usually involved in inherited forms of cancer because most occur as so-matic mutations and can't be passed from parent to child.A few important oncogenes:HER-2/neuHER-2/neu encodes for a cell surface receptor that can stimulate cell division. The HER-2/neu gene is amplified in up to 30% of human breast cancers.RASThe Ras gene products are involved in kinase signaling pathways that ultimately control transcription of genes, regulating cell growth and differentiation.MYCThe Myc protein is a transcription factor and controls expression of several genes.SRCSrc was the first oncogene ever discovered. The Src protein is a tyrosine kinase, which regulates cell activity.hTERThTERT codes for an enzyme (telomerase) that maintains chromosome ends. 

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Other Bad Guys:While the prime suspects for cancer-linked mutations are the oncogenes, mutated tumor suppressor genes, and faulty DNA repair genes, the mutations listed below also do dam-age.Mutations also are seen in genes that:Activate and deactivate carcinogensGovern the cell cycControl cell senescence (or "aging")Control cell suicide (apoptosis)Control cell signalingControl cell differentiationEnable cancer to invade and metastasize to other parts of the body. Tumor-Suppressor Genes: The good guys, turn cell growth off (stop/brake pedal)Tumor suppressor genes in normal cells act as braking signals during phase G1 of the cell cycle, to stop or slow the cell cycle before S phase. If tumor-suppressor genes are mu-tated, the normal brake mechanism will be disabled, resulting in uncontrolled growth, i.e. cancer.

Tumor suppressorgenes are normal genes whose ABSENCE can lead to cancer.

Mutations in tumor-suppressor genes cause loss-of-function. Loss-of-function mutations generally only show up when both copies of the gene are mutated. In other words, if a pair of tumor suppressor genes are lost or mutated, their functional absence might allow can-cer to develop.Individuals who inherit an increased risk of developing cancer often are born with one de-fective copy of a tumor suppressor gene.Because genes come in pairs (one inherited from each parent), an inherited defect in one copy will not lead to cancer because the other normal copy is still functional. But if the sec-ond copy undergoes mutation, the person then may develop cancer because there no longer is any functional copy of the gene.A few important tumor-suppressor genes:

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p53: a transcription factor that regulates cell division and cell death.Rb: alters the activity of transcription factors and therefore controls cell division.APC: controls the availability of a transcription factor. More Good Guys - DNA Repair Genes: Correct errorsDNA repair genes code for proteins whose normal function is to correct errors that arise when cells duplicate their DNA prior to cell division.DNA repair genes are active throughout the cell cycle, particularly during G2 after DNA replication and before the chromosomes divide.Mutations in DNA repair genes can lead to a failure in repair, which in turn allows subse-quent mutations to accumulate. Certain forms of hereditary colon cancer involve defects in DNA repair.

If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in cancer.A few important DNA repair genes:BRCA1 and BRCA2 CISN Summary: Oncogenes, Tumor-Suppressor Genes andDNA Repair GenesThis is a lot of information to understand, so we have a short summary for those who just want to remember the basics.For those that want to know more - reread the section, print the entire section, maybe even take notes to help you memorize the information, if that is important to you. It always helps to have study buddies, take breaks and remember you don't have to memorize all the ma-terial. It is here to help you when you need to understand something specific.

Most cancer cells acquire a number of common abnormalitiesThe causes and sequence of the abnormalities variesEffective therapies reverse at least several of the abnormalitiesMutated genes: see table

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Name of Gene

This Mutation Causes

Examples

 Oncogene Uncontrolled

growth:step on the gas

Her2-neu, Ras, Myc, Src, Htert

 Tumor Suppres-sor

Uncontrolled growth:remove the brake

P53, Rb, APC

 DNA Repair No longer able

to correct celldivision mis-takes

BRCA1 and BRCA2

Breast calcifications are calcium deposits within breast tissue. They appear as white spots or flecks on a mammogram and are usually so small that you can't feel them.Breast calcifications are common on mammograms and they're especially prevalent after menopause. Although breast calcifications are usually noncancerous (benign), certain pat-terns of calcifications — such as tight clusters with irregular shapes — may indicate breast cancer.On a mammogram, breast calcifications can appear as macrocalcifications or microcalcifi-cations.Macrocalcifications. These show up as large white dots or dashes. They're almost always noncancerous and require no further testing or follow-up.Microcalcifications. These show up as fine, white specks, similar to grains of salt. They're usually noncancerous, but certain patterns can be a sign of cancer.If calcifications are suspicious, more testing may be necessary, including additional mam-mograms with magnification views or a breast biopsy.

WHEN IS FURTHER TESTING NEEDED?When microcalcifications are seen on a mammogram, the doctor (a radiologist) may ask for a magnified view so the calcifications can be seen more closely.Calcifications that do not appear to be a problem are called “benign.” No specific follow-up is needed.Calcifications are slightly abnormal but do not look like a problem are called “probably be-nign.” Usually, a 6-month mammogram is recommended.

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Calcifications that are irregular in size or shape, or tightly clustered together, are called "suspicious calcifications." Your health care provider will recommend a stereotactic core biopsy. This is a needle biopsy that uses a type of mammogram machine to help find the calcifications.Most patients who have suspicious calcifications do not have cancer.

Calcifications are small calcium deposits in

the breast that show up as white spots on a mammogram. Large, round, well-defined calci-fications (left column) are more likely to be noncancerous (benign). Tight clusters of tiny, ir-regularly shaped calcifications (right column) may indicate cancer.

