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Breast Cancer

Table of Contents
1 Disease Overview
        1.1 Risk Factors and Prevention
        1.2 Screening
        1.3 History, Symptoms and Signs
        1.4 Diagnosis and Tumour Assessment
        1.5 Staging Investigations
2 Staging
3 Stage Grouping
4 Treatment Modalities
        4.1 Surgery
        4.2 Adjuvant Systemic Therapy
        4.3 Adjuvant chemotherapy
        4.4 Triple Negative Breast Cancer
        4.5 HER2-positive Breast Cancer (15-20%)
        4.6 Endocrine or Hormonal Therapy
        4.7 Adjuvant Radiation
5 Metastatic Disease
6 Follow-up
7 Pivotal Trials
        7.1 Prevention Trials
        7.2 Surgical Trials
        7.3 Adjuvant Endocrine Therapy Trials in Early Breast Cancer
        7.4 Adjuvant Chemotherapy in Early Breast Cancer
        7.5 Decision Tool on Chemotherapy in node negative Breast Cancer
        7.6 Adjuvant Chemotherapy in Trastuzumab in HER2 positive Early               Stage Breast Cancer

Disease Overview

    Breast cancer is the number one cancer diagnosis in women in North America. 1 in 9 women is expected to be diagnosed with breast cancer in her life time. Second leading cause of cancer death in Canadian women. In recent years, decrease in breast cancer mortality is due to early diagnosis of breast cancer by way of screening mammography and the use of adjuvant systemic treatments.

Risk Factors and Prevention

Source: ASCO SEP 4th ed.

    Other modifiable risk factors include obesity, sedentary lifestyle and alcohol consumption.

    Patients who meet the following criteria are referred for genetic testing:

  • Age 50 or younger with triple-negative breast cancer
  • Breast cancer at age 35 or less
  • Breast cancer diagnosis, with any family member at age 50 or younger also diagnosed with breast/ovarian cancer
  • Ashkenazi Jew with diagnosis of breast cancer

    Women with a high risk of breast cancer may benefit from pharmacologic intervention or prophylactic mastectomy or oophorectomy after completion of family and need counseling.

Screening

    Screening mammography is a well-proven and cost-effective tool, but sensitivity and specificity of mammography are not optimal. Ultrasound and magnetic resonance imaging (especially for early detection in women with BRCA1/BRCA2 mutations) may be used in conjunction with mammography.

Prevention of Breast Cancer

There have been multiple trials showing 50% reduction of hormone-receptor positive, invasive and non-invasive breast cancer in high-risk women, with the use ofSERMS (Tamoxifen and Raloxifene)and Aromatase Inhibitors (AI) (Anastrazole, Letrozole, and Exemestene) for 5 years (Lancet, 2014). Tamoxifen was the first pharmacologic intervention in prevention of breast cancer.

History, Symptoms and Signs

    Mammography often identifies a malignancy before a lump is felt. Pain is an uncommon symptom, but skin changes such as thickening, redness, or nipple abnormalities may be seen.

Diagnosis and Tumour Assessment

    Diagnosis of breast cancer is usually based on mammography, followed by ultrasound and/or image-guided core biopsy. A titanium marker clip placed at the biopsy site may assist in localizing lesions prior to lumpectomy or evaluating response to neoadjuvant chemotherapy. Pathologic analysis of tumour samples provide information about type of tumour (i.e. ductal, lobular, etc.), grade of tumour, hormone receptor status (receptor assays or immunohistochemistry), and HER2 expression (by immunohistochemistry or fluorescence in situ hybridization (FISH)). Estrogen and progesterone receptors have a weak prognostic value and their primary value is in predicting efficacy of endocrine therapy in ER/PR/positive tumours. HER2 overexpression on FISH (ratio greater than 2.2) or 3+ on immunoassay is prognostic and also predictive for response to anti-HER2 agents (Trastuzumab, Lapatinib, Pertuzumab, Emtansine Trastuzumab).

