Published: Thursday, May 03, 2007

Overview:

1. Adjuvant systemic therapy
2. Pathology features that are used to determine risk of recurrence
3. Definition of menopause

Adjuvant Chemotherapy:

1. Use of adjuvant chemotherapy used to treat breast cancer
2. Risks of adjuvant chemotherapy

Adjuvant Hormonal Therapy:

1. Use of hormone therapy in breast cancer treatment
2. Four types of hormone therapies
3. How selective estrogen receptor modulator (SERM) work (e.g. tamoxifen)
4. Major risks of tamoxifen
5. How Aromatase Inhibitors (AIs) work
6. Major risks of AIs
7. Why AIs are only used in post-menopausal women
8. "Early" and "late" switch hormone treatment
9. Current BC Cancer Agency Breast Tumour Group recommendation for the use of AIs
10. How estrogen-receptor down regulators (ERDs) work
11. Ovarian suppression in breast cancer
12. Three ways to stop the ovaries' production of estrogen
13. Patient considerations when contemplating ovarian shutdown or removal

Adjuvant Trastuzumab Therapy:

1. What is trastuzumab
2. Uses of trastuzumab
3. Eligibility for trastuzumab
4. Major risks of trastuzumab

Overview:

1. Adjuvant systemic therapy (AST)

Adjuvant systemic therapy is the use of chemotherapy, hormone therapy and/or targeted therapy or a combination of these given after surgery to target the entire body in hopes of destroying any cancer cells that may have travelled to distant body parts but are below the level of clinical detection. AST is used to decrease the risk of recurrence and improve survival. The decision to use adjuvant systemic therapy requires balancing risk for disease recurrence and death after local therapy alone versus the added benefit of adjuvant therapy while considering toxicity of the therapy and comorbidity.

The decision-making process requires a collaboration involving the health care provider and the patient. Clinical practice guidelines and algorithms have been published and a validated computer-based model (Adjuvant! Online) is available to estimate 10-year disease free and overall survival that incorporates all standard prognostic factors. These tools can help the oncologist to estimate recurrence and/or death after local treatment only and also assist in estimating proportional reduction and the absolute benefits from systemic adjuvant endocrine therapy and chemotherapy.¹

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2. Pathology features that are used to determine risk of recurrence

A patient’s risk for recurrence or death can be categorized as low, intermediate, or high on the basis of tumour size, histologic or nuclear grade, estrogen receptor (ER) status, lymphatic and vascular invasion (LVI), HER2 status, and nodal status.

3. Definition of menopause

Menopause is the permanent cessation of menses, and as the term is utilized in breast cancer management includes a profound and permanent decrease in ovarian estrogen synthesis. Reasonable criteria for determining menopause include any of the following:¹

• Prior bilateral oopherectomy
• Age greater than or equal to 60 years
• Age less than 60 years and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, or ovarian suppression and FSH and estradiol in the postmenopausal range
• If taking tamoxifen, and age less than 60 years, then FSH and plasma estradiol level in postmenopausal ranges

It is not possible to assign menopausal status to women who are receiving an LH-RH agonist or antagonist. In women premenopausal at the time of adjuvant chemotherapy, amenorrhea is not a reliable indicator of menopausal status.¹

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Adjuvant Chemotherapy:

1. Use of adjuvant chemotherapy to treat breast cancer

Generally speaking, adjuvant chemotherapy is recommended if one or more of the following situations is present:

• Axillary lymph nodes contain cancer cells
• The tumour is more than 1 cm in size and high grade (grade 3)
• The tumour is more than 2 cm in size and low to moderate grade (grades 1 and 2)
• Tumours with cancer cells that have invaded the lymphatic or vascular channels of the breast are present
• The woman is 35 years old and less even without other risk factors ²

Table 1 provides a general overview of adjuvant systemic treatment options based on risk of recurrence. Go to Adjuvant Systemic for HER2 Negative Breast Cancer and scroll to the bottom of the page to see a chart that outlines the BC Cancer Agency adjuvant treatment recommendations based on categories of risk.