Bagaimana diagnosisnya ?

Mamografi- Merupakan pemotretan pada payudara dengan alat khusus menggunakan radiasi ringan sinar-x  yang dapat mendeteksi tumor sangat kecil yang tidak teraba oleh dokter sekalipun. Selain itu, bermanfaat dalam menemukan lesi berukuran sangat kecil, sampai 2 mm, yang tidak teraba dalam pemeriksaan klinis (biasanya berukuran di bawah 1 cm).

BiopsiFine-needle aspiration Biopsy- Dokter dapat menggunakan jarum tipis untuk mengambil sel atau cairan dari benjolan pada payudaraCore biopsy- Dokter menggunakan jarum yang lebar untuk mengambil sampel dari jaringan payudara

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Skin biopsy- Bila ditemukan perubahan pada kulit payudara, dokter akan mengambil sedikit sampel dari kulitSurgical biopsy- Ahli bedah akan mengambil contoh jaringan payudara

Pemeriksaan Biomarker pada jaringan payudara - Berupa pemeriksaan penanda biokimia pada jaringan payudara (yang diperoleh dari hasil biopsi), yang dihasilkan selama terjadi abnormalitas pada tubuh dapat membantu menetapkan diagnosis kanker payudara.Pemeriksaan reseptor hormon - Seperti sel sehat lainnya, tumor payudara memerlukan hormon untuk tumbuh. Tumor ini memiliki reseptor untuk hormon estrogen, progesteron atau keduanya. Bila hasil pemeriksaan menunjukkan bahwa tumor payudara memiliki re-septor tersebut maka terapi hormon adalah pilihan terapi yang paling direkomendasikan.Pemeriksaan Her2/neu (Human Epidermal Growth Factor Receptor – 2) - Protein Her2/neu ditemukan pada beberapa jenis sel kanker. Pemeriksaan ini menun-jukkan apakah jaringan memiliki protein her2/neu atau kopi gen yang berlebih. Bila tumor payudara memiliki jumlah her2/neu dalam jumlah berlebih, terapi tertarget (targeted ther-apy) bias menjadi salah satu pilihan pengobatan. Untuk mendapatkan hasil membutuhkan waktu beberapa minggu. Hasil pemeriksaan ini dapat membantu dokter memutuskan pen-gobatan yang tepat.

Pengobatan yang dilakukan

Radioterapi, pada payudara dan daerah ketiak dilakukan serangkaian radiasi berdosis ringan untuk membunuh sel kanker. Radiasi dilakukan untuk membersihkan sisa-sisa sel kanker yang tersisa pasca operasi.Kemoterapi (chemotherapy), pengobatan dengan obat-obatan anti kanker untuk mencegah pembiakan sel-sel kanker. Bias dilakukan terpisah, ataupun disertai dengan bedah atau radioterapi. Kemoterapi bias menimbulkan efek samping berupa rasa mual, rambut rontok dan kehilangan tenaga.Terapi hormon, sasaran dari terapi hormon adalah mencegah estrogen memperparah sel kanker yang ada, dengan menyeimbangkan hormon. Seperti diketahui, hormon esterogen merupakan salah satu faktor yang bertanggung jawab terhadap risiko terjadinya kanker payudara. Pada terapi hormon terdapat beberapa golongan obat yang digunakan, antara lain adalah golongan antiesterogen, salah satunya adalah tamoksifen.Terapi antibodi monoklonal (Monoclonal Antibody drug), terapi inovasi baru untuk mengatasi kanker dengan meningkatkan imunitas tubuh untuk mengatasi perkembangan sel kanker. Obat-obatan golongan antibodi monoklonal, seperti Rituximab membuat sel kanker akan lebih dikenali oleh sistem imun, sedangkan Cetux-imab bekerja menghambat ikatan antara growth factordengan reseptor pada sel. Selain itu, kombinasi obat antibodi monoklonal dengan partikel radioaktif (terapi radiasi) dapat menghantarkan radiasi langsung tepat sasaran pada sel kanker. Hal ini digunakan untuk memastikan  radiasi tersebut tidak merusak sel yang se-hat.

HER2

General

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=========================================================================● Also called Human Epidermal growth factor Receptor 2, c-erbB2, neu, ERBB2 and CD340● HER2 gene encodes transmembrane glycoprotein (p185) with tyrosine kinase activity● Related to EGFR; may cross reactive with P-glycoprotein/CD243● Receptor acts via homo- or heterodimerization with other EGFR family receptors; in em-bryogenesis, helps establish several cell lineages through mesenchyme-epithelial-neu-roectodermal inductive processes; influences cellular migration, differentiation, and inter-actions between cells● DNA microarray profiling studies have divided invasive breast carcinoma into molecular subtypes: luminal A (ER+, HER2-), luminal B (ER+, HER2+), HER2 positive (ER-, HER2+), normal breast-like (ER+, PR+, HER2-) and basal-like (ER-, HER2-, EGFR+ or cy-tokeratin 5/6+)

Interpretation=========================================================================● HER2 testing valid on breast specimens fixed in fomalin up to 96 hours (Am J Clin Pathol 2012;137:691), but not accurate with Bouin fixative (Am J Clin Pathol 2011;136:754)● For GI specimens, results vary by type of HER2 antibody used (Am J Clin Pathol. 2012;137:583)● HER2 IHC analysis for breast cancer performed by image analysis can produce accu-rate results (Am J Clin Pathol 2012;137:270)● Can perform IHC and ISH on single slide (Am J Clin Pathol 2012;137:102, Am J Clin Pathol. 2012;138:837)● For interpretation and images with breast cancer, see Breast malignant chapter

