Endocrine Therapy for Breast Cancer

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Questions and Answers

What is the primary reason endocrine therapies are often preferred over other cancer treatments?

  • They are more effective at shrinking tumors.
  • They are easier to administer.
  • They have fewer side effects. (correct)
  • They are less expensive.

Which of the following is NOT a commonly used hormonal treatment for breast cancer?

  • Aromatase inhibitors (AIs)
  • Selective estrogen receptor degraders (SERDs)
  • Selective estrogen receptor modulators (SERMs)
  • Androgen receptor antagonists (correct)

What cellular characteristic determines a tumor's potential dependency on hormones?

  • The genetic mutations present in the tumor cells.
  • The rate of tumor growth.
  • The size and location of the tumor.
  • The presence of specific steroid hormone receptors. (correct)

What is the primary goal of ovarian ablation/suppression in the treatment of hormone-dependent cancers?

<p>To reduce the production of hormones that stimulate tumor growth. (B)</p> Signup and view all the answers

How is the number of hormone receptors in a tumor quantified?

<p>Using a biopsy followed by immunohistochemistry. (A)</p> Signup and view all the answers

What is the primary method of oestrogen synthesis in premenopausal women?

<p>Aromatase catalyzes the conversion of testosterone to estradiol in the ovaries. (D)</p> Signup and view all the answers

What is the dominant source of oestrogen in postmenopausal women?

<p>Peripheral tissues like adipose tissue. (A)</p> Signup and view all the answers

What is the role of fulvestrant in treating ER+ve metastatic breast cancer?

<p>It blocks the binding of oestrogen to its receptor in cancer cells. (C)</p> Signup and view all the answers

Why is ovarian suppression with GnRH agonists or ablation required for AIs to be used in premenopausal women?

<p>To prevent the feedback stimulation of the ovaries by the reduced oestrogen levels. (A)</p> Signup and view all the answers

How do aromatase inhibitors (AIs) reduce oestrogen production in postmenopausal women?

<p>By blocking the conversion of androstenedione to estrone in peripheral tissues. (D)</p> Signup and view all the answers

Which of the following is NOT a characteristic of Selective Oestrogen Receptor Modulators (SERMs)?

<p>They share the steroid structure of oestrogens. (A)</p> Signup and view all the answers

What role do co-regulator proteins play in the action of SERMs?

<p>They influence the activity of the ER by interacting with SERMs. (A)</p> Signup and view all the answers

What is the active form of Tamoxifen?

<p>4-hydroxytamoxifen (D)</p> Signup and view all the answers

What is the primary function of Tamoxifen in breast tissue?

<p>It acts as an antagonist, blocking the effects of natural oestrogens. (C)</p> Signup and view all the answers

Which of the following statements about Tamoxifen is TRUE?

<p>It is effective for treating both early and advanced ER-positive breast cancer across pre- and post-menopausal women. (D)</p> Signup and view all the answers

How does Tamoxifen exert its action?

<p>By competitively binding to the oestrogen receptor. (A)</p> Signup and view all the answers

What is the clinical use of Tamoxifen?

<p>Treatment of ER-positive breast cancer. (C)</p> Signup and view all the answers

Which of the following drugs is an androgen receptor inhibitor?

<p>Enzalutamide (B)</p> Signup and view all the answers

Which of the following is another example of a SERM?

<p>Raloxifene (B)</p> Signup and view all the answers

Which of the following drugs is a GnRH antagonist?

<p>Degarelix (C)</p> Signup and view all the answers

Which of the following drugs is a synthetic progestin?

<p>Medroxyprogesterone (C)</p> Signup and view all the answers

Which of the following drugs is used to block the production of testosterone?

<p>Abiraterone (D)</p> Signup and view all the answers

Which of the following websites is a resource for information on chemotherapy drugs?

<p><a href="http://www.bccancer.bc.ca/health-professionals/clinical-resources/pharmacy">http://www.bccancer.bc.ca/health-professionals/clinical-resources/pharmacy</a> (B), <a href="http://www.bccancer.bc.ca/HPI/DrugDatabase/DrugIndexPro/default.htm">http://www.bccancer.bc.ca/HPI/DrugDatabase/DrugIndexPro/default.htm</a> (D)</p> Signup and view all the answers

What cellular process is directly inhibited by Trastuzumab, ultimately hindering cancer cell growth?

