Breast Cancer Guidelines: Guidelines Summary, Phar...

Guidelines Summary

Guideline contributor: Kathy D Miller, MD Professor of Medicine and Ballve-Lantero Scholar, Indiana University School of Medicine; Co-Leader, Breast Cancer Program, Indiana University Melvin and Bren Simon Cancer Center

Breast Cancer Screening

Guidelines on breast cancer screening have been issued by the following organizations:

American Cancer Society (ACS)
U.S. Preventive Services Task Force (USPSTF)
American College of Obstetricians and Gynecologists (ACOG)

The guidelines differ in their recommendations regarding breast self-examination and clinical breast examination, use of screening mammography in women 40-49 years old, age at which to discontinue screening mammography, and MRI mammography. All three guidelines recommend routine screening mammography in asymptomatic, average-risk women aged 50 to 74, but differ with regard to frequency of screening.

American Cancer Society screening guidelines

The ACS updated its guidelines for breast cancer screening in average-risk women in October 2015.^[161]At this time, the ACS is in the process of updating the breast cancer screening guidelines for women at high risk, which were last updated in 2007.^[162]

Breast examination

It is acceptable for women to choose not to do breast self-examination (BSE) or to do BSE regularly (monthly) or irregularly. Beginning in their early 20s, women should be told about the benefits and limitations of BSE. Whether a woman ever performs BSE, the importance of prompt reporting of any new breast symptoms to a health professional should be emphasized. Women who choose to do BSE should receive instruction and have their technique reviewed on the occasion of a periodic health examination

The ACS does not recommend clinical breast examination for breast cancer screening in average-risk women at any age

Mammography

ACS recommendations are as follows^[161]:

Women should begin regular screening mammography at age 45 years (strong recommendation)
Women aged 45-54 years should be screened annually (qualified recommendation)
Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified recommendation)
Women should have the opportunity to begin annual screening at 40-44 years of age (qualified recommendation)
Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer (qualified recommendation)

Breast MRI Screening as an Adjunct to Mammography

The ACS recommends annual MRI screening along with mammography, based on evidence from nonrandomized screening trials and observational studies, in women with the following risk factors^[163]:

BRCA mutation
First-degree relative of BRCA carrier, but untested
Lifetime risk ∼20–25% or greater, as defined by BRCAPRO or other models that are largely dependent on family history

The ACS recommends annual MRI screening, based on expert consensus opinion that considers evidence of lifetime risk for breast cancer, in women with the following risk factors^[163]:

Radiation to chest between age 10 and 30 years
Li-Fraumeni syndrome or first-degree relatives with the syndrome
Cowden and Bannayan-Riley-Ruvalcaba syndromes or first-degree relatives with those syndromes

The ACS found insufficient evidence to recommend for or against MRI screening in women with the following risk factors^[163]:

Lifetime risk 15–20%, as defined by BRCAPRO or other models that are largely dependent on family history
Lobular carcinoma in situ (LCIS) or atypical lobular hyperplasia (ALH)
Atypical ductal hyperplasia (ADH)
Heterogeneously or extremely dense breast on mammography
Personal history of breast cancer, including ductal carcinoma in situ (DCIS)

The ACS recommends against MRI screening (based on expert consensus opinion) in women at <15% lifetime risk.

Finally, the ACS advises that screening decisions should be made on a case-by-case basis, as there may be particular factors to support MRI. Payment should not be a barrier.

USPSTF screening guidelines

In 2016, the USPSTF released updated recommendations on breast cancer screening, but did not update its 2009 recommendations for breast examination. In its 2016 statement, the USPSTF encouraged patients to be aware of changes in their bodies and discussing these changes with clinicians.^[164]

The 2009 breast examination recommendations are as follows^[93]:

No requirement for clinicians to teach women how to perform BSE (Grade D recommendation)
Insufficient current evidence to assess the additional benefits and harms of clinical breast examination (CBE) beyond screening mammography in women 40 years or older

The 2016 screening mammography recommendations are as follows^[164]:

No requirement for routine screening mammography in women aged 40 to 49 years (Grade C recommendation); the decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take into account patient context, including the patient's values regarding specific benefits and harms
Biennial screening mammography for women between the ages of 50 and 74 years (Grade B recommendation)
Insufficient current evidence to assess the additional benefits and harms of screening mammography in women 75 years or older
Insufficient current evidence to assess the additional benefits and harms of digital breast tomosynthesis (DBT) as a primary screening method for breast cancer
Insufficient current evidence to assess the additional benefits and harms of adjunctive screening for breast cancer using breast ultrasonography, magnetic resonance imaging, DBT, or other methods in women identified to have dense breasts on an otherwise negative screening mammogram