Pathologic Types

    The usual pathologic types of breast cancer are ductal carcinoma (85%) non-invasive and invasive, lobular carcinoma (15%) non-invasive and invasive, and others(10%). Pathology is reviewed in the tumour board.

    Molecular profiling has identified several breast cancer subtypes with distinct clinical behaviours (Publication by Sorlie et al., 2001.)

Molecular Subtypes of Breast Cancer and Prognosis

Staging Investigations

    For women with newly diagnosed breast cancer who have undergone surgical resection and have no symptoms, physical signs or biomedical evidence of metastases:

  • For distant metastases, a Chest X-Ray, Ultrasound of the abdomen and pelvis or a CT scan of the thorax, abdomen and pelvis, and bone scan is needed in Stage II-IV disease.
  • Stage 0: Full examination done no staging investigations.
  • Stage I: Staging testing is optional as very rarely have metastasis and are usually false positive.

Staging

    Tumour stage is determined after surgical resection. It gives prognostic information and guides treatment.

*Note: Invasion of the dermis alone does not qualify as T4.

**Note: Inflammatory carcinoma is restricted to cases with typical skin changes involving a third or more of the skin of the breast. While the histologic presence of invasive carcinoma invading dermal lymphatics is supportive of the diagnosis, it is not required, nor is dermal lymphatic invasion without typical clinical findings sufficient for a diagnosis of inflammatory breast cancer.


Stage Grouping

* T1 includes T1mi

** T0 and T1 tumours with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB.

Prognosis


Treatment Modalities

Neoadjuvant Treatment for Locally Advanced Breast Cancer (LABC)

    Stage III disease is often classified as “locally advanced disease” and can be grouped into two categories: a) large tumours (>5cm) but operable, or b) inoperable disease, on the basis of skin involvement, attachment to the chest wall, and matted lymph nodes.

    LABC is treated with neoadjuvant systemic therapy (chemotherapy, endocrine therapy and targeted therapy) according to the age of the patient, hormone receptors, and HER2 status. Local treatment is according to the response to systemic therapy, either lumpectomy and radiation, or mastectomy and radiation.

    There is an ongoing clinical trial assessing neoadjuvant chemotherapy with targeted therapy in HER2 positive invasive breast cancer.

    The treatments described below apply to Stage I-III breast cancer.

Surgery

Stage 0:
    Non-invasive or carcinoma in situ (ductal or lobular) is curative by surgery and patients do not require sentinel or axillary node dissection. Lumpectomy alone has a risk of 10-30% local recurrence over 10 years, which can be reduced by 50% with breast radiation. Oncotype testing is experimental to see if radiation can be spared in low risk ductal carcinoma in situ patients.

Stage I-III:
The goals of surgery are the following:

  • Remove the primary tumour with negative margins to reduce the recurrence risk and allow pathologic tumour staging.
  • Remove axillary lymph nodes to provide prognostic information. Most patients undergo sentinel node instead of axillary node dissection to reduce toxicity.

    The surgical options 1) lumpectomy (complete resection of the tumour with a negative margin), or 2) modified radical mastectomy (complete removal of the breast). The presence of positive margins usually necessitates re-operation.

    In general, there is no difference in local recurrence between mastectomy versus lumpectomy plus local radiation. Breast reconstruction may be performed either immediately or delayed until all treatment has been completed.

    Complications include pain, wound infection, fibrosis, and lymphedema in the arm on the operated side. Local recurrence may be managed similarly to the initial disease treatment.

Adjuvant Systemic Therapy

    After surgery, systemic therapy is given to reduce risk of recurrence. Patients are seen in the multidisciplinary clinic with the medical and radiation oncologist and pathology review is done in the tumour board. The decision of adjuvant systemic therapy after surgery in early stage breast (stage I-III) is made on the basis of pathologic or prognostic factors (tumour size, nodal status, tumour grade, lymphovascular invasion, hormone receptor and HER2 status) and patient factors (age, comorbidities and patient preference).

    Biology of the tumour, defined by targets such as hormone receptors and HER2 amplification is important, although lymph node involvement and the size of the tumour still remain as the most important prognostic factors and major determinants of treatment.