<p>Signal transduction (B)</p> Signup and view all the answers

Which of the following is NOT a disadvantage associated with Trastuzumab therapy?

<p>Risk of developing resistance to treatment (C)</p> Signup and view all the answers

How does Trastuzumab-Emtansine (TDM-1) differ from Trastuzumab in its mechanism of action?

<p>TDM-1 targets the microtubule polymerization process, unlike Trastuzumab. (D)</p> Signup and view all the answers

What is the primary function of the gonadotropin-releasing hormone (GnRH) in the male reproductive system?

<p>Regulates the release of gonadotropins from the anterior pituitary gland. (B)</p> Signup and view all the answers

Which of the following hormones is directly responsible for the production of testosterone in the male reproductive system?

<p>LH/ICSH (A)</p> Signup and view all the answers

What is the primary role of Sertoli cells in the male reproductive system?

<p>Supporting sperm development within the seminiferous tubules (C)</p> Signup and view all the answers

Which of the following statements accurately describes the release pattern of GnRH in the male reproductive system?

<p>GnRH is released in pulsatile bursts, with intermittent periods of inactivity. (B)</p> Signup and view all the answers

What is the primary cellular target of DM-1 (emtansine), the cytotoxic agent in Trastuzumab-Emtansine (TDM-1)?

<p>Microtubules (D)</p> Signup and view all the answers

Which of the following is a Type II aromatase inhibitor?

<p>Letrozole (A), Anastrozole (D)</p> Signup and view all the answers

Which of the following is NOT a side effect of aromatase inhibitors?

<p>Increased bone mineral density (D)</p> Signup and view all the answers

Which of the following describes the mechanism of action of SERDs?

<p>They cause the degradation of the ER. (D)</p> Signup and view all the answers

Which of the following techniques is NOT used for ovarian ablation?

<p>Hormone replacement therapy (B)</p> Signup and view all the answers

What is the role of HER2 in normal cells?

<p>HER2 plays a role in transmitting signals that ensure controlled cell growth with a regulated rate of division. (B)</p> Signup and view all the answers

What is the approximate percentage of women with breast cancer who have HER2 over-expression in their tumor cells?

<p>15% (A)</p> Signup and view all the answers

What is the purpose of the HercepTest?

<p>The HercepTest is used to detect the amount of HER2 protein in the tumor cells. (C)</p> Signup and view all the answers

Which of the following is NOT a method for detecting HER2?

<p>CT scan (A)</p> Signup and view all the answers

Which of the following drugs acts as a selective estrogen receptor modulator (SERM) and exhibits anti-estrogenic effects in breast tissue while potentially having estrogenic effects in other tissues?

<p>Tamoxifen (B)</p> Signup and view all the answers

Which of the following drugs is an androgen receptor inhibitor that works by blocking the binding of testosterone to its receptor, ultimately inhibiting the growth of prostate cancer cells?

<p>Bicalutamide (A)</p> Signup and view all the answers

Which of the following drugs is a GnRH antagonist that directly blocks the binding of GnRH to its receptor, leading to a rapid decrease in testosterone production?

<p>Degarelix (B)</p> Signup and view all the answers

Which of the following describes a drug that binds to estrogen receptors and acts as a strong antagonist in breast tissue, effectively blocking estrogen from binding and activating its receptor?

<p>Fulvestrant (D)</p> Signup and view all the answers

Which of the following drugs is an aromatase inhibitor that blocks the enzyme aromatase, preventing the conversion of androgens to estrogens, primarily used for the treatment of estrogen-sensitive breast cancer in postmenopausal women?

<p>Exemestane (A)</p> Signup and view all the answers

A patient with hormone-dependent breast cancer, known to be estrogen receptor positive, is being considered for endocrine therapy. Which of the following situations would make the use of an aromatase inhibitor (AI) an inappropriate treatment choice?