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See the Breast section of the Chemotherapy Protocols for adjuvant chemotherapy for breast cancer.

2. Risks of adjuvant chemotherapy

The major risks of chemotherapy (depending on the chemotherapy agent) for breast cancer are:

• infection;
• anemia;
• abnormal bleeding or bruising;
• mucositis;
• leukemia;
• heat rash; and
• menopausal symptoms.

Please see the Managing Symptoms and Side Effects section for information on how to support patients experiencing these and other symptoms.

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Adjuvant Hormonal Therapy:

1. Use of hormone therapy in breast cancer treatment

Adjuvant hormonal therapy refers to several different anti-estrogen treatments given in hormone sensitive tumours [estrogen receptor positive (ER+) or progesterone positive (PR+)]. These treatments affect the level of female hormones in the body and can include the use of drugs for both pre-menopausal and post-menopausal women or the removal or destruction of the ovaries in pre-menopausal women by either surgery, medications or radiation.⁴ The treatment decision, in part, will depend on whether the patient is pre- or post-menopausal, the stage of the woman's disease, her overall condition, and personal considerations.

Table 2 provides a general overview of recommendations for the use of adjuvant therapy for hormone sensitive breast cancers.

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2. Four types of hormone therapies

1. Selective estrogen-receptor modulators (SERMS)
2. Aromatase inhibitors (AIs)
3. Estrogen receptor down regulators (ERDs)
4. Ovarian shutdown or removal

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3. How selective estrogen receptor modulator (SERM) works (e.g. tamoxifen)

SERMs block the action of estrogen in the breast and certain other tissues by occupying estrogen receptors inside cells. The SERM blocks the more powerful estrogen signals from getting into the estrogen receptor and telling the cell to grow and spread (Table 3).

• SERMs do not affect all estrogen receptors in the same way, because, as the name states, they are "selective"
• SERMs block (or selectively inhibit) estrogen receptors in breast cells, acting as antagonists. Therefore, cells don't get the signals they need to grow and multiply
• SERMs stimulate estrogen receptors in other organs (acting as antagonists), with good and bad results. For example, the SERM tamoxifen stimulates liver cells, lowering cholesterol levels, stimulates bone cells, resulting in stronger bones and reduced risk of bone breaks, and stimulates growth of uterine cells (cells in the uterus), slightly increasing the risk of uterine cancer⁶

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4. Major risks of tamoxifen

• Endometrial Cancer: Annual gynecological examinations are recommended. Pelvic complaints, such as unusual vaginal bleeding, require prompt evaluation
• Retinopathy: Such toxicity is very rare and may occur after only a few weeks of therapy, although it is more common with prolonged treatment. It has been mainly reported in doses higher than 20 mg/day. Ophthalmologic examination is recommended if visual disturbances occur
• Cataracts: Those at risk or who have cataracts are at increased risk of having surgery earlier if they take tamoxifen
• Thromboembolism: Tamoxifen is associated with an increased risk of thromboembolism that is comparable to estrogen replacement therapy
• Hepatotoxicity: While hepatotoxicity is rare and usually presents as elevated hepatic enzymes, more serious liver abnormalities have been reported
• Ovulation Induction: Tamoxifen may induce ovulation in pre- and peri-menopausal women. Barrier forms of contraception are recommended. Tamoxifen is contraindicated in pregnancy due to fetal risk
• Hyperlipidemia: Tamoxifen affects lipid profiles by decreasing total and low density lipoprotein cholesterol but also decreases high density lipoprotein cholesterol and increases triglyceride. Periodic checks of blood lipid profiles in those at risk are appropriate
• Interaction with anti-depressants: Tamoxifen's active metabolites are inhibited by the drug paroxetine, a potent inhibitor of the CYP2D6 enzyme. Other anti-depressants that do not affect or have little effect on CYP 2D6 should be considered.