Uses by pathologists=========================================================================● Breast cancer: confirm histologic classification (based on molecular classification), deter-mine use of anti-HER2 therapies including Herceptin and Tykerb, negative prognostic fac-tor● Gastric and gastroesophageal junction adenocarcinoma: determine use of anti-HER2 therapies (Arch Pathol Lab Med 2012;136:691), which improve survival in HER2+ patients

Positive staining - disease=========================================================================● Bladder: high grade papillary urothelial carcinoma (noninvasive), micropapillary carci-noma (Mod Pathol 2011;24:1111), urothelial carcinoma in situ (full thickness HER2+, Am J Clin Pathol 2011;136:881)● Breast: apocrine carcinoma (30%), apocrine DCIS (47%), ductal carcinoma (20%), DCIS (15-30%), inflammatory carcinoma (50%), lipid-rich carcinoma (71%+, Tumori 2008;94:342, Ann Diagn Pathol 2011;15:225), lobular carcinoma-pleomorphic variant, mi-cropapillary (95%), mucinous cystadenocarcinoma (Hum Pathol 2010;41:910), oncocytic, Paget's disease● Esophagus: adenocarcinoma (29%, Mod Pathol 2011;24:908)● Lung: adenocarcinoma (10-12%, Mod Pathol 2012;25:1566)

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● Neuroblastic tumors: HER2 staining is NOT accompanied by gene amplification (Mod Pathol 2010;23:1261)● Skin: apocrine hidrocytoma and nodular hidradenoma (Mod Pathol 2004;1:28)● Stomach: adenocarcinomas (5-15% intestinal type, < 1% diffuse type)● Uterus: serous carcinoma (18-61%)

Negative staining=========================================================================● Breast myoepithelial and Toker cells● Breast: adenoid cystic carcinoma, lobular carcinoma, triple negative carcinomas [basal-like, medullary (Arch Pathol Lab Med 2003;127:1458), metaplastic, squamous]● Skin: Bowen's disease

Contents of a Pathology Report The technical wording on a pathology report can be confusing. Because it is prepared for health care providers, a pathology report is written in medical language. However, under-standing the basic parts of the report can help you be better informed about your diagno-sis.Different pathology labs may use different terms to describe the same information. So, your report may not have the exact wording found here.Needle biopsy reports may contain less information than surgical biopsy reports. Also, some tests are only done when invasive breast cancer or certain types of breast cancer are found. If your tissue is found to be free of cancer or if your diagnosis is ductal carci-noma in situ (DCIS), many of the sections described below will not appear on your report.  Diagnosis or final diagnosisThis is the most important section of the report. It gives the pathologist's final diagnosis and may include information on features of the tumor such as size, type, grade, hormone receptor status and HER2/neu status. If lymph nodes were removed, the status of these lymph nodes will also be included. These characteristics may appear grouped together or as separate sections, depending on your pathology report.  Microscopic descriptionThe microscopic description details what the pathologist saw and measured when he/she looked at the biopsy tissue under a microscope.Tumor sizeTumor size is most often reported in centimeters or millimeters (1 inch = 2.54 centimeters = 25.4 millimeters). The best way to measure tumor size is under a microscope (especially for small tumors). When the length and width of the biopsy that contains cancer cells are measured (for example, 1.5 x 1.9 centimeters), the longer of the two is reported as the tu-mor size. This may be much smaller than the size of the tissue sample (the measurement of entire sample is reported in the gross description).In general, the smaller the tumor, the better the prognosis tends to be.  Learn more about tumor size.Non-invasive vs. invasiveDuctal carcinoma in situ (DCIS) is a non-invasive breast cancer (stage 0). The cancer cells are contained within the milk ducts (“in situ” means "in place").Invasive breast cancer (also called infiltrating cancer) means the cancer cells inside of a milk duct or lobule have broken out and spread to nearby tissues. Tumor grade

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For invasive breast cancers, the pathologist notes the shape of the cancer cells and as-signs a histologic grade, using either a number system or words. Tumor grade describes the structure of the cells and is different from tumor stage. In general, the more the cancer cells look like normal breast cells, the lower the grade and the better the prognosis.The most common grading system in current clinical practice is the Nottingham system: Grade 1=Well-differentiated (cells look most similar to normal and are not growing rapidly)Grade 2=Moderately-differentiated (cells look somewhat different than normal)Grade 3=Poorly-differentiated (cells look very abnormal, and may be growing and spreading rapidly)Nuclear gradeThe nuclear grade describes how closely the nuclei of cancer cells look like the nuclei of normal breast cells. In general, the higher the grade, the more abnormal the nuclei are and the more aggressive the tumor cells tend to be. The nuclear grade is a part of overall tu-mor grade.  Learn more about histologic grading and prognosis.  Hormone receptor statusHormone receptors are proteins found inside some cancer cells. When hormones (estro-gen and progesterone) attach to these receptors, they make the cancer cells grow.Estrogen and progesterone receptor-positive (ER+ and PR+) tumors have many hormone receptorsEstrogen and progesterone receptor-negative (ER- and PR-) tumors have few or no hor-mone receptorsThe hormone receptor status of your tumor helps guide your treatment plan. If your tumor is ER+ and/or PR+, treatments that prevent the cancer cells from getting the hormones they need to grow (hormone therapies, such as tamoxifen or aromatase inhibitors) may stop tumor growth. Tumors that are ER- and PR- are not treated with hormone therapies.  The American Society for Clinical Oncology and the National Comprehensive Cancer Net-work recommend hormone receptor testing for all tumors.Learn more about hormone receptor status and prognosis.Learn more about hormone therapies.  HER2/neu statusHER2/neu (human epidermal growth factor receptor 2), also called ErbB2, is a protein that appears on the surface of some breast cancer cells. It is an important part of the cellular pathway for growth and survival.HER2/neu-positive (HER2+) tumors have many HER2/neu genes inside the cancer cells (also called HER2/neu over-expression) and a large amount of HER2/neu protein on the surface of the cancer cellsHER2/neu-negative (HER2-) tumors have few HER2/neu genes inside the cancer cells and little or no HER2/neu protein on the surface of the cancer cellsAbout 15 to 20 percent of breast cancers are HER2+ [30-31]. These breast cancers tend to be more aggressive than other tumors.HER2/neu status helps guide your treatment plan. HER2+ cancers can benefit from trastuzumab (Herceptin) therapy, which directly targets the HER2/neu receptor. This type of therapy is not used to treat HER2- cancers. Both the American Society for Clinical Oncology and the National Comprehensive Cancer Network recommend HER2/neu testing for all tumors. HER2/neu status can be determined in two ways:

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Immunohistochemistry (IHC) testing which detects the amount of HER2/neu protein on the surface of the cancer cellsFluorescence in situ hybridization (FISH) testing which detects the number of HER2/neu genes in the cancer cellsMost often, IHC is the first test and if the score is +2 (or borderline), the tumor is sent for FISH testing to confirm the status.   Results of an IHC test Score is 0 or +1Tumor is HER2-Score is +2Results are unclear and should be confirmed by FISHScore is +3Tumor is HER2+Results of a FISH test  Positive (amplified)The tumor is HER2+Negative (non-amplified)The tumor is HER2-Learn more about HER2/neu status and prognosis.Learn more about treatment with trastuzumab (Herceptin).  Tumor marginsDuring a surgical biopsy, a rim of normal breast tissue (called a margin) surrounding the suspicious area is taken out to be sure the entire tumor was removed. The pathologist looks at the margins and decides whether or not they contain cancer cells.  Positive (also called "involved") margins  The margins along the edge of the biopsy contain cancer cells.More surgery may be needed to obtain clear margins. (This should be discussed with your surgeon.)Sometimes it is not possible to get a clear margin due to its location (for example, if it is at the chest wall).Close margins  The cancer cells approach, but do not touch the edge of the biopsy.More surgery may be needed. (This should be discussed with your surgeon.)Negative (also called "not involved", "clear" or "clean") margins  The margins do not contain cancer cells.No more surgery is needed.Vascular invasion (blood vessel invasion/angiolymphatic invasion/lymphovascular inva-sion)Vascular invasion occurs when cancer cells enter blood vessels or lymph channels. This may suggest a more aggressive tumor.  Lymph node statusIf lymph nodes were removed during the biopsy, the pathologist determines whether or not the lymph nodes in the underarm area (axillary nodes) contain cancer.Lymph node-negative means the lymph nodes do not contain cancer.Lymph node-positive means the lymph nodes contain cancer.In general, lymph node-negative breast cancers have a better prognosis than lymph node-positive breast cancers. Learn more about lymph node status and prognosis.Other information on a pathology reportThe following items are included on all pathology reports, but do not impact prognosis or treatment.  Patient information

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This section of the report has basic information including your name, medical record num-ber, date of birth, age and sex, date of the biopsy and name of the health care provider who ordered the report (most often your surgeon). It is a good idea to check all this infor-mation to make sure you have the correct pathology report.  Specimen(s) received (specimen source/specimen submitted)This section records the location in the breast where the biopsy sample(s) was removed. It may simply state left or right breast, or may give more detail. It also includes the date the pathologist received the tissue.Procedure (description of procedure)This is a description of the type of biopsies used to remove the tissue sample and lymph nodes (if lymph nodes removed). Needle biopsy or surgical biopsy for tumor tissueSentinel node biopsy or axillary dissection for lymph nodesLearn more about biopsies.  Clinical history (clinical information/clinical diagnosis/pre-operative diagnosis)The clinical history describes the initial diagnosis before the biopsy and sometimes, a brief summary of your symptoms. If there was a prior biopsy, the pathologist often will review this tissue so he/she can distinguish the recurrence of a past tumor from a new breast can-cer. The location of the tumor biopsy is also noted (for example, left or right breast).  Gross description (macroscopic description)One of the first things the pathologist does when he/she receives the biopsy tissue is to take measurements and record a description of the tissue as it appears to the naked eye (without a microscope). This gross description may include the size, weight, color, texture or other features of the tissue and any other visual notes.If there are multiple samples, there is often a separate gross description section for each sample. In these cases, the pathologist assigns a reference number or letter to each tissue sample to avoid confusion.The gross description also includes information on how the sample was handled once it reached the pathologist. Pathologist's signatureThe pathologist who is responsible for the contents signs and dates the report (most often, electronically).  Information sometimes seen on a pathology reportThe following items do not impact prognosis or treatment and may not appear on your re-port. Some of these tests are only done for certain diagnoses. Others are not routinely done because they do not predict prognosis over and above standard measures or be-cause they are not reliable measures for all tumors.Immunohistochemistry (IHC) for prognostic markersBeyond HER2/neu status testing, IHC can detect other molecular markers that may give information on prognosis.Proliferation rate (Ki-67, MIB1)The proliferation rate represents the percentage of cancer cells that are actively dividing. In general, the higher the proliferation rate, the more aggressive the tumor tends to be.Proliferation rate could be a good predictor of prognosis. However, there are issues related to its measurement, so it is not widely used by health care providers to make treatment de-cisions.The Ki-67 test is a common way to measure proliferation rate. MIB1 is the antibody most often used to label the Ki-67 antigen. You may see these terms on your pathology report. A higher value shows a higher proliferation rate.