<p>The patient is premenopausal and has not undergone ovarian ablation or suppression. (A)</p> Signup and view all the answers

A physician is evaluating a patient with advanced prostate cancer who is currently receiving LHRH agonist therapy. The patient presents with persistent symptoms of hyperandrogenism, including elevated PSA levels and ongoing hot flashes despite consistent treatment. What is the most likely explanation for these observations?

<p>The patient has developed resistance to the LHRH agonist. (A)</p> Signup and view all the answers

Which of the following statements accurately describes the mechanism by which selective estrogen receptor degraders (SERDs) exert their anti-cancer effect?

<p>SERDs bind to the estrogen receptor and induce its degradation, preventing estrogen signaling. (A)</p> Signup and view all the answers

A patient diagnosed with HER2-positive breast cancer undergoes treatment with the monoclonal antibody Trastuzumab. Which of the following best describes the primary mechanism by which Trastuzumab exerts its therapeutic effect?

<p>Trastuzumab blocks the binding of HER2 to its ligands, preventing its activation and downstream signaling. (A)</p> Signup and view all the answers

A new breast cancer drug, X, is being developed. Preclinical studies suggest that drug X exerts its anti-cancer effect by blocking the interaction of co-regulator proteins with the estrogen receptor. Which of the following classes of drugs does drug X most likely belong to?

<p>Selective estrogen receptor modulators (SERMs) (B)</p> Signup and view all the answers

Which of the following statements accurately describes the role of the hypothalamus-pituitary-ovary axis in the regulation of estrogen production?

<p>The hypothalamus-pituitary-ovary axis regulates estrogen production in both pre- and postmenopausal women, but its role is more pronounced in premenopausal women. (A)</p> Signup and view all the answers

Which of the following best describes the mechanism of action of Aromatase Inhibitors (AIs) in postmenopausal women?

<p>AIs inhibit the enzyme aromatase, primarily reducing the conversion of androstenedione to estrone in peripheral tissues like adipose tissue. (D)</p> Signup and view all the answers

Which of the following drug types directly blocks the androgen receptor, preventing the action of androgens in prostate cancer treatment?

<p>Anti-androgens (B)</p> Signup and view all the answers

Which of the following scenarios would NOT require the use of GnRH agonists or ovarian ablation in conjunction with Aromatase Inhibitors (AIs)?

<p>A postmenopausal woman with ER+ breast cancer undergoing treatment with AIs. (C)</p> Signup and view all the answers

A patient with advanced prostate cancer is experiencing severe bone pain. Which of the following treatment options is most likely responsible for this symptom?

<p>GnRH Agonists (C)</p> Signup and view all the answers

Which of the following treatment options for prostate cancer directly targets the production of testosterone by removing the source?

<p>Orchiectomy (A)</p> Signup and view all the answers

Which of the following correctly describes the difference between Fulvestrant and Aromatase Inhibitors (AIs) in terms of their mechanism of action?

<p>Fulvestrant acts as a pure antagonist by directly blocking estrogen receptors, while AIs act as enzyme inhibitors, reducing estrogen synthesis. (B)</p> Signup and view all the answers

Which of the following is a significant advantage of using Fulvestrant compared to Aromatase Inhibitors (AIs) in the treatment of ER+ve metastatic breast cancer?

<p>Fulvestrant has a longer half-life, allowing for less frequent administration compared to AIs. (A)</p> Signup and view all the answers

A patient is prescribed Buserelin (Suprefact®) for prostate cancer treatment. This drug is classified as which type of medication?

<p>GnRH Agonist (D)</p> Signup and view all the answers

Which of the following hormone therapies for prostate cancer acts by rapidly and continuously suppressing testosterone production?

<p>GnRH Antagonists (D)</p> Signup and view all the answers

Which of the following accurately describes the difference between GnRH agonists and antagonists in prostate cancer treatment?