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5. How Aromatase Inhibitors (AIs) work

AIs reduce the amount of estrogen produced in post-menopausal women by stopping the enzyme called aromatase from turning androgen into estrogen, lowering the amount of estrogen produced outside the ovaries. That means less estrogen in the bloodstream, less estrogen reaching estrogen receptors, and less cancer cell growth. Examples of AIs are:

• Anastrozole
• Exemestane
• Letrozole

6. Major risks of AIs

• Bone density: The use of adjuvant AIs can lead to a 7% risk of osteoporosis.⁸ Supplementation with calcium and vitamin D and regular weight bearing exercise is recommended. A bisphosphonate should be considered if clinically indicated. Caution in patients with an already established diagnosis of clinically significant osteoporosis
• Hyperlipidemia: An increase in cholesterol or triglyceride levels may occur when an aromatase inhibitor is initiated. Levels may need to be checked during the first few months of therapy, especially in those patients with prior significant lipid elevations

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7. Why AIs are only useful in post-menopausal women

Before menopause, the ovaries produce most of a woman's estrogen. In post-menopausal women, most of the body's estrogen is made from androgen. Therefore, utilizing therapies that reduce estrogen from other sources (like stopping androgen from being turned into estrogen) has little of no effect in pre-menopasual women.

8. "Early" and "late" switch hormone treatment

Early switch refers to two to three years of adjuvant tamoxifen followed by an AI to complete five years in total. Late switch refers to four and a half to six years of adjuvant tamoxifen followed by an AI for three more years (the AI must be started within 12 months of the completion of tamoxifen).

Multiple strategies for incorporation of aromatase inhibitors into adjuvant hormonal therapy have been studied or are the subject of ongoing studies. The optimal strategy has not yet been determined. No studies have yet determined the optimal duration of an AI.⁹

The strategy of a sequential approach, incorporating tamoxifen first for some period, followed by an AI, has some theoretic advantages compared to monotherapy with either tamoxifen or an AI alone. This strategy allows for two treatments with differing mechanisms of action, thus potentially superior in overcoming treatment resistance. Also, the osteoporosis risk produced by prolonged use of an AI may be offset by the prior use of tamoxifen. The cumulative risks of uterine hyperplasia and malignancy and thrombosis related to tamoxifen may be limited by switching after two to three years to an AI. For those women completing adjuvant chemotherapy with loss of menses during therapy, upfront use of tamoxifen allows hormone therapy to proceed while the impact of adjuvant chemotherapy on ongoing menstrual status is determined.⁹

The theoretic disadvantage of using tamoxifen for two to three years followed by an AI is that some patients with higher risk disease may relapse while on tamoxifen prior to the switch in therapy. It is impossible to know at this time whether early relapsers would have a different survival outcome ultimately by use of an AI upfront. The various AI adjuvant studies have uniformly demonstrated an improvement in disease-free survival (DFS), but an overall survival (OS) difference is not yet clearly apparent. The studies have included a majority of low risk patients. There is a possibility that DFS and OS impact would be greater in patients at high risk for early relapse or with relative tamoxifen resistance.⁹

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9. Current BC Cancer Agency Breast Tumour Group recommendations for the use of AIs

Premenopausal women:

• Tamoxifen for five years, unless they become post-menopausal during therapy (no menses >12 months and FSH/LH in postmenopausal range), then see Strategy C below

Postmenopausal women:

• Strategy A: Tamoxifen monotherapy: Low grade T1N0 tumours: Tamoxifen for five years. Substitution of AI allowed if intolerant or if serious complications or contraindications exist
• Strategy B: AI monotherapy: High risk for early relapse, defined as:
  • high grade;
  • low ER (1+); or
  • stage III (Includes any N2/N3, T4, or T3N+).
  • May consider using AI upfront for five years
• Strategy C: All other tumours: Sequential therapy
  • Tamoxifen for two to three years followed by AI for two to three years, for total five years of hormone therapy ("early switch"); or
  • Tamoxifen for five years followed by AI for three years, for women who have finished >3 years of tamoxifen already at this time, or who become postmenopausal AFTER completing three years of tamoxifen ("late switch")⁹

10. How estrogen-receptor down regulators (ERDs) work

ERDs block and break down the estrogen receptor. With fewer hormone receptors available, fewer cancer cells receive the signal telling them to grow.