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Estrogens influence many physiological processes in mammals, including but not limited to reproduction, cardiovascular health, bone integrity, cognition, and behavior. Given this widespread role for estrogen in human physiology, it is not surprising that estrogen is also implicated in the development or progression of numerous diseases, which include but are not limited to various types of cancer (breast, ovarian, colorectal, prostate, endometrial), osteoporosis, neurodegenerative diseases, cardiovascular disease, insulin resistance, lu-pus erythematosus, endometriosis, and obesity. In many of these diseases, estrogen me-diates its effects through the estrogen receptor (ER), which serves as the basis for many therapeutic interventions. This Review will describe diseases in which estrogen, through the ER, plays a role in the development or severity of disease.

Treatment of invasive breast cancer, by stageBreast-conserving surgery (BCS) is often appropriate for earlier-stage invasive breast can-cers if the cancer is small enough, although mastectomy is also an option. If the cancer is too large, a mastectomy will be needed, unless pre-operative (neoadjuvant) chemotherapy (chemo) can shrink the tumor enough to allow BCS. In either case, one or more underarm lymph nodes will need to be checked for cancer. Radiation will be needed for almost all patients who have BCS and some who have mastectomy. Adjuvant systemic therapy after surgery is typically recommended for all cancers larger than 1 cm (about 1/2 inch) across, and also sometimes for smaller tumors.If you’d like more information on a drug used in your treatment or a specific drug men-tioned in this section, see our Guide to Cancer Drugs , or call us with the names of the medicines you’re taking.Stage IThese cancers are still relatively small and either have not spread to the lymph nodes (N0) or have a tiny area of cancer spread in the sentinel lymph node (N1mi).Local therapy: Stage I cancers can be treated with either BCS (lumpectomy, partial mas-tectomy) or mastectomy. The lymph nodes will also need to be evaluated, with a sentinel lymph node biopsy or an axillary lymph node dissection. Breast reconstruction can be done either at the same time as surgery or later.Radiation therapy is usually given after BCS. Women may consider BCS without radiation therapy if they are at least 70 years old and ALL of the following are true:The tumor was 2 cm or less across and it has been completely removed.The tumor contains hormone receptors and hormone therapy is given.None of the lymph nodes removed contained cancer.Some women who do not meet these criteria may be tempted to avoid radiation, but stud-ies have shown that not getting radiation increases the chances of the cancer coming back.Adjuvant systemic therapy: Most doctors will discuss the pros and cons of adjuvant hor-mone therapy (either tamoxifen, an aromatase inhibitor, or one following the other) with all women who have a hormone receptor–positive (estrogen or progesterone) breast cancer, no matter how small the tumor. Women with tumors larger than 0.5 cm (about ¼ inch) across may be more likely to benefit from it.If the tumor is smaller than 1 cm (about ½ inch) across, adjuvant chemo is not usually of-fered. Some doctors may suggest chemo if a cancer smaller than 1 cm has any unfavor-able features (such as being high-grade, hormone receptor–negative, HER2-positive, or

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having a high score on a gene panel like Oncotype Dx). Adjuvant chemo is usually recom-mended for larger tumors.For HER2-positive cancers, adjuvant trastuzumab (Herceptin) is usually recommended as well.See below for more information on adjuvant therapy.Stage IIThese cancers are larger and/or have spread to a few nearby lymph nodes.Local therapy: Surgery and radiation therapy options for stage II tumors are similar to those for stage I tumors, except that for stage II, radiation therapy to the chest wall may be considered even after mastectomy if the tumor is large (more than 5 cm across) or cancer cells are found in several lymph nodes.Adjuvant systemic therapy: Adjuvant systemic therapy is recommended for women with stage II breast cancer. It may be hormone therapy, chemo, trastuzumab, or some combi-nation of these, depending on the patient's age, estrogen-receptor status, and HER2/neu status. See the following section for more information on adjuvant therapy.Neoadjuvant therapy: An option for some women who would like to have BCS, but the sur-geon thinks the tumor is too large to have a good result, is to have systemic treatment be-fore surgery to shrink the tumor. This is called neoadjuvant therapy and it can include chemo or hormone therapy. For HER2-positive tumors, the targeted drug trastuzumab is also used, sometimes along with pertuzumab (Perjeta).If the neoadjuvant treatment shrinks the tumor enough, women may then be able to have BCS (such as lumpectomy) followed by radiation therapy. More adjuvant therapy may also be given after surgery.If the tumor does not shrink enough for BCS, then mastectomy may be required. Adjuvant therapy may also be given after surgery, but would likely be with different drugs, since the tumor did not shrink with the first set given. Radiation therapy may be given after surgery, as well.A woman's chance for survival from breast cancer does not seem to be affected by whether she gets chemo before or after her breast surgery.Stage IIIFor a cancer to be stage III, the tumor must be large (greater than 5 cm or about 2 inches across) or growing into nearby tissues (the skin over the breast or the muscle underneath), or the cancer has spread to many nearby lymph nodes. Local treatment for some stage III breast cancers is largely the same as that for stage II breast cancers. Tumors that are small enough (and have not grown into nearby tissues) may be removed by BCS (such as lumpectomy) which is followed by radiation therapy. Otherwise, the treatment is mastec-tomy (with or without breast reconstruction). Sentinel lymph node biopsy may be an option for some patients, but most require an axillary lymph node dissection. Surgery is usually followed by adjuvant systemic chemotherapy, and/or hormone therapy, and/or trastuzumab. Radiation after mastectomy is often recommended.Often, stage III cancers are treated with chemo before surgery (neoadjuvant chemo). For HER2-positive tumors, the targeted drug trastuzumab is given as well, sometimes along with pertuzumab. This may shrink the tumor enough to allow BCS. Otherwise, a mastec-tomy is done. Usually an axillary lymph node dissection is done as well. Immediate recon-struction may be an option for some, but reconstruction is often delayed until after radia-tion therapy, which is often given even if a mastectomy is done. Adjuvant chemo may also be given, with trastuzumab added to chemo for HER2-positive cancers. Adjuvant hormone therapy is offered to all women with hormone receptor–positive breast cancers.Some inflammatory breast cancers are stage III. They are treated with neoadjuvant chemo (with trastuzumab and sometimes pertuzumab if the cancer is HER2-positive). If the can-cer doesn’t shrink with chemo, radiation may be given. This is followed by a mastectomy and axillary lymph node dissection. Then adjuvant treatment with chemo (and trastuzumab