<p>GnRH agonists suppress LH production over time, while antagonists block LHRH-R signalling immediately. (A)</p> Signup and view all the answers

A patient undergoing treatment for prostate cancer with GnRH agonists experiences a temporary increase in testosterone levels. This is known as:

<p>Clinical flare (D)</p> Signup and view all the answers

Dihydrotestosterone (DHT) is a key player in prostate cancer development. It is produced from which hormone?

<p>Testosterone (A)</p> Signup and view all the answers

Tamoxifen, a Selective Oestrogen Receptor Modulator (SERM), exhibits a complex mode of action. Which of the following statements accurately describes its action in various tissues?

<p>Tamoxifen acts as an antagonist in breast tissue, a full agonist in the uterus, and a partial agonist in bone. (D)</p> Signup and view all the answers

The mechanism of action of SERMs like Tamoxifen relies on several factors. What is the key step that initiates their modulation of oestrogen receptor activity?

<p>Induction of conformational changes in the oestrogen receptor upon binding, altering its activity. (B)</p> Signup and view all the answers

Selective Oestrogen Receptor Modulators (SERMs) exhibit tissue-specific effects. What molecular mechanism underlies this selective action?

<p>All of the above mechanisms contribute to the tissue-specific actions of SERMs. (D)</p> Signup and view all the answers

The clinical use of Tamoxifen in breast cancer is significant. Which of the following accurately describes its application in treating this disease?

<p>Tamoxifen is effective for treating both early and advanced ER-positive breast cancer across pre- and postmenopausal women. (D)</p> Signup and view all the answers

The active form of Tamoxifen, responsible for its therapeutic action, results from metabolic activation. Which of the following accurately describes this metabolic process?

<p>Tamoxifen is metabolized into its active form, 4-hydroxytamoxifen, through enzymatic oxidation. (D)</p> Signup and view all the answers

The mechanism of action of Tamoxifen involves its interaction with the oestrogen receptor. Which of the following accurately describes this binding event?

<p>Tamoxifen binds to the oestrogen receptor, preventing the binding of natural oestrogens, thereby blocking their action. (A)</p> Signup and view all the answers

The efficacy of Tamoxifen in breast cancer treatment is primarily dependent on the tumor's ER status. Which of the following statements accurately describes the significance of ER status in predicting Tamoxifen's effectiveness?

<p>Tamoxifen is more effective in ER-positive breast cancers, as it specifically targets oestrogen receptor signaling. (A)</p> Signup and view all the answers

The clinical use of SERMs like Tamoxifen involves specific considerations related to the patient's hormonal status. Which of the following statements accurately reflects the impact of menopause on Tamoxifen's efficacy?

<p>Tamoxifen's efficacy is similar in both pre- and postmenopausal women, as it specifically targets the oestrogen receptor. (A)</p> Signup and view all the answers

Which of the following is a characteristic that specifically distinguishes Type II aromatase inhibitors from Type I inhibitors?

<p>Type II inhibitors are more potent than Type I inhibitors. (B)</p> Signup and view all the answers

Which of the following describes the mechanism of action by which Selective Estrogen Receptor Downregulators (SERDs) inhibit estrogen signaling?

<p>SERDs bind to the estrogen receptor (ER) and induce its degradation, thereby preventing ER signaling. (A)</p> Signup and view all the answers

In the context of breast cancer, what is the significance of HER2 over-expression in tumor cells?

<p>HER2 over-expression leads to increased production of a protein that promotes cell growth and division, potentially contributing to tumor development. (A)</p> Signup and view all the answers

Which of the following is a primary reason why ovarian ablation/suppression might be used in conjunction with aromatase inhibitors for the treatment of hormone-dependent cancers?

<p>Ovarian ablation/suppression ensures that aromatase inhibitors can effectively target estrogen production from all sources, including the ovaries. (B)</p> Signup and view all the answers

Which of the following accurately describes a common side effect of aromatase inhibitors?

<p>Aromatase inhibitors can cause a decrease in bone mineral density (BMD), which can increase the risk of osteoporosis. (A)</p> Signup and view all the answers

Which of the following accurately describes the mechanism of action of Trastuzumab in the treatment of HER2+ breast cancer?