ERDs do not seem to affect brain hormones, which stimulate the body's thermostat. For this reason, ERDs may cause fewer menopause-like side effects than tamoxifen, including hot flashes. ERDs are more like aromatase inhibitors in the degree and frequency of hot flashes and other menopausal symptoms, such as vaginal dryness and mood swings, they may cause.¹⁰

Fulvestrant is the only ERD so far. It is not approved or funded for use in B.C.

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11. Ovarian suppression in breast cancer

Ovarian suppression or removal (radiation, surgery or drug therapy) is only effective in pre-menopausal women with hormone-receptor-positive breast cancer who decline chemotherapy. Where tamoxifen blocks estrogen from binding to estrogen receptors, ovarian shutdown or removal decreases the amount of estrogen in the body. Because they deal with estrogen in the body in different ways, ovarian shutdown or removal and tamoxifen can be combined to keep the amount of estrogen in the body to the lowest levels possible to avoid further estrogen stimulation of cancer cell growth.¹¹

12. Three ways to stop the ovaries' production of estrogen

1. LHRH-agonists – These medications interfere with the normal pathway of the pituitary hormones, LH and FSH. By blocking the release of LH and FSH, the ovaries temporarily stop producing estrogen. When the drugs are stopped, the ovaries generally start working normally again. LHRH-agonists are given as an intramuscular injection every month to three months for two to five years when used as adjuvant treatment. Examples of LHRH-agonists are: goserelin, buserelin, leuprolide, and triptorelin
2. Oopherectomy – The surgical removal of the ovaries can dramatically lower the amount of estrogen in the body. However, other tissues, such as the adrenal glands (glands over the kidneys that help control important body functions), will still produce small amounts of estrogen
3. Radiation to the ovaries - Low-dose radiation to the ovaries shuts down the production of estrogen in the ovaries. This technique, sometimes called ovarian ablation, is rarely used today¹¹

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13. Patients considerations when contemplating ovarian shutdown or removal

• Does the patient want to have a family or has not finished having a family?
• Does the patient have a risk of developing ovarian cancer (BRCA1 or BRCA2)?
• Is the patient concerned with how early menopause will affect quality of life (fertility, hot flashes, etc.) and overall health considerations (such as increased cholesterol and bone loss)?¹²

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Adjuvant Trastuzumab Therapy:

1. What is trastuzumab?

Trastuzumab is a monoclonal antibody (biologic therapy) which is produced in a laboratory. It is designed to recognize a specific protein on the human epidermal growth factor receptor 2 (HER2/neu). Trastuzumab may work by binding to HER2-positive cancer cells and blocking them from dividing and growing signaling the body's immune system to destroy the cell or by working with chemotherapy to destroy the cells. (Image 1).

Image 1. Image sourced with permission from Roche Pharmaceuticals.

2. Use of trastuzumab

Trastuzumab is a type of "targeted therapy" which can be used as adjuvant therapy, with chemotherapy, in newly diagnosed early and locally advanced high risk HER2 overexpressing breast cancers (approximately 20-25% of all newly diagnosed breast cancers).¹³ To date, studies have demonstrated clinically significant improvements in the disease free survival and overall survival with acceptable rates of generally reversible cardiac toxicity among eligible patients.