BCRA-related cancer

In 2013, the USPSTF issued updated guidelines on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women. The current USPSTF recommendations are as follows^[165]:

Women who have family members with breast, ovarian, tubal, or peritoneal cancer should be screened to identify a family history that may be associated with an increased risk for mutations in the breast cancer susceptibility genes BRCA1 or BRCA2
Women who have positive screening results should receive genetic counseling and then BRCA testing if warranted
Women without a family history associated with an increased risk for mutations should not receive routine genetic counseling or BRCA testing

ACOG screening guidelines

The ACOG released guidelines for breast cancer risk assessment and screening in average-risk women in 2017.^[166]For women at average risk, ACOG categorizes its recommendations as follows:

Level A – Based on good and consistent scientific evidence
Level B – Based on limited or inconsistent scientific evidence
Level C – Based primarily on consensus and expert opinion

ACOG recommends that health care providers periodically assess patients' breast cancer risk by reviewing the history (level B). Breast cancer risk factors include the following:

Family history of breast cancer, ovarian cancer, or other hereditary breast and ovatrians syndrome-associated cancer (eg, prostate cancer, pancreatic cancer)
Known deleterious gene mutation
Prior breast biopsy with atypical hyperplasia (lobular or ductal) or lobular carcinoma in situ
Early menarche
Late menopause
Nulliparity
Prolonged interval between menarche and first pregnancy
Menopausal hormone therapy with estrogen and progestin (decreased risk with progestin alone)
Not breastfeeding
Increasing age
Certain ethnicities (eg, higher likelihood of BRCA mutation in Ashkenazi Jewish women)
Higher body mass index
Alcohol consumption
Smoking
Dense breasts on mammography
Prior exposure to high-dose therapeutic chest irradiation at age 10-30 years

Women whose initial history indicates a potentially increased risk of breast cancer should have further risk assessment (level B), using the Gail model or another of the validated assessment tools available online, such as the BRCAPRO, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, International Breast Cancer Intervention Studies (IBIS, also known as Tyrer–Cuzick), or the Claus model.

Breast examination

Women should be counseled about breast self-awareness (ie, awareness of the normal appearance and feel of their breasts) and encouraged to notify their health care provider if they experience a change (level C). However, breast self-examination is not recommended (level B).

Clinical breast examination remains a recommended part of the evaluation of women who are at high risk or have symptoms. Screening clinical breast examination may be offered to asymptomatic, average-risk women on the following schedules, in the context of an informed, shared decision-making approach that recognizes the uncertainty of its benefits and the possibility of adverse consequences (level C):

For women aged 25–39 years, clinical breast examinations may be offered every 1–3 years.
For women aged 40 years and older, clinical breast examination may be offered annually

Mammography

The decision about the age to begin mammography screening should be made through a shared decision-making process that includes information about the potential benefits and harms. Recommendations (level A) for average-risk women are as follows:

Screening mammography should be offered starting at age 40 years.
If patient desires, after counseling, initiate mammography at age 40-49 years.
Women should begin screening mammography by no later than age 50 years.
Mammography may be performed every 1 or 2 years; biennial screening mammography, particularly after age 55 years, is a reasonable option to reduce the frequency of harms, as long as patient counseling includes a discussion that with decreased screening comes some reduction in benefits.
Continue screening mammography until age 75 years; beyond that age, the decision to discontinue screening should be based on a shared decision-making process that includes a discussion of the woman's health status and longevity.

ACOG considers that age alone should not be the basis to continue or discontinue screening. Beyond age 75 years, the decision to discontinue screening mammography should be based on a shared decision-making process informed by the woman’s health status and longevity (level C).

Pharmacologic Interventions for Breast Cancer Risk Reduction

Guidelines for pharmacologic intervention in women who are at increased risk for breast cancer, but do not have a personal history of breast cancer, have been issued by the American Society of Clinical Oncology (ASCO)^[167]and the U.S. Preventive Services Task Force (USPSTF).^[168]The guidelines differ in their classification of increased risk and in their inclusion of women with lobular carcinoma in situ (LCIS).