<p>Trastuzumab targets and binds to the HER2 protein on the surface of cancer cells, effectively blocking its signaling activity and inhibiting uncontrolled cell growth. (B)</p> Signup and view all the answers

Which of the following is NOT a technique used for ovarian ablation?

<p>Chemotherapy-induced ovarian suppression. (A)</p> Signup and view all the answers

In the context of HER2 and breast cancer, what does FISH stand for, and what is its purpose?

<p>Fluorescent in situ hybridization, used to identify HER2 gene amplification. (D)</p> Signup and view all the answers

Flashcards

Endocrine Therapy

A treatment approach targeting hormone-dependent cancers.

Hormone-Sensitive Tumours

Tumours that require hormones for growth, like breast or prostate cancers.

Selective Oestrogen Receptor Modulators (SERMs)

Drugs that bind to oestrogen receptors to block or activate their effects in different tissues.

Aromatase Inhibitors (AIs)

Medications that block the enzyme aromatase, reducing oestrogen production.

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Receptor Quantification

Measuring hormone receptor levels in tumours to guide therapy effectiveness.

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Aromatase inhibitors

Medications that prevent estrogen production by blocking the aromatase enzyme.

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Selective Oestrogen Receptor Down-Regulator (SERD)

A drug that down-regulates and degrades oestrogen receptors, acting as a pure antagonist.

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Fulvestrant

An example of a SERD used in treating ER+ metastatic breast cancer in postmenopausal women.

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GnRH agonists

Drugs that stimulate the secretion of gonadotropins from the pituitary gland.

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GnRH antagonist

Medications that block the action of GnRH, inhibiting hormone release.

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Aromatase Enzyme (CYP19)

An enzyme that converts androgens to oestrogens, critical for hormone biosynthesis.

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Tamoxifen

A selective estrogen receptor modulator used to treat breast cancer.

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Enzalutamide

An androgen receptor inhibitor used in prostate cancer treatment.

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ER+ Breast Cancer Cells

Breast cancer cells that express oestrogen receptors and may produce oestrogen to stimulate growth.

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Breast Cancer

A type of cancer that originates in breast tissue.

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ER and PR Status

Assessment of estrogen and progesterone receptors in breast cancer.

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GnRH/LHRH Agonists

Medications like Leuprolide and Goserelin that suppress ovarian function.

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Prodrug

A medication that is metabolized into an active form, such as Tamoxifen.

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Trastuzumab

A monoclonal antibody used to treat HER2-positive cancers by marking cells for destruction.

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HER2-positive cancer

Cancers that overexpress the HER2 protein, leading to aggressive growth.

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Cytotoxic T-cells

Immune cells that kill cancer cells or infected cells.

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Receptor endocytosis

Process where binding of a molecule leads to its internalization in the cell.

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Trastuzumab-Emtansine (TDM-1)

A drug pairing trastuzumab with DM-1 for targeted cancer therapy.

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Microtubule polymerization

Process essential for cell structure and division that can be blocked by DM-1, leading to cancer cell death.

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GnRH

Gonadotropin-releasing hormone that stimulates the release of gonadotropins from the pituitary gland.

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LH/ICSH

Luteinizing hormone, stimulates testosterone production in males and development of reproductive organs.

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Type I Aromatase Inhibitors

Enzyme inactivators like Exemestane that irreversibly inhibit aromatase.

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Type II Aromatase Inhibitors

Competitive antagonists such as Anastrozole and Letrozole that reversibly compete for the androstenedione binding site.

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SERM

Selective Estrogen Receptor Modulators that prevent ER signaling by binding to ER, creating an inactive complex.

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SERD

Selective Estrogen Receptor Degraders that prevent ER signaling by causing degradation of the receptor.

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Ovarian Ablation

Techniques that cause permanent cessation of menstruation via surgical or radiation methods.

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Ovarian Suppression

The use of GnRH/LHRH analogues to suppress ovarian function.

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HER2 Over-Expression

Excess HER2 protein in tumor cells leading to uncontrolled cell growth, seen in ~15% of breast cancers.

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Hormone Dependency

The reliance of certain tumors on specific hormones for growth and survival.