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if the cancer is HER2-positive), radiation therapy (if it wasn’t given before surgery), and hormone therapy (if the cancer is hormone receptor−positive) is given. Inflammatory breast cancer is discussed in more detail in our document, Inflammatory Breast Cancer.Adjuvant drug therapy for stages I to III breast cancerAdjuvant drug therapy may be recommended, based on the tumor's size, spread to lymph nodes, and other prognostic features. If it is, you may get chemo, trastuzumab (Herceptin), hormone therapy, or some combination of these.Hormone therapy: Hormone therapy is not likely to be effective for women with hormone receptor-negative tumors. Hormone therapy is frequently offered to all women with hor-mone receptor–positive invasive breast cancer regardless of the size of the tumor or the number of lymph nodes with cancer cells.Women who haven’t gone through menopause and have hormone receptor–positive tu-mors are most often treated with tamoxifen, which block the effects of estrogen being made by the ovaries. Some doctors also give a luteinizing hormone-releasing hormone (LHRH) analog, which temporarily stops the ovaries from functioning. Another (permanent) option is surgical removal of the ovaries (oophorectomy). Still, it is not clear that removing the ovaries or stopping them from working helps tamoxifen work better for cancers that have been removed completely. If the woman becomes post-menopausal within 5 years of starting tamoxifen (either naturally or because her ovaries are removed), she may be switched from tamoxifen to an aromatase inhibitor.Sometimes a woman will stop having periods after chemotherapy or while on tamoxifen. But this does not necessarily mean she is truly post-menopausal. The woman's doctor can check the levels of certain hormones to determine her menopausal status. This is impor-tant because the aromatase inhibitors will not help if her ovaries are still working (and she is pre-menopausal).Women have gone through menopause and who have hormone receptor–positive tumors will generally get adjuvant hormone therapy either with an aromatase inhibitor (typically for 5 years), or with tamoxifen for 2 to 5 years followed by an aromatase inhibitor for 3 to 5 more years. For women who can't take aromatase inhibitors, an alternative is tamoxifen for 5 years. Women who had their uterus removed (a hysterectomy) but still have their ovaries may need to have blood tests to check hormone levels to see if they have gone through menopause.If chemo is to be given as well, hormone therapy is usually not started until after chemo is completed.Chemotherapy: Chemo is usually recommended for all women with an invasive breast cancer whose tumor is hormone receptor-negative, and for women with hormone receptor−positive tumors who might additionally benefit from having chemo along with their hormone therapy, based on the stage and characteristics of their tumor.Adjuvant chemo can decrease the risk of the cancer coming back, but it does not remove the risk completely. Before deciding if it's right for you, it is important to understand the chance of your cancer returning and how much adjuvant therapy will decrease that risk.Your doctor should discuss what specific drug regimens are best for you based on your cancer, its stage, your other health issues, and your preferences. The typical chemo regi-mens are listed in the chemotherapy section. The length of these regimens usually ranges from 3 to 6 months. In some cases, dose-dense chemo may be used (see the Chemother-apy section for an explanation of dose-dense chemo).Trastuzumab (Herceptin): Women who have HER2-positive cancers are usually given trastuzumab along with chemo as part of their treatment. After the chemo is finished, the trastuzumab is continued to complete a year of treatment.Because trastuzumab can lead to heart problems, heart function is watched closely during treatment with tests such as echocardiograms or MUGA scans.