    Adjuvant online (www.adjuvantonline.com) is a tool used to assess the risk of recurrence and mortality based on traditional prognostic factors and to assess the benefits of systemic therapy.

    In the era of personalized medicine, prospective clinical trials are integrating traditional prognostic factors, such as age of the patient, size of the tumour, grade, number of nodes, and receptor status with molecular profiling to better determine risk of recurrence and treatment options for breast cancer patients. Breast cancer is a heterogeneous disease, and the commonest (75%) is estrogen receptors positive cases, 15-30% HER2 positive cases and 15-20% triple negative cases. The options for systemic therapy are chemotherapy, biologic and endocrine therapy.

Hormone Receptor Positive Breast Cancer

    Oncotype Dx testing is offered to patients with ER positive and node negative breast cancer to individualize treatments depending on the recurrence score. The score estimates the risk of recurrence, which shows most benefit of chemotherapy in those with a high recurrence score (>30) and very little benefit in those with a low recurrence score (<18). There is a clinical trial looking at Oncotype testing for node positive HR positive disease.

    In hormone receptor-positive breast cancer, anthracycline-containing chemotherapy reduces the relative risk of recurrence by 36% and reduces the relative risk of death by 35% when added to Tamoxifen. In hormone receptor-positive breast cancer, the addition of Taxanes to anthracycline-based regimens reduces the relative recurrence risk by an additional 26% and reduces relative mortality risk by an additional 23%. In hormone receptor-positive breast cancer, overall prognosis is good, but the risk of recurrence continues for at least 10 to 15 years in chronic disease.

    Chemotherapy reduces the risk of relapse early and can benefit hormone receptor-positive disease with high risk factors such as node positive and grade 3. There has been a decrease in the use of chemotherapy for luminal A group patients hormone receptor-positive (and HER2-negative) disease, as on average, chemotherapy is less beneficial in this subgroup than in those with HER2-positive or triple-negative disease.

Triple Negative Breast Cancer (TNBC)

    The risk of systemic recurrence is greatest within the first 2 to 3 years, compared with hormone receptor-positive disease. Adjuvant or neoadjuvant chemotherapy remains the mainstay of adjuvant treatment for TNBC (ER/PR-negative and HER2-negative). TNBC is more common in young and/or black women, and is usually high-grade. Tumour size greater than 0.5 cm (T1b or higher) has a high enough risk of disease recurrence and death to warrant a discussion of adjuvant chemotherapy. Most of the time dose dense AC-TAXOL is used with growth factor support. Patients with BRCA I/II gene mutation benefit from platinum chemotherapy.

HER2-Positive Breast Cancer

    About 15-30% of breast cancer patients have overexpression of a proliferative HER2 oncogene, which is a trans-membrane protein receptor tyrosine kinase and is an adverse prognostic factor and predictor of response to trastuzumab.

    Trastuzumab (t-mab) is a recombinant humanized monoclonal antibody directed against the HER2 receptor. Chemotherapy with trastuzumab in metastatic breast cancer showed a six month survival benefit in HER 2 positive breast cancer and was available in 1999 in the clinics. In 2005, practice changing results of four randomized trial of adjuvant chemotherapy with trastuzumab in more than 12000 patients showed 50% reduction in recurrence and 30% reduction in mortality and became the standard of care for HER2 positive cancers. HER2 amplified means ratio greater than 2.2 or 3+ on immunohistochemistry.

    Patients with HER2-positive cancer regardless of tumour size, or node-negative disease with tumour size larger than 1 cm (T1c or higher) are offered combination chemotherapy (anthracyclines are not given concurrently with trastuzumab) and trastuzumab for adjuvant treatment for 18 treatments, as there is no benefit of more than one year of adjuvant trastuzumab. Approval of trastuzumab in <1 cm and special requests from Cancer Care Ontario.

    These practice-changing results are being further explored in the ATEMPT trial, which involves patients with stage I HER2-positive breast cancer, randomly assigned to 12 weeks of paclitaxel/trastuzumab followed by trastuzumab for 9 months or 12 months of trastuzumab emtansine (T-DM1).