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Endocrine Therapies

Cancer treatments that target hormone receptors with fewer side effects than traditional treatments.

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Luteinizing Hormone-Releasing Hormone Agonists

Medications that stimulate the release of hormones from the pituitary, often used in prostate cancer treatment.

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Selective Estrogen Receptor Degraders (SERDs)

Drugs that both block and degrade estrogen receptors, used in ER+ breast cancer treatment.

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Her2 Blockade

Therapeutic strategy targeting the Her2 protein to treat Her2-positive cancers, slowing tumor growth.

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Postmenopausal Oestrogen Source

After menopause, estrogen is mainly synthesized in peripheral tissues like adipose tissue rather than ovaries.

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ER+ Breast Cancer Mechanism

ER+ breast cancer cells can produce estrogen locally via aromatase, promoting tumor growth.

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Exemestane

A Type I aromatase inhibitor that irreversibly inactivates the enzyme.

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Anastrozole

A Type II aromatase inhibitor that reversibly competes for binding to androstenedione.

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Letrozole

A Type II aromatase inhibitor more potent than steroidal types, also competes for binding.

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Side Effects of AIs

Common side effects include antiestrogenic effects, musculoskeletal pains, and BMD loss.

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Ovarian Ablation Techniques

Methods that cause permanent cessation of menstruation, including surgical and radiative options.

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HER2+ Detection

Immunohistochemical analysis or FISH is used to detect HER2 protein expression or gene amplification.

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Testosterone

A hormone that sustains spermatogenesis, matures sperm, and affects muscle and bone growth.

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Androgens

Hormones like testosterone and DHT that stimulate prostate growth and cancer progression.

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Prostate Cancer Treatment Options

Methods include observation, prostatectomy, radiation, chemotherapy, and hormone therapy.

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Orchiectomy

Surgical removal of testicles to decrease androgen levels rapidly.

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Hormone Therapy

A treatment aimed at reducing male hormones to control prostate cancer growth.

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Dihydrotestosterone (DHT)

An active form of testosterone that promotes prostate growth.

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Estrogen Receptor (ER)

A protein that binds to estrogen, influencing cell growth in breast cancer.

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Progesterone Receptor (PR)

A protein that indicates a functional ER pathway; not directly targeted but important for treatment decisions.

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SERM Mechanism

Selective Estrogen Receptor Modulators alter ER activity based on tissue type, acting as antagonists or agonists.

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Tamoxifen Action

A SERM that antagonizes ER in breast tissue but can stimulate it in others like uterus and bones.

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Gland Ablation

Surgical or therapeutic removal of hormone-producing glands to reduce estrogen sources.

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Study Notes

Lecture Learning Outcomes

  • Outcome 1: Describe the role of endocrine therapy in cancer treatment.
  • Outcome 2: Outline the molecular basis for hormone-dependent cancers.
  • Outcome 3: Describe the mechanisms of action of commonly used hormonal treatments of breast cancer, including:
    • Selective estrogen receptor modulators (SERMs)
    • Selective estrogen receptor degraders (SERDs)
    • Aromatase inhibitors (Als)
    • Ovarian ablation/suppression
  • Outcome 4: Describe the mechanisms of action of commonly used hormonal treatments of prostate cancer, including luteinizing hormone-releasing hormone (LHRH) agonists and antagonists and anti-androgens.
  • Outcome 5: Describe the role of Her2 blockade.

Hormones as Anti-Cancer Targets/Agents

  • Hormone-sensitive tumors originate from hormone-responsive tissues (breast, prostate, ovary, endometrium, testes) and may be hormone-dependent.
  • Hormone dependency is linked to the presence of specific steroid hormone receptors within tumor cells.
  • Receptor quantification through immunohistochemistry of biopsies helps determine the likelihood of hormone therapy effectiveness.
  • Endocrine therapies are often chosen for favorable toxicity profiles compared to other cancer treatments.

Breast Cancer

  • Various histological and molecular subtypes of breast cancer exist, including ductal and lobular subtypes, basal, basoluminal, luminal A, luminal B, HER2-enriched, and normal-like.
  • Molecular subtypes' receptor expression, histological grade, prognosis, and response to medical therapy vary significantly.