American Society of Clinical Oncology

ASCO has updated its practice guidelines regarding pharmacologic intervention (eg, tamoxifen, raloxifene, and aromatase inhibitors) for breast cancer risk reduction.^[167]

ASCO guidelines recommend the following^[167]:

For premenopausal or postmenopausal women with increased risk for breast cancer, offer tamoxifen (20 mg/day for 5 years) to reduce the risk of invasive ER-positive breast cancer
In postmenopausal women, raloxifene (60 mg/day for 5 years) may also be considered
Off-label use of exemestane (25 mg/day for 5 years) should be discussed as an alternative to reduce the risk in postmenopausal women
All three agents should be discussed (including risks and benefits) with women aged 35 years or older without a personal history of breast cancer who are at increased risk of developing invasive breast cancer

ASCO guidelines recommend that discussions with patients and health care providers should include both the risks and benefits of pharmacologic breast cancer risk reduction in the preventive setting.

Tamoxifen

ASCO guidelines recommend that use of tamoxifen, 20 mg per day orally for 5 years, should be discussed as an option to reduce the risk of invasive breast cancer (BC), specifically ER-positive BC, in women 35 years of age or older who are premenopausal or postmenopausal and have a 5-year projected absolute breast cancer risk ≥ 1.66% or with LCIS. Risk reduction benefit continues for at least 10 years.^[167]

ASCO guidelines advise that tamoxifen not be used in the following cases^[167]:

In women with a history of deep vein thrombosis, pulmonary embolus, stroke, or transient ischemic attack or during prolonged immobilization
In combination with hormone therapy
In women who are pregnant, may become pregnant, or are nursing mothers

Raloxifene

ASCO guidelines recommend that raloxifene should be discussed as an option to reduce the risk of invasive BC, specifically ER-positive BC, in postmenopausal women who are age ≥ 35 years with a 5-year projected absolute BC risk ≥ 1.66% or with LCIS. Raloxifene is given in a dosage of 60 mg/ day orally for 5 years; it can be used for longer than 5 years in women with osteoporosis, in whom BC risk reduction is a secondary benefit.^[167]

ASCO guidelines advise that raloxifene not be used in the following cases^[167]:

For BC risk reduction in premenopausal women
In women with a history of deep vein thrombosis, pulmonary embolus, stroke, or transient ischemic attack or during prolonged immobilization

Exemestane

Exemestane is not FDA approved for breast cancer risk reduction. However, ASCO guidelines recommend that it should be discussed as an alternative to tamoxifen and/or raloxifene to reduce the risk of invasive BC, specifically ER-positive BC, in postmenopausal women age ≥ 35 years with a 5-year projected absolute BC risk ≥ 1.66% or with LCIS or atypical hyperplasia. It should not be used for BC risk reduction in premenopausal women. Exemestane is given in a dosage of 25 mg per day orally for 5 years.^[167]

USPSTF guidelines

The USPSTF updated its guidelines for primary breast cancer risk reduction in 2013.^[168] The USPSTF recommends that clinicians engage in shared, informed decision making with women who are at increased risk for breast cancer about medications to reduce their risk. For women who are at increased risk for breast cancer and at low risk for adverse medication effects, clinicians should offer to prescribe risk-reducing medications, such as tamoxifen or raloxifene.

The USPSTF concluded that women with an estimated 5-year risk of 3% or greater are, on the basis of model estimates (specifically, the Freedman risk-benefit tables for women aged 50 years or older), more likely to benefit from tamoxifen or raloxifene.^[168]

Lymph Node Biopsy and Dissection

Guidelines for sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) have been issued by the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN).

American Society of Clinical Oncology

A 2014 update on SLNB for patients with early-stage breast cancer by ASCO advises that SLNB may be offered to the following patients^[169]:

Women with operable breast cancer and multicentric tumors
Women with DCIS who will be undergoing mastectomy
Women who previously underwent breast and/or axillary surgery
Women who received preoperative/neoadjuvant systemic therapy

According to the ASCO guidelines, SLNB should not be performed in patients with any of the following:

Large or locally advanced invasive breast cancer (tumor size T3/T4)
Inflammatory breast cancer
DCIS (when breast-conserving surgery is planned)
Pregnancy

ASCO recommendations regarding ALND in patients who have undergone SLNB are as follows:

ALND should not be performed in women with no sentinel lymph node (SLN) metastases
In most cases, ALND should not be performed in women with one to two metastatic SLNs who are planning to undergo breast-conserving surgery with whole-breast radiotherapy
ALND should be offered to women with SLN metastases who will be undergoing mastectomy

National Comprehensive Cancer Network

The 2017 NCCN guidelines recommend that SLNB should be performed and is the preferred method of axillary lymph node staging if the patient is an appropriate candidate for SLNB.^[72]Candidates include patients with clinical stage I, IIA, IIB, and IIIA T3, N1, M0 who are clinically node negative at the time of diagnosis, as well as those who are clinically node positive but have negative results on fine needle aspiration or core biopsy.