    Cardiac monitoring with an echocardiogram or nuclear ventriculogram should be performed every 3 months.

Adjuvant chemotherapy

    Adjuvant chemotherapy is given within 6-12 weeks post operatively. Principles for administering adjuvant chemotherapy are: full-dose polychemotherapy and should be administered based upon actual height and weight.

    A variety of chemotherapy regimens have been used for the treatment of breast cancer in the last four decades. Commonly used agents in the regimens include cyclophosphamide, anthracyclines (doxorubicin or epirubicin), methotrexate, 5-flourouracil, and taxanes (docetaxel or paclitaxel). But the optimal regimen remains controversial.

    Chemotherapy regimens are divided into:

  1. First generation (CMF, AC)
  2. Second generation (TC, FAC)
  3. Third generation (AC-Taxol dose dense every 2 weeks, or AC every 3 weeks for 4 cycles and weekly taxol for 12 weeks, FEC100-Taxotere)

    Most studies involve women younger than age 70; therefore, administration of chemotherapy in elderly patients is based upon individual risk/ benefit ratios. Polychemotherapy is preferred and is associated with greater benefits in women younger than age 50, with higher-risk disease (node-positive), and with hormone receptor– negative disease.

    In general, multidrug regimens containing anthracyclines and taxanes are appropriate for higher-risk disease (i.e., node-positive or node-negative with large tumour size [T2 or higher]), whereas shorter and less complex regimens are usually used for smaller node-negative tumours, and selected node-positive tumours. The choice of regimen is dependent upon the overall risk of disease recurrence and the relative reduction of risk with the administration of chemotherapy, balanced by the toxicity of the drugs.

    Intravenous chemotherapy is generally administered using peripheral or a central line inserted in a vein in the arm or in the chest (port-a-cath) and terminating either in the thoracic vena cava or the right atrium. A central line reduces complications associated with administration of concentrated solutions including extravasation of the chemotherapy.

Triple Negative Breast Cancer (TNBC)

    The risk of systemic recurrence is greatest within the first 2 to 3 years, compared with hormone receptor –positive disease, where the risk of recurrence continues for at least 10 to 15 years. Adjuvant endocrine therapies and trastuzumab are not effective without the presence of their target, as in ER- and/ or PR- and HER 2NEU negative disease. For this reason, chemotherapy is the mainstay of adjuvant treatment for TNBC (ER/ PR-negative and HER2-negative), a subtype of breast cancer that lacks a specific therapeutic target. TNBC only accounts for approximately 10% to 15% of all breast cancer, is more common among young and/ or black women, and is usually high-grade. Unlike other subtypes of breast cancer, the biology of TNBC is such that its prognosis does not correlate as closely with tumor size or nodal involvement. Tumor size greater than 0.5 cm (T1b or higher) has a high enough risk of disease recurrence and death to warrant a discussion of adjuvant chemotherapy. Based upon a meta-analysis of 13 randomized trials involving 22,453 women, the addition of taxanes to anthracycline-containing regimens resulted in a 17% reduction in the relative risk of relapse, and a 15% relative reduction in risk of death at 5 years. This translates into a 5% absolute improvement in DFS and a 3% improvement in OS. Based upon a meta-analysis of 13 randomized trials involving 22,453 women, the addition of taxanes to anthracycline- containing regimens resulted in a 17% reduction in the relative risk of relapse, and a 15% relative reduction in risk of death at 5 years. This translates into a 5% absolute improvement in DFS and a 3% improvement in OS. While there was no difference between the concurrent or sequential regimens, the dose-dense regimen (every 2 week administration) did result in a 26% relative reduction in risk of recurrence and a 31% relative reduction in risk of death.

    As stated previously, the efficacy of chemotherapy is greater in the adjuvant setting, however, the chemotherapy regimens recommended for treatment are identical for both TNBC and hormone receptor– positive cancer.