5 Main Intrinsic or Molecular Subtypes of Breast Cancer

  • Luminal A (~40%): HR+, HER2-, Low Ki-67, Best prognosis
  • Normal-like (~2-8%): HR+, HER2-, Low Ki-67, Slightly worse than Luminal A
  • Luminal B (~20%): HR+, HER2+/-, High Ki-67,
  • HER2-enriched (~10-15%): HR-, HER2+, Faster growth than luminal subtypes
  • Triple Negative (~15-20%): HR-, HER2-, Most aggressive, higher association with BRCA1 mutations, Worst prognosis

Breast Cancer and Estrogen Signaling

  • Estrogen production, function, and receptor signaling in breast cancer are crucial for cell proliferation.
  • Aromatase converts androgens to estrogens, a crucial step in estrogen synthesis in postmenopausal women.
  • Estrogens act on target cells, leading to receptor dimerization and cell proliferation, triggering various cellular processes.

ER and PR Status

  • ER and PR are essential biomarkers in breast cancer treatment.
  • Endocrine therapies target the estrogen receptor to varying degrees, affecting estrogen signaling pathways.
  • PR status helps determine an ER pathway's functionality.

Breast Cancer Endocrine Therapies

  • SERMs (Selective Estrogen Receptor Modulators): Tamoxifen
  • SERDs (Selective Estrogen Receptor Down-Regulators): Fulvestrant
  • Aromatase Inhibitors: Exemestane, Anastrozole, Letrozole
  • GnRH/LHRH Agonists: Leuprolide, Goserelin
  • Gland Ablation: Ovary, pituitary, adrenals (to eliminate androgen sources in females)

Selective Estrogen Receptor Modulators (SERMs)

  • Chemical nature: Structurally diverse with a tertiary structure for estrogen receptor binding.
  • Examples: Tamoxifen, Raloxifene, Toremifene
  • Mechanism:
    • ER expression affects SERM effect depending on tissue.
    • Ligand-induced ER conformation
    • Co-regulator proteins, influencing ER activity.

Tamoxifen

  • Function: Acts as an ER antagonist in breast tissue, partial agonist in other tissues (uterus, bone).
  • Action: Competitively binds to the estrogen receptor, blocking natural estrogens.
  • Clinical use: Effective for early and advanced ER-positive breast cancer.
  • Adverse effects: hot flashes, irregular menstrual cycles, vaginal discharge, endometrial cancer risk, DVT, PE.

Tamoxifen: Mechanism of Action

  • Metabolic activation: prodrug Tamoxifen metabolized to active form 4-hydroxytamoxifen.
  • ER binding: active metabolite binds the estrogen receptor.
  • Transcriptional Inhibition: Tamoxifen-ER complex inhibits estrogen response element (ERE) hindering estrogen-responsive gene transcription.
  • Receptor interaction: stable complex disrupts receptor recycling.

Tamoxifen: Antagonist and Partial Agonist Activity

  • ER contains AF1 and AF2 recruitment domains.
  • Tamoxifen competitively binds to AF2 site, affecting transactivation.
  • AF2 activity dominant in breast tissue; Tamoxifen primary antagonist.

Tamoxifen's Selectivity and Adverse Effects

  • Selective binding to AF2 in breast tissue, antagonist function.
  • Partial agonist activity in other tissues (uterus, bone).
  • Adverse effects: hot flashes, irregular menstrual cycles, vaginal discharge, endometrial cancer risk, DVT, PE

Resistance to Tamoxifen

  • De novo resistance affects ~30% of ER+ breast cancers, presenting challenges in treatment.
  • Acquired resistance develops over time in a majority of initial responders.

Selective Estrogen Receptor Down-Regulator (SERD)

  • Fulvestrant – a pure antagonist, downregulates and degrades ER.
  • Treatment of ER+ metastatic breast cancer following anti-estrogen treatment, in postmenopausal women with disease progression.
  • Administered monthly.
  • Adverse effects are generally well-tolerated.