The NCCN recommends axillary dissection level I/II if the sentinel node is not identified or if the sentinel node is positive but the patient fails to meet all the following criteria:

T1 or T2 tumor
Only one or two positive sentinel lymph nodes
Breast-conserving therapy
Whole-breast radiation therapy planned
No preoperative chemotherapy

If the patient does meet all those criteria, the NCCN recommends against further axillary surgery. In addition, no further axillary surgery is a category 1 recommendation for patients with a negative sentinal lymph node. The NCCN guidelines state that lymph node dissection is optional in the following cases:

Strongly favorable tumors
When the result would not affect the choice of adjuvant systemic therapy
Elderly patients
Patients with comorbid conditions

Finally, for patients with clinically negative axillae who are undergoing mastectomy and for whom radiation therapy is planned, the NCCN states that axillary radiation may replace axillary dissection level I/II for regional control of disease.

In contrast with ASCO, the NCCN concluded that insufficient data exist on which to base recommendations regarding the use of SLNB in pregnant women. The NCCN advises that whether to use SLNB in pregnancy should be an individualized decision, but cites a review recommending that SLNB should not be offered to pregnant women under 30 weeks' gestation. If SLNB is used, the NCCN advises that isosulfan blue or methylene blue dye is contraindicated for SLNB in pregnancy, but radiolabeled sulfur colloid appears to be safe.^[72]

Lumpectomy Margins

In 2016, the Society of Surgical Oncology, American Society for Radiation Oncology and American Society of Clinical Oncology released a consensus guideline that addresses margins for breast-conserving surgery with whole-breast radiation therapy (WBRT) in ductal carcinoma in situ (DCIS). Key recommendations include^[170]:

A positive margin is associated with a significant increase in ipsilateral breast tumor recurrence (IBTR); this increased risk is not nullified by the use of WBRT
Negative margins halve the risk of IBTR and a 2 mm margin minimizes the risk of IBTR compared with smaller negative margins.
More widely clear margins do not significantly decrease IBTR compared with 2 mm margins.
Negative margins < 2 mm alone are not an indication for mastectomy; clinical judgment should be used in determining the need for further surgery in patients with negative margins < 2 mm.

The following consensus guideline, released in 2014 by the Society of Surgical Oncology and the American Society for Radiation Oncology, addresses margins for breast-conserving surgery with whole-breast irradiation (WBI) in stages I and II invasive breast cancer.^[171]:

Positive margins are associated with at least a two-fold increase in ipsilateral breast tumor recurrence (IBTR)
Negative margins optimize IBTR; this risk is not significantly lowered by wider margin widths
IBTR rates are reduced with the use of systemic therapy; in patients who do not receive adjuvant systemic therapy, margins wider than no ink on tumor are not needed
Biologic subtypes do not indicate the need for margins wider than no ink on tumor
Margin width should not determine the choice of WBI delivery technique, fractionation, and boost dose
Wider negative margins than no ink on tumor are not indicated for patients with invasive lobular cancer; classic lobular carcinoma in situ (LCIS) at the margin is not an indication for reexcision; the significance of pleomorphic LCIS at the margin is not clear
Young age is associated with an increased risk for IBTR after breast-conserving therapy, an increased risk for local relapse on the chest wall after mastectomy, and adverse biologic and pathologic features; an increased margin width does not nullify the increased risk for IBTR in young patients
An extensive intraductal component (EIC) identifies patients who may have a large residual ductal carcinoma in situ (DCIS) burden after lumpectomy; when margins are negative, there is no evidence of an association between an increased risk for IBTR and EIC

Radical Mastectomy

According to National Comprehensive Cancer Network (NCCN) guidelines, mastectomy with level I/II axillary lymph node dissection is the recommended procedure in patients who respond to neoadjuvant chemotherapy. Other NCCN indications for mastectomy include the following^[72]:

Prior radiation therapy to the breast or chest wall
Radiation therapy contraindicated by pregnancy (except patients in the third trimester who can receive radiation postpartum)
Inflammatory breast cancer
Diffuse suspicious or malignant-appearing microcalcifications
Widespread disease that is multicentric, located in more than one quadrant, and cannot be removed through a single incision with negative margins
A positive pathologic margin after repeat re-excision and suboptimal cosmetic outcome

Relative indications for mastectomy include the following:

Active connective tissue disease involving skin (eg, scleroderma, lupus)
Tumors greater than 5 cm in diameter
Focally positive margin

Patients who are younger than 35 years of age or premenopausal with known BRCA1/2 mutations have an increased risk of local recurrence. Prophylactic bilateral mastectomy may be considered for risk reduction.

Postmastectomy Radiation Therapy

Clinical practice guidelines developed by the American Society of Clinical Oncology (ASCO), recommend that postmastectomy radiation therapy be performed according to the following criteria^[172]:

Positive postmastectomy margins
Primary tumors >5 cm
Involvement of ≥4 lymph nodes

Patients with more than four positive lymph nodes should also undergo prophylactic nodal radiation therapy at doses of 45-50 Gy to the axillary and supraclavicular regions. For patients in whom ALND shows no node involvement, axillary radiation therapy is not recommended.

Treatment of HER2-Positive Breast Cancer

Evidence-based guidelines from the American Society of Clinical Oncology (ASCO) for treatment of HER2 -positive breast cancer, which are largely adapted from the 2015 Cancer Care Ontario (CCO) clinical practice guidelines, are as follows^{[173, 174, 175]}:

Trastuzumab plus chemotherapy is recommended for all patients with HER2-positive, node-positive breast cancer and for patients with HER2-positive, node-negative breast cancer (>1 cm)
Trastuzumab plus chemotherapy may be considered in small (≤1 cm), node-negative tumors in patients with HER2-positive T1a-b N0 disease
In high-risk HER2-positive disease, the recommended regimen is sequential anthracycline and taxanes given concurrently with trastuzumab; or docetaxel, carboplatin, and trastuzumab for six cycles
For lower-risk node-negative HER2-positive disease, an alternative regimen is paclitaxel and trastuzumab in combination once weekly for 12 weeks, with trastuzumab then given for 1 year
In patients with high-risk disease and when a taxane is contraindicated, the optimal dose of an anthracycline three-drug regimen that contains cyclophosphamide is recommended, with a cumulative dose of doxorubicin ≥240 mg/m² or epirubicin ≥600 mg/m², but no higher than 720 mg/m²; the cumulative dose of doxorubicin in two-drug regimens should not exceed 240 mg/m²
Docetaxel and cyclophosphamide for four cycles is an acceptable non-anthracycline regimen
For patients in whom anthracycline-taxane is contraindicated, cyclophosphamide-methotrexate-fluorouracil (with oral cyclophosphamide) is an acceptable chemotherapy alternative to doxorubicin-cyclophosphamide
Concurrent administration of trastuzumab with the anthracycline component of a chemotherapy regimen is not recommended because of the potential for increased cardiotoxicity, but trastuzumab should be preferentially administered concurrently (not sequentially) with a non-anthracycline chemotherapy regimen
Second-line treatment, for patients whose disease progresses during or after first-line treatment with HER2-targeted agents, is with ado-trastuzumab emtansine (T-DM1)
T-DM1 can be used as third-line treatment if the cancer progresses during or after second-line treatment, in patients who have not previously received the drug

Hormonal Adjuvant Therapy

In 2016, the American Society of Clinical Oncology (ASCO) issued an updated clinical practice guideline on adjuvant endocrine therapy for premenopausal women with hormone receptor–positive breast cancer. ASCO recommends high-risk women receive adjuvant endocrine therapy with ovarian suppression but lower-risk patients should not.^[176]

Specific recommendations include ^[176]:

Women with stage II or stage III breast cancers who would ordinarily be advised to receive adjuvant chemotherapy should receive ovarian suppression in addition to endocrine therapy
Women with stage I or II breast cancers at higher risk of recurrence, who might consider chemotherapy, may also be offered ovarian suppression in addition to endocrine therapy
Women with stage I breast cancers not warranting chemotherapy should receive endocrine therapy but not receive ovarian suppression
Women with node-negative cancers 1 cm or less (T1a, T1b) should receive endocrine therapy but not receive ovarian suppression
Ovarian suppression may be administered with either tamoxifen or an aromatase inhibitor