HER2-positive Breast Cancer (15-20%)

    HER2 is an important therapeutic target for the 15% to 20% of breast cancers that are classified as HER2-positive either by over-expression of the HER2 protein (3 + by ICH) or by HER2 gene amplification (FISH ≥ 2.0). HER2 is an adverse independent prognostic indicator, and predicts benefit with trastuzumab, the humanized monoclonal antibody against the extracellular domain of HER2. Trastuzumab has limited efficacy as a single agent in metastatic disease, and has only been studied in combination with chemotherapy in adjuvant setting. A meta-analysis of five adjuvant therapy studies involving 9,748 patients demonstrated a 38% reduction in the relative risk of recurrence and a 34% relative reduction in risk of dying from any cause.

    Patients with HER2-positive cancer that is node-positive, regardless of tumor size, or node-negative disease with tumor size larger than 1 cm (T1c or higher) should be offered combination chemotherapy and trastuzumab for adjuvant treatment for 18 treatments and there is no benefit of more than one year of adjuvant Trastuzumab. The phase II APT trial (Adjuvant Paclitaxel and Trastuzumab) involved 406 patients with node-negative, HER2-positive breast cancers that measured 3 cm or smaller in size, though over 90% had tumors 2 cm or larger. In this single-arm, multi-institutional study, patients received 12 weeks of standard paclitaxel and trastuzumab given at the doses prescribed in the ACTH regimen, followed by 9 months of single-agent trastuzumab. The 3-year DFS was 98.7% at a median follow-up of 3.6 years, with two of the 10 DFS events being distant metastasis. The regimen was well tolerated, with minimal neuropathy and cardiac compromise.

    Approval of Herceptin in < 1 cm and special requests need to be done.

    Risk of cardiac compromise was associated with advanced age, hypertension, and initial ventricular function. Concern for cardiac toxicity prompted investigation into a nonanthracycline-containing trastuzumab regimen: taxotere, carboplatin, and trastuzumab (TCH) administered every 3 weeks for six cycles. BCIRG 006 compared this regimen with four cycles of AC every 3 weeks followed by four cycles of docetaxel alone or with 1 year of trastuzumab beginning with the docetaxel. BCIRG 006 confirmed a benefit with the addition of trastuzumab to chemotherapy; there was a 3% absolute difference in DFS and a 1% difference in OS at 5 years favoring the AC/ docetaxel/ trastuzumab arm over the TCH arm. It should be noted, however, that the study was not designed to compare the two trastuzumab-containing arms and any conclusions about the benefits of one regimen over another should be considered exploratory.

    TCH was associated with significantly less cardiac toxicity (p < 0.001 ) and risk of secondary leukemia compared with the AC/ docetaxel/ trastuzumab regimen, making it an acceptable treatment alternative in select patients. Doxorubicin/ cyclophosphamide/ paclitaxel/ trastuzumab (ACTH) with concurrent trastuzumab administration is commonly chosen as treatment for a patient who is at substantial risk of disease recurrence and who does not have risk factors for cardiac toxicity. For patients at lower risk of disease recurrence or with cardiac risk factors, TCH represents a reasonable alternative.

    These practice-changing results are being further explored in the ATEMPT trial, which involves patients with stage I HER2-positive breast cancer, randomly assigned to 12 weeks of paclitaxel/ trastuzumab followed by trastuzumab for 9 months or 12 months of trastuzumab emtansine (T-DM1).

    When trastuzumab is used as a single agent following chemotherapy, it is commonly given every 3 weeks. Cardiac monitoring with an echocardiogram or nuclear ventriculogram should be performed every 3 months.

Endocrine or Hormonal Therapy

    Adjuvant endocrine therapy with a selective estrogen receptor modulator (SERM) or an aromatase inhibitor (Aromatase Inhibitor, in postmenopausal woman), is an important treatment approach in patients with ER/PR+ early-stage breast cancer, either alone or after completion of chemotherapy. The EBCTCG meta-analysis showed that 5 years of tamoxifen reduces the relative risk of distant recurrence by approximately 41% and reduces the relative risk of dying by 34% (Lancet, 2011). Endocrine therapy reduces the risk of recurrence by decreasing the ability of estrogen to stimulate existing micro-metastases or dormant cancer cells.