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3. Eligibility for trastuzumab

Patients are eligible for trastuzumab if they are HER2 positive and are otherwise candidates for adjuvant chemotherapy. There is no evidence at this time for the addition of trastuzumab to hormonal treatment alone in low risk disease.¹⁴

Trastuzumab is usually given after, or in combination with, other chemotherapy agents. For patients receiving adjuvant radiation following chemotherapy, trastuzumab can continue as there is no increase in toxicity reported at this time. It can also be given at the same time as hormone therapy.¹⁴

Trastuzumab is given intravenously once every two to three weeks for one year in total.

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4. Major risks of trastuzumab

Cardiac toxicity: a MUGA scan or echocardiogram should be done prior to the first treatment and every 12 weeks during treatment and at completion of therapy. Doses may need to be adjusted or treatment discontinued based on these test results.¹⁴

References

1. Breast cancer: practice guidelines in oncology, Version 2.2006, 12-05-05 © 2005, National Comprehensive Cancer Network, Inc.

2. Olivotto I, Gelmon K, McCready D, Pritchard K, Kuusk U. Intelligent patient guide to breast cancer. 4th ed. Edwards C, editor.Vancouver (B.C.): Intelligent Patient Guide Limited; 2006, pg.145.

3. Olivotto I, Gelmon K, McCready D, Pritchard K, Kuusk U. Intelligent patient guide to breast cancer. 4th ed. Edwards C, editor.Vancouver (B.C.): Intelligent Patient Guide Limited; 2006, pg. 146.

4. Olivotto I, Gelmon K, McCready D, Pritchard K, Kuusk U. Intelligent patient guide to breast cancer. 4th ed. Edwards C, editor.Vancouver (B.C.): Intelligent Patient Guide Limited; 2006, pg.164.

5. Olivotto I, Gelmon K, McCready D, Pritchard K, Kuusk U. Intelligent patient guide to breast cancer. 4th ed. Edwards C, editor.Vancouver (B.C.): Intelligent Patient Guide Limited; 2006, pg.169

6. Breastcancer.org (http://www.breastcancer.org). Narberth (PA): breastcancer.org; c2000-06. (cited Sep 22, 2006). Available from: http://www.breastcancer.org/tre_sys_hrt_serm.html

7. Breastcancer.org (http://www.breastcancer.org). Narberth (PA): breastcancer.org; c2000-06. (cited Sep 22, 2006). Available from: http://www.breastcancer.org/tamoxifen_receptor.html

8. BC Cancer Agency (http://www.bccancer.bc.ca). Vancouver (B.C.): 2006. (cited Sep 22, 2006). Available from: http://www.bccancer.bc.ca/HPI/DrugDatabase/DrugIndexPro/Anastrozole.htm

9. BC Cancer Agency (http://www.bccancer.bc.ca). Vancouver (B.C.): 2006. (cited Sep 22, 2006). Available from: BC Cancer Agency's Cancer Management Guidelines -> Breast -> Management

10. Breastcancer.org (http://www.breastcancer.org). Narberth (PA): breastcancer.org; c2000-06. (cited Sep 22, 2006). Available from: http://www.breastcancer.org/tre_sys_hrt_erds.html

11. Olivotto I, Gelmon K, McCready D, Pritchard K, Kuusk U. Intelligent patient guide to breast cancer. 4th ed. Edwards C, editor. Vancouver (B.C.): Intelligent Patient Guide Limited; 2006, pg.165-166.

12. Breastcancer.org (http://www.breastcancer.org). Narberth (PA): breastcancer.org; c2000-06. (cited Sep 22, 2006). Available from: http://www.breastcancer.org/tre_sys_hrt_ovryrev_benefits.html

13. Olivotto I, Gelmon K, McCready D, Pritchard K, Kuusk U. Intelligent patient guide to breast cancer. 4th ed. Edwards C, editor. Vancouver (B.C.): Intelligent Patient Guide Limited; 2006, pg.72.

14. BC Cancer Agency (http://www.bccancer.bc.ca). Vancouver (B.C.): 2006. (cited Sep 22, 2006). Available from: BC Cancer Agency's Cancer Management Guidelines -> Breast -> Management

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