Aromatase Inhibitors (Als)

  • Aromatase (CYP19) is responsible for critical steps in estrogen biosynthesis.
  • Mechanisms:
    • Inhibits aromatization; reduces estrogen levels in postmenopausal women.
    • In premenopausal women, reduces estrogen levels, requiring ovarian function suppression.
  • Clinical Use: Post-menopause, ER-positive breast cancer, effective in reducing estrogen levels.
  • Adverse effects: hot flashes, musculoskeletal pains, reduced bone mineral density (BMD) loss.

Drugs that Inhibit Aromatase

  • Type I: Enzyme inactivators (steroid analogues) – Exemestane: Irreversibly inhibits aromatase.
  • Type II: Competitive antagonists (non-steroidal) – Anastrozole, Letrozole: Competitively bind to androstenedione binding site.

Aromatase Inhibitors: Side Effects

  • Antiestrogenic effects
  • Musculoskeletal pains
  • Reduced bone mineral density (BMD) loss

Endocrine Therapies: Effects on Estrogen Receptor Pathway

  • SERMs prevent ER signaling by binding to it to create an inactive complex.
  • SERDs prevent ER signaling by causing ER degradation
  • Als prevent ER signaling by inhibiting estrogen (estradiol) synthesis.

Ovarian Ablation/Suppression

  • Techniques include surgical removal, (oophorectomy) radiation.
  • Suppresses ovarian function by using GnRH/LHRH analogues to effectively prevent estrogen production. Less common compared to medical therapies

Trastuzumab (Herceptin) and HER2+ Breast Cancer

  • Monoclonal antibody directed against HER2.
  • Blocks HER2/receptor dimerization, activating ADCC (antibody-dependent cell-mediated cytotoxicity).
  • Inhibits proliferation of HER2 overexpressing cancer cells.

Trastuzumab (Herceptin) Disadvantages

  • Expensive therapy
  • Regular cardiac screening for associated cardiac dysfunction.
  • Necessary to determine HER2+ status.

New Generation HER2 Therapies

  • Trastuzumab-emtansine (TDM-1, Kadcyla): Uses HER2 to target emtansine to cancer cells, retaining ADCC effect, and inhibits HER2 signaling.
  • Degrades internalized TDM-1 into DM-1, preventing microtubule polymerization.

Prostate Cancer

  • High testosterone and DHT drives prostate cancer growth.
  • Treatment options include observation, surgically removing the prostate(prostatectomy), radiation therapy, chemotherapy, and hormone therapy to reduce testosterone levels. Specific hormone therapies include Orchiectomy, GnRH agonists (temporarily increase then decrease levels), GnRH antagonists (rapid suppression), and anti-androgens.

Hormonal Control of Male Reproductive System

  • GnRH controls anterior pituitary's gonadotropin release.
  • FSH maintains seminiferous tubules.
  • LH/ICSH stimulates Leydig cells to produce testosterone.
  • Testosterone sustains spermatogenesis and influences pubertal growth.

Prostate Cancer: Role of Androgens and Treatment Options

  • Testosterone and DHT are critical growth factors in prostate cancer, influencing cancer development and progression.
  • Treatment modalities include observation, prostatectomy, radiation, chemotherapy, hormone therapy reducing testosterone levels, surgical castration (orchiectomy), GnRH agonists, GnRH antagonists, and anti-androgens.

GnRH Agonists vs. Antagonists

  • GnRH Agonists: Over time, inhibit testosterone and DHT production, but can initially cause a temporary testosterone surge.
  • GnRH Antagonists: Rapid and ongoing testosterone suppression, avoiding the surge.

Anti-Androgens

  • Finasteride: inhibits 5-alpha reductase to inhibit DHT.
  • Flutamide: non-steroidal anti-androgen, largely replaced by enzalutamide.
  • Enzalutamide: androgen receptor inhibitor, blocking the androgen receptor and inhibiting androgen signaling.

Hormone Therapy (for reference only)

  • Lists various drugs for hormone therapies, important for reference purposes.

Resources/Further Reading

  • List of websites and a textbook, crucial for further research opportunities.

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