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Online tools to help make decisions: To decide if adjuvant therapy is right for you, you might want to visit the Mayo Clinic website at www.mayoclinic.com and type "adjuvant therapy for breast cancer" into the search box. You will find a page that will help you to un-derstand the possible benefits and limits of adjuvant therapy.Other online guides, such as www.adjuvantonline.com, are designed to be used by health care professionals. This website provides information about your risk of the cancer return-ing within the next 10 years and what benefits you might expect from hormone therapy and/or chemotherapy. You may want to ask your doctor if he or she uses this site.Stage IVStage IV cancers have spread beyond the breast and lymph nodes to other parts of the body. Breast cancer most commonly spreads to the bones, liver, and lung. As the cancer progresses, it may spread to the brain, but it can affect any organ, even the eye.Although surgery and/or radiation may be useful in some situations (see below), systemic therapy is the main treatment. Depending on many factors, this may consist of hormone therapy, chemotherapy, targeted therapies, or some combination of these treatments. Treatment can shrink tumors, improve symptoms, and help patients live longer, but it isn’t able to cure these cancers (make the cancer go away and stay away).Trastuzumab may help women with HER2-positive cancers live longer if it is given with the first chemo for stage IV disease. Trastuzumab can also be given with the hormone therapy drug letrozole. Other options include ado-trastuzumab emtansine (Kadcyla) or giving per-tuzumab with chemo and trastuzumab. Treatment with ado-trastuzumab emtansine contin-ues until the cancer starts growing again. It is not clear how long treatment with trastuzumab (with or without pertuzumab) should continue.All of the systemic therapies given for breast cancer—hormone therapy, chemo, and tar-geted therapies—have possible side effects, which were described in previous sections. Your doctor will explain to you the benefits and risks of these treatments before prescribing them.Radiation therapy and/or surgery may also be used in certain situations, such as:When the breast tumor is causing an open wound in the breast (or chest)To treat a small number of metastases in a certain areaTo prevent bone fracturesWhen an area of cancer spread is pressing on the spinal cordTo treat a blockage in the liverTo provide relief of pain or other symptomsWhen the cancer has spread to the brainIf your doctor recommends such local treatments, it is important that you understand their goal—whether it is to try to cure the cancer or to prevent or treat symptoms.In some cases, regional chemo (where drugs are delivered directly into a certain area, such as the fluid around the brain or into the liver) may be useful as well.Treatment to relieve symptoms depends on where the cancer has spread. For example, pain from bone metastases may be treated with external beam radiation therapy and/or bisphosphonates such as pamidronate (Aredia) or zoledronic acid (Zometa). Most doctors recommend bisphosphonates or denosumab (Xgeva), along with calcium and vitamin D, for all patients whose breast cancer has spread to their bones. (For more information about treatment of bone metastases, see our document, Bone Metastasis.)Advanced cancer that progresses during treatment: Treatment for advanced breast cancer can often shrink the cancer or slow its growth (often for many years), but after a time, it stops working. Further treatment at this point depends on several factors, including previ-ous treatments, where the cancer is located, and a woman's age, general health, and de-sire to continue getting treatment.For hormone receptor–positive cancers that were being treated with hormone therapy, switching to another type of hormone therapy sometimes helps. If either letrozole (Femara)

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or anastrozole (Arimidex) were given, using everolimus (Afinitor) with exemestane may be an option. If hormone drugs stop working, chemo is usually the next step.If the cancer is no longer responding to one chemo regimen, trying another may be helpful. Many different drugs and combinations can be used to treat breast cancer. However, each time a cancer progresses during treatment it becomes less likely that further treatment will have an effect.HER2-positive cancers that no longer respond to trastuzumab might respond to lapatinib. Lapatinib also attacks the HER2 protein. This drug is often given along with the chemo-therapy drug capecitabine (Xeloda), but it can be used with other chemo drugs, with trastuzumab, or even alone (without chemo). Other options for patients with HER2 positive cancers include giving pertuzumab with chemo and trastuzumab and using the drug ado-trastuzumab emtansine.Because current treatments are very unlikely to cure advanced breast cancer, patients in otherwise good health are encouraged to think about taking part in clinical trials of other promising treatments.Recurrent breast cancerCancer is called recurrent when it come backs after treatment. Recurrence can be local (in the same breast or in the mastectomy scar) or in a distant area. Rarely, breast cancer comes back in nearby lymph nodes. This is called regional recurrence. Cancer that is found in the opposite breast is not a recurrence—it is a new cancer that requires its own treatment.Local recurrence: Treatment of women whose breast cancer has recurred locally depends on their initial treatment. If the woman had breast-conserving surgery, a local recurrence in the breast is usually treated with mastectomy. If the initial treatment was mastectomy, re-currence near the mastectomy site is treated by removing the tumor whenever possible. This is followed by radiation therapy, but only if none had been given after the original surgery. (Radiation can't be given to the same area twice.) In either case, hormone ther-apy, targeted therapy (like trastuzumab), chemo, or some combination of these may be used after surgery and/or radiation therapy.Regional recurrence: When breast cancer comes back in nearby lymph nodes (such as those under the arm or around the collar bone), it is treated by removing those lymph nodes. This may be followed by radiation treatments aimed at the area. Systemic treat-ment (like chemo, targeted therapy, or hormone therapy) may be considered after the local treatment as well.Distant recurrence: In general, women whose cancer comes back in organs like the bones, lungs, brain, etc., are treated the same way as those found to have stage IV breast cancer in these organs when they were first diagnosed (see treatment for stage IV). The only dif-ference is that treatment may be affected by previous treatments a woman has had.