In its 2014 practice guidelines, ASCO addressed postmenopausal women and recommended they be offered adjuvant endocrine therapy with one of the following treatments^{[177, 178]}:

Postmenopausal patients should be offered adjuvant endocrine therapy with one of the following treatments^{[177, 178]}:

Tamoxifen for 10 years
An aromatase inhibitor for 5 years
Tamoxifen for 5 years, then switching to an aromatase inhibitor for up to 5 years
Tamoxifen for 2-3 years, then switching to an aromatase inhibitor for up to 5 years

Postmenopausal patients who are intolerant of either tamoxifen or an aromatase inhibitor should be offered an alternative adjuvant endocrine therapy. Patients who have received an aromatase inhibitor but discontinued treatment at less than 5 years may be offered tamoxifen for a total of 5 years. Patients who have received tamoxifen for 2-3 years should be offered an aromatase inhibitor for up to 5 years, for a total duration of up to 7-8 years of adjuvant endocrine therapy.^{[177, 178]}

Breast Cancer in Young Women

Guidelines on the management of breast cancer in young women from the European School of Oncology (ESO) and the European Society of Medical Oncologists (ESMO), and endorsed by the European Society of Breast Specialists (EUSOMA), include 75 statements.^[179]Among them are the following recommendations:

There is no clear role for routine screening by any imaging technique for early breast cancer detection in healthy, average-risk young women. However, in young women with a cancer predisposition syndrome (germline mutation in a known cancer predisposition gene), significant family history, or prior personal history of ionizing radiation to the chest, consideration may be given to screening breast MRI.
In young women with the diagnosis of either invasive disease or preinvasive lesions who are not high-risk mutation carriers, there is no evidence that performing risk-reducing bilateral mastectomy leads to improved overall survival (OS)
In patients with triple-negative breast cancer (TNBC) or BRCA-associated tumors, the incorporation of platinum agents increases pathologic complete response (pCR) rates and may be considered when neoadjuvant chemotherapy is indicated. Data on the impact of incremental increases in pCR on long-term outcome are inconclusive.
The use of platinum derivatives has potential additional impact on fertility and increased toxicity that may compromise standard duration and dosing of systemic treatment, and this needs to be clearly communicated to patients.
For patients with TNBC not achieving a pCR after standard neoadjuvant regimens, the routine addition of adjuvant chemotherapy (such as capecitabine or metronomiccyclophosphamide and methotrexate [CM]) is not recommended; however, it may be considered in highly selected patients, as in other age groups
It is recommended that young women with ER-positive advanced breast cancer have adequate ovarian suppression or ablation and then be treated in the same way as postmenopausal women with endocrine agents and targeted therapies, such as an aromatase inhibitor or fulvestrant plus a cyclin-dependent kinase (CDK) 4/6 inhibitor or exemestane with everolimus.
Olaparib monotherapy may be considered in women with advanced breast cancer harboring a germline BRCA mutation in early lines of therapy.
All patients with hormone receptor–positive disease should receive adjuvant endocrine therapy (ET). Tamoxifen alone for 5 years is indicated for low-risk patients. Tamoxifen for 10 years should be considered in high-risk patients, if tolerated. The addition of a gonadotropin-releasing hormone (GnRH) agonist (or ovarian ablation) to tamoxifen is indicated in patients at higher risk who remain premenopausal after chemotherapy.
Young women with stage I or II breast cancer who cannot take tamoxifen (due to contraindications or severe side effects) may receive a GnRH agonist alone, oophorectomy, or an aromatase inhibitor GnRH agonist.

Follow-up for Breast Cancer Survivors

The National Comprehensive Cancer Network (NCCN)^[72] and the American Cancer Society/American Society of Clinical Oncology (ACS/ASCO)^[180] have issued guidelines on followup care for breast cancer survivors. The guidelines differ principally in the timing of care. See the table below.