    Adjuvant endocrine or hormonal therapy with the SERM, tamoxifen, is given for at least five years in the pre-menopausal or post-menopausal patient population. More recently, two trials show benefit for 10 years of adjuvant tamoxifen especially in pre-menopausal patients (ATLAS and aTTOM trials– see website)although with increased risk of uterine cancer (Davies C, Lancet 2013; Gray RG, J Clin Oncol 2013).

    In post-menopausal women, there are additional endocrine treatment strategies that can be offered. Extended adjuvant treatment with an AI (letrozole) for 5 years after five years of tamoxifen has been shown to be beneficial in a landmark randomized trial especially in women with node positive breast cancer (Goss, NEJM 2004). Randomized trials have also shown that 5 years of AIs (anastrozole, letrozole, exemestene) were associated with improved disease free survival by 26%compared to 5 years of tamoxifen. No survival difference between tamoxifen and aromatase inhibitors was demonstrated in the individual clinical trials.

    There are trials showing survival benefit of switching to an AI after 2-3 years of tamoxifen versus five years of tamoxifen, alone. There are ongoing trials looking at five vs. ten years of aromatase inhibitor use after the initial five years of tamoxifen. Randomized comparison of adjuvant AI, exemestene plus ovarian function suppression (OFS), to tamoxifen plus OFS in pre-menopausal women showed benefit of AI 3.8% at 5years (91.1 vs 87.3%) and no difference in overall survival. Exemestene and OFSas compared to tamoxifen and OFS is a new treatment option for pre-menopausal women with estrogen receptor positive early breast cancer.

Side Effects of Antiestrogen Therapy

Adjuvant Radiation

    Radiation therapy is performed after lumpectomy to eradicate local subclinical disease and reduce local recurrence, even in patients with low-risk disease and favourable prognostic features. Radiation is done four weeks after chemotherapy and given for 3-5 weeks, and at times, additional boost. Several approaches may be used, including partial or whole-breast radiotherapy. Radiation is offered to patients with mastectomy if the breast tumour is large (>5cm) or if there is axillary lymph node involvement or if sentinel node is positive. Complications include fibrosis, pain, sarcoma and cardiac side effects of radiation on the left breast.


Metastatic Breast Cancer

    Breast cancer can metastasize at any site and the commonest site is bone followed by, liver, lung, brain etc. In about 20% of patients with breast cancer, the receptor status may change at recurrence. Biopsy of metastases may determine the receptor status so that proper treatment can be offered. Overall survival of metastatic breast cancer is 36-60 months. In some patients, breast cancer is a chronic disease.

    Metastatic breast cancer is considered to be incurable; therefore, the goal of treatment is to control disease progression and improve quality of life. The choice of systemic therapy is based upon the hormone receptor and HER2 status, as well as the extent and pace of metastatic disease, effect of disease on the patients quality of life and performance status, and patient preference and choice.

    However, prognosis of metastatic breast cancer depends on duration of remission, response to treatment, the sites and burden of the disease, and performance status of the patient. Treatment and management of metastatic breast cancer is individualized depending on the hormone receptors and HER2 status.

Hormone Receptor Positive Metastatic Breast Cancer

    If hormone receptors are positive, endocrine therapy is effective and the median response duration is up to 9 months. The treatment options include endocrine therapy with aromatase inhibitors (AI) or tamoxifen or vice versa. If progression occurs on first or second line endocrine therapy, patients can be offered mTOR inhibitor(afinitor or everolimus) with Exemestene.

  • First line hormonal therapy: Tamoxifen.
  • Second line hormonal therapy: Aromatase inhibitor options for the treatment of hormone receptor-positive breast cancer progressing on a non-steroidal AI include exemestane alone or fulvestrant alone (Mehta R, N Engl J Med 2012; Bergh J, J Clin Oncol 2012; Johnston S, Lancet Oncol 2013).
  • Third line hormonal therapy: Aromatase inhibitors with everolimus mTOR inhibitorfor patients progressing on non-steroidal AI.