The Genetics of Breast CancerThis section has been reviewed and approved by the Cancer.Net Editorial Board, 4/2011What are genes?Genes carry information in the form of DNA within each cell of the human body. Re-searchers estimate that there are 30,000 different genes in each cell. Genes are packaged onto chromosomes. There are 23 pairs of chromosomes in each cell. One chromosome of each pair is inherited from the person's father and one from the person's mother.Genes control how a cell functions, including how quickly it grows, how often it divides, and how long it lives. To control these functions, genes produce proteins that perform spe-cific tasks and act as messengers for the cell. Therefore, it is essential that each gene

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have the correct instructions or "code" for making its protein so that the protein can per-form the proper function for the cell.What role do genes play in breast cancer?Many cancers begin when one or more genes in a cell are mutated (changed), creating an abnormal protein or no protein at all. The information provided by an abnormal protein is different from that of a normal protein, which can cause cells to multiply uncontrollably and become cancerous.A person may either be born with a genetic mutation in all of their cells (germline mutation) or acquire a genetic mutation in a single cell during his or her lifetime. An acquired muta-tion is passed on to all cells that develop from that single cell (called a somatic mutation). Somatic mutations can sometimes be caused by environmental factors, such as cigarette smoke. Most breast cancers (about 90% to 95%) are considered sporadic, meaning that the damage to the genes occurs by chance after a person is born and there is no risk of passing on the gene to a person's children. Inherited breast cancers are less common (5% to 10%) and occur when gene mutations are passed within a family from one generation to the next.What are the chances a mutated gene is inherited?Every cell usually has two copies of each gene: one inherited from a person's mother and one inherited from a person's father. Breast cancer usually follows an autosomal dominant inheritance pattern, in which a mutation needs to happen in only one copy of the gene for the person to have an increased risk of getting the disease. This means that a parent with a gene mutation may pass on a copy of the normal gene or a copy of the gene with a mu-tation. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. A brother, sister, or parent of a person who has a gene mutation also has a 50% chance of having the same mutation.What is a person's average risk for breast cancer?A woman with an average risk of breast cancer has about a 12% chance of developing breast cancer. Breast cancer in men is rare; out of 1,000 men, one will develop breast can-cer.How can a person know if he or she has inherited a genetic mutation that increases his or her risk of breast cancer?Only genetic testing can determine whether a person has a genetic mutation. Most experts strongly recommend that people considering genetic testing first talk with a genetic coun-selor. Genetic counselors are trained to explain the risks and benefits of genetic testing.How does a person know if breast cancer runs in the family?Breast cancer may run in the family if first-degree relatives (mothers, sisters, brothers, chil-dren) or many close relatives (first-degree relatives, grandmothers, aunts, nieces, grand-daughters, cousins) have been diagnosed with breast cancer, especially before age 50.What is a person's risk if breast cancer runs in the family?If a woman's first-degree relative developed breast cancer, the woman's risk is double the average woman's risk. If two first-degree relatives developed breast cancer, the woman's risk is five times the average risk. It is uncertain how much a woman's risk of breast cancer is increased when a man in the family has breast cancer. One out of five men who develop breast cancer has a family history of the disease.Which inherited genetic mutations raise the risk of breast cancer?There are several genes linked to an increased risk of breast cancer. Some of the most common hereditary cancer syndromes associated with breast cancer risk are described below.Hereditary breast and ovarian cancer (HBOC) syndrome. HBOC is associated with muta-tions in the BRCA1 and/or BRCA2 (BRCA stands for BReast CAncer). Women with HBOC have an increased risk of breast cancer and ovarian cancer. Men with HBOC have an in-creased risk of breast cancer and prostate cancer.

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Ataxia telangiectasia (A-T). A-T is a rare disorder associated with a specific genetic muta-tion. It causes progressive neurological problems that lead to difficulty walking, slurred speech, and difficulty with writing and other tasks. People with A-T have an increased risk of leukemia and lymphoma, and possibly melanoma, sarcoma, breast cancer, ovarian can-cer, and stomach cancer.Li-Fraumeni syndrome (LFS). LFS is a rare condition associated with a specific genetic mutation. People with LFS have a higher risk of developing osteosarcoma (a type of bone cancer), soft tissue sarcoma, leukemia, breast cancer, brain cancer, and adrenal cortical tumors.Cowden syndrome (CS). CS is a rare genetic condition caused by a specific genetic muta-tion. People with CS have an increased risk of developing breast cancer and noncancer-ous breast changes and noncancerous and cancerous tumors of the thyroid and en-dometrium (lining of the uterus).Peutz-Jeghers syndrome (PJS). PJS is caused by a specific genetic mutation and is asso-ciated with multiple polyps in the digestive tract that become noncancerous tumors, in-creased pigmentation (dark spots on the skin) on the face and hands, and an increased risk of colorectal cancer, breast cancer, uterine cancer, ovarian cancer, and lung cancer.Other genes. Other genes may cause hereditary breast cancer. However, more research is needed to understand how gene mutations can increase breast cancer risk and to find other genes that may increase a person's risk of breast cancer.What is your risk level?In addition to family history, other environmental and lifestyle factors may increase your risk of breast cancer. Discussing your family history and personal risk factors with a doctor helps you better understand your risk. People with a higher than average risk may benefit from genetic counseling and early detection strategies.A risk factor is anything that increases a person's risk of developing cancer. Having a par-ticular genetic mutation linked to breast cancer cannot predict that a person will develop cancer. Controllable risk factors, such as eating a balanced diet, maintaining a healthy weight, exercising, limiting alcoholic beverages, and avoiding tobacco products also play a role. Most people who develop breast cancer have few known risk factors. Research to better understand the link between genetic mutations and breast cancer is ongoing. Talk with a doctor for more information about risk factors, prevention, and screening for breast cancer.

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