Table Follow-up Recommendations for Breast Cancer Survivors (Open Table in a new window)

	NCCN	ACS/ASCO
History and physical examination	Year 1, every 3-4 mo Year 2, every 4 mo Year 3-5, every 6 mo Year 6 , annually	Year 1-3, every 3-6 mo Year 4-5, every 6-12 mo Year 6 , annually
Signs of recurrance	No recommendation	Educated and counseled about signs and symptoms
Mammography	6 mo after post-BCS radiation therapy Annually thereafter	Annually
MRI	No recommendation	Not recommended for routine screening unless patient meets high-risk criteria for increased surveillance
Pelvic examination	Annually, for women on tamoxifen Annual exam if uterus present	No recommendation
Routine blood tests	Not recommended	Not recommended
Imaging studies	Not recommended	Not recommended
Tumor marker testing	Not recommended	No recommendation

Use of Biomarkers to Guide Adjuvant Systemic Therapy

A guideline from the American Society of Clinical Oncology (ASCO) advises that the only biomarkers that can guide choices of specific treatment regimens in breast cancer are as follows^[181]:

Estrogen receptor (ER)
Progesterone receptor (PR)
Human epidermal growth factor receptor 2 (HER2)

ASCO recommendations regarding further biomarker use include the following^[181]:

The Oncotype DX 21-gene recurrence score may be used in patients with ER/PR-positive, HER2-negative (node-negative) breast cancer; however, it should not be used in patients with HER2-positive or triple-negative (ER,PR, HER2 negative) breast cancer
The EndoPredict 12-gene risk score may be used in patients with ER/PR-positive, HER2-negative (node-negative) breast cancer; however, it should not be used in patients with ER/PR-positive, HER2-negative (node-positive) breast cancer or in patients with HER2-positive or triple-negative breast cancer
The MammaPrint (Agendia) 70-gene assay should not be used in patients with triple-negative breast cancer; in patients with ER/PR-positive, HER2-negative (node-positive or node-negative) breast cancer; or in patients with HER2-positive breast cancer
PAM50 risk of recurrence score may be used, in combination with other clinicopathologic variables, in patients with ER/PR-positive, HER2-negative (node-negative) breast cancer; however, it should not be used in patients with ER/PR-positive, HER2-negative (node-positive) breast cancer or in patients with HER2-positive or triple-negative breast cancer
The Breast Cancer Index may be used in patients with ER/PR-positive, HER2-negative (node-negative) breast cancer; however, it should not be used in patients with ER/PR-positive, HER2-negative (node-positive) breast cancer or in patients with HER2-positive or triple-negative breast cancer
The Mammostrat (Clarient) five-protein assay should not be used in patients with ER/PR-positive, HER2-negative (node-positive or node-negative) breast cancer or in patients with HER2-positive or triple-negative breast cancer.
Immunohistochemistry 4 may be used in patients with ER/PR-positive, HER2-negative (node-negative) breast cancer; however, it should not be used in patients with HER2-positive or triple-negative breast cancer
Urokinase plasminogen activator and plasminogen activator inhibitor type 1 may be used in patients with ER/PR-positive, HER2-negative (node-negative) breast cancer; however, they should not be used in patients with HER2-positive breast cancer or triple-negative breast cancer
Circulating tumor cells should not be used to guide decisions on adjuvant systemic therapy
Tumor-infiltrating lymphocytes should not be used in patients with ER/PR-positive, HER2-negative (node-positive or node-negative) breast cancer or in patients with HER2-positive or triple-negative breast cancer
Protein encoded by the MKI67 gene should not be used to guide the selection of adjuvant chemotherapy
CYP2D6 polymorphisms or p27 expression determined by immunohistochemistry should not be used to guide the selection of adjuvant tamoxifen
Protein encoded by the immunohistochemistry MKI67 gene labeling index should not be used to guide the selection of adjuvant aromatase inhibitors
For patients with ER/PR-positive, HER2-negative (node-negative) breast cancer who have had 5 yr of endocrine therapy without evidence of recurrence, clinicians should not use multiparameter gene expression or protein assays (Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, or immunohistochemistry 4) to guide decisions on extended endocrine therapy
Clinicians should not use microtubule-associated protein Tau messenger (m)RNA expression or mRNA expression determined by immunohistochemistry or HER1/epidermal growth-factor receptor expression by immunohistochemistry to guide the selection of adjuvant taxanes
Clinicians should not use TOP2A gene amplification or TOP2A protein expression determined by immunohistochemistry and should not use HER2 and TOP2A gene coamplification, CEP17 duplication, TIMP-1, FOXP3, or p53 to guide the selection of adjuvant anthracyclines

Medication

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