    The phase III BOLERO-2 trial demonstrated a superior median progression-free survival with combination everolimus (mTOR inhibitor) and exemestane compared with exemestane alone (10.6 months vs. 4.1 months, respectively; HR 0.36; p < 0.001) among postmenopausal women whose disease progressed or recurred while on a nonsteroidal AI (Baselga J, N Engl J Med 2012).

    Phase III randomized trial of fulvestrant (faslodex) plus pablociclib vs placebo showed benefit in ER positive HER2 negative metastatic breast cancer (PFS 9.2 months vs 3.8 months p<.000001). Side-effects were manageable and mostly hematologic (Turner et al ASCO, 2015) this is an option for ER positive metastatic breast cancer.

    Sequential single-agent palliative chemotherapy is preferable to combination chemotherapy unless a rapid disease response is needed as in liver metastasis.

    Goals of care and end-of-life issues need to be discussed and support should be provided upfront with early referrals to a social worker.

HER2 Positive Metastatic Breast Cancer

    Trastuzumab (monoclonal antibody against HER2), pertuzumab (HER2 and HER3 dimerization inhibitor) and docetaxel vs trastuzumab and doctaxel (56months vs 40.8 months) is standard first line treatment for metastatic breast cancer (Swain et al., 2013).

    The antibody-drug conjugate T-DM1 is an effective treatment for recurrent HER2-positive disease after progression on trastuzumab.

Triple-Negative Metastatic Breast Cancer (TNBC)

    Prognosis of patients with triple negative metastatic breast cancer is poor and these patients should be offered clinical trials. Chemotherapy is the standard treatment. Cisplatinum containing regimens are showing benefit in TNBC.

    For more information regarding side-effects of systemic treatments , go to www.cancercare.on.ca.

Supportive Care

    Metastatic breast cancer patients with bone metastasis require bisphosphonates, such as pamidronate intravenously (first line) or zoledronic acid (second line) every 4 weeks for one year and then every 3 months. Denusomab or Xgeva compared to bisphosphonates have similar benefits and are given every 4 weeks subcutaneously. Blood work is done to observe calcium levels. Furthermore, patients should be educated to not to have dental surgical procedures during treatment, to avoid the low risk of osteonecrosis of the jaw. Patients with bone metastasis are referred for radiation for palliation (i.e. pain control).


Follow-up

    The challenge is that cancer treatments are complex and multimodal, with short and long term toxicity, and patients need follow-up. Goals of follow-up include: early recognition and treatment of potentially curable disease recurrences or a second primary; identification and management of treatment related complications and other comorbid conditions; recognizing symptoms related to metastasis; and prompt referral to the specialists. Primary care provider need a better understanding of the cancer-related toxicities. These challenges and experiences are different for each individual cancer survivor.

    Cancer care is not ‘one-size-fits-all’; it should be personalized and patient centered. Although the majority of cancer survivors lead productive lives, all domains of health should be addressed when these individuals are seen. Cancer in some instances behaves like a chronic disease–a shared care model may work, but coordination of care is essential between the health care professionals. Care plan will be implemented in patients receiving chemotherapy as personalized multifaceted care plan research at SMH showed statistically significant self-efficacy scores in the chemotherapy arm.

    Patients need to be educated about recurrence and healthy lifestyles. Follow up care needs to be individualized depending on the type of treatment, overall health status and potential side effects of the treatments.

    Regular post-treatment surveillance is recommended for women with breast cancer after completion of primary therapy. Although the risk of recurrence is highest during the first five years of primary treatment, the threat of a breast cancer recurrence may persist for 20 years or longer especially in patients with ER positive tumours. Triple negative tumours tend to relapse early and need close follow-up for first 2 years.

  • In asymptomatic women treated with curative intent:
    Conduct a careful history and physical examination every 3-6 months for the first three years then every 6-12 months for the next two years and annually thereafter; counsel patients regarding possible symptoms of recurrence, including new lumps, bone pain, dyspnea, abdominal pain or persistent headaches.
  • Women treated with breast-conserving therapy:
    Order post-treatment mammogram no earlier than six months after definitive radiation therapy (subsequent mammograms should be obtained every 6-12 months). Perform mammography annually if stability of mammographic findings is achieved after completion of loco-regional therapy.
  • Breast magnetic resonance imaging (MRI) is currently not recommended for routine breast cancer surveillance; may be an option for post-therapy surveillance in women at high risk of bilateral breast cancer.
  • Regular gynaecologic follow-up is recommended. Patient should be advised to report any vaginal bleeding promptly.
  • Consider baseline and periodic bone density determinations in women taking aromatase inhibitors.
  • ACP recommends BMD for women on aromatase inhibitors and intervention to prevent osteoporosis.
  • ASCO recommends healthy lifestyle, well balanced diet and regular exercise.
  • Routine use of complete blood count (CBC), liver function testing (LFT), chest x-ray, tumour markers, liver ultrasound, bone scan, CT and PET scans, are not currently recommended for surveillance in otherwise asymptomatic patients and thus should only be performed as clinically indicated.

    Local recurrence may be managed similarly to the initial disease treatment, whereas distant recurrences indicate metastatic disease and are managed systemically. Clinical trial participation may also be offered to women with recurrent disease.

    For further information, go to the Survivorship Guide for primary care physicians here: http://breastcancer09.utorontoeit.com/Home.html


Pivotal Trials

Prevention Trials

Fisher B. Highlights from recent National Surgical Adjuvant Breast and Bowel Project studies in the treatment and prevention of breast cancer. CA Cancer J Clin. 1999;49(3):159-177

Davies C, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet.2013; 381:805-816.

Vogel VG, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prev Res. 2010;3(6):696-706

Surgical Trials

Fisher B et al. Eight-Year Results of a Randomized Clinical Trial Comparing Total Mastectomy and Lumpectomy with or without Irradiation in the Treatment of Breast Cancer. N Engl J Med. 1989;320:822-828

Adjuvant Endocrine Therapy Trials in Early Breast Cancer

Coombes C et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350(11):1081-92.

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet.2005; 365:1687-1717.

ATAC Trialists Group. ATAC Trial Update. The Lancet. 2005;365(9466):1225-1226

Rae JM, et al. CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst. 2012; 104:452-460.

Regan MM, et al. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial. J Natl Cancer Inst. 2012; 104:441-451.

Thürlimann BJ, Keshaviah A, Mouridsen H, et al. BIG 1-98: Randomized double-blind phase III study to evaluate letrozole (L) vs. tamoxifen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. ASCO. 2005 (Abstract 511)

Goss PE, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003; 349(19):1793-802.

Adjuvant Chemotherapy in Early Breast Cancer

Jones S, et al. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol. 2009; 27(8): 1177-83.

Roché H, Fumoleau P, Spielmann M, et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006; 24(36):5664-71.

Bonnadonna, G et al. Adjuvant CMF chemotherapy in operable breast cancer: Ten years later. World J Surgery. 1985; 9:707-713

Carpenter JT, Velez-Garcia E, Aron BS, et al. Five year results of a randomized comparison of cyclophosphamide, doxorubicin and fluorouracil versus cyclophosphamide, methotrexate and fluorouracil for node positive breast cancer. Proc Am Soc Clin Oncol. 1994;13:66. Abstract 68.

Trudeau M, et al. Selection of adjuvant chemotherapy for treatment of node-positive breast cancer. Lancet Oncol. 2005; 6(11):886-98.

Citron ML, Berry DA, Cirrincione C, et al: Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 974. J Clin Oncol. 2003;21:1431-1439, 2003

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Decision Tool on Chemotherapy in node negative Breast Cancer

Soon Paik et al. A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cance. N Engl J Med. 2004; 351:2817-2826

Adjuvant Chemotherapy in Trastuzumab in HER2 positive Early Stage Breast Cancer

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl J Med. 2005;353(16):1659-1672


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