Consider initial systemic therapyqqq
No visceral crisis andPrior endocrine therapy within 1 y
No visceral crisis and No prior
endocrine
therapy within 1 y
Premenopausalppp
Postmenopausalppp Visceral crisis
Premenopausalppp
Postmenopausalppp
Ovarian ablation or suppression + systemic therapyrrr,sss
Ovarian ablation or suppression + systemic therapyrrr orSelective ER modulatorsrrr
Systemic therapyrrr
d See Principles of Biomarker Testing (BINV-A).
ppp See Definition of Menopause (BINV-O).
qqq See Systemic Therapy Regimens for Recurrent or Stage IV (M1) Disease (BINV-Q).
rrr See Systemic Therapy for ER- and/or PR-Positive Recurrent or Stage IV (M1) Disease (BINV-P).
sss If progression on initial endocrine therapy, switch to a different endocrine therapy option.
ttt See Principles of Monitoring Metastatic Disease (BINV-S).
Continue endocrine therapy until progressionttt or unacceptable toxicity
Systemic therapyrrr,sss
Progression See BINV-21 Continue
therapy until progressionttt or unacceptable toxicity
Progression See BINV-21
d See Principles of Biomarker Testing (BINV-A).
v See Special Considerations for Breast Cancer in Men (BINV-J).
eee False-negative ER and/or PR determinations occur, and there may be discordance between the ER and/or PR determination between the primary and metastatic tumor(s). Therefore, endocrine therapy with its low attendant toxicity may be considered in patients with non-visceral or asymptomatic visceral tumors, especially in patients with clinical characteristics predicting for a hormone receptor-positive tumor (eg, long disease-free interval, limited sites of recurrence, indolent disease, older age).
qqq See Systemic Therapy Regimens for Recurrent or Stage IV (M1) Disease (BINV-Q).
rrr See Systemic Therapy for ER- and/or PR-Positive Recurrent or Stage IV (M1) Disease (BINV-P).
ttt See Principles of Monitoring Metastatic Disease (BINV-S).
uuu If there is disease progression while on CDK4/6 inhibitor therapy, there are limited data to support an additional line of therapy with another CDK4/6- containing regimen. Likewise, if there is disease progression while on a everolimus-containing regimen, there are no data to support an additional line of therapy with another everolimus regimen.
vvv The potential side effects of additional chemotherapy may outweigh any clinical benefit in a patient who has a compromised performance status. Patient preference must be taken into account.
If not endocrine therapy refractory, consider:
Additional line of endocrine therapyeee ± targeted therapy (see second-line therapy options on BINV-P)rrr,ttt,uuu
or
Systemic therapyqqq,ttt
Another line of
systemic therapyqqq,ttt
Consider no further cytotoxic therapyvvv and
Continue supportive care
(See NCCN Guidelines for Palliative Care and NCCN Guidelines for Supportive Care)
Progression or unacceptable toxicity on first-line endocrine therapy
No clinical benefit after up to 3
sequential endocrine therapy regimens
orSymptomatic visceral disease Systemic therapyqqq,ttt
For those with visceral crisis:
Progression or unacceptable toxicity on first-line systemic therapy
Most patients will be candidates for multiple lines of systemic therapy to palliate advanced breast cancer. At each reassessment clinicians should assess value of ongoing treatment, the risks and benefits of an additional line of systemic therapy, patient performance status, and patient
preferences through a shared decision- making process.
Progression See BINV-23 Continue therapy until
progressionttt
or unacceptable toxicity
d See Principles of Biomarker Testing (BINV-A).
ppp See Definition of Menopause (BINV-O).
qqq See Systemic Therapy Regimens for Recurrent or Stage IV (M1) Disease (BINV-Q).
rrr See Systemic Therapy for ER- and/or PR-Positive Recurrent or Stage IV (M1) Disease (BINV-P).
ttt See Principles of Monitoring Metastatic Disease (BINV-S).
www If treatment was initiated with chemotherapy and trastuzumab + pertuzumab, and the chemotherapy was stopped, endocrine therapy may be added to trastuzumab + pertuzumab.
Systemic therapy + HER2-targeted therapy with:
Pertuzumab + trastuzumab + taxane (preferred)qqq,www or Ado-trastuzumab emtansine (T-DM1)qqq
orFam-trastuzumab deruxtecan-nxkiqqq,xxx orTrastuzumab + chemotherapyqqq,yyy
orEndocrine therapyzzz ± HER2-targeted therapy (if premenopausal,ppp consider ovarian ablation or suppression)rrr,aaaa
orOther HER2-targeted therapiesqqq,yyy
xxx Fam-trastuzumab deruxtecan-nxki is indicated following two or more lines of prior HER2-targeted therapy in the metastatic setting. This agent is contraindicated for patients with pneumonitis or interstitial lung disease (ILD).
yyy Trastuzumab given in combination with an anthracycline is associated with significant cardiac toxicity. Concurrent use of trastuzumab and pertuzumab with an anthracycline should be avoided.
zzz If prior endocrine therapy within 1 y, consider a different endocrine therapy.
aaaa For premenopausal women, selective ER modulators alone (without ovarian ablation/suppression) + HER2-targeted therapy is also an option.
Consider
additional line of endocrine therapy, if not endocrine refractoryeee,rrr
± HER2-targeted therapyqqq,xxx,yyy,bbbb
Another line of systemic therapy + HER2-targeted therapyqqq,xxx,yyy,bbbb d See Principles of Biomarker Testing (BINV-A).
eee False-negative ER and/or PR determinations occur, and there may be discordance between the ER and/or PR determination between the primary and metastatic tumor(s). Therefore, endocrine therapy with its low attendant toxicity may be considered in patients with non-visceral or asymptomatic visceral tumors, especially in patients with clinical characteristics predicting for a hormone receptor-positive tumor (eg, long disease-free interval, limited sites of recurrence, indolent disease, older age).
qqq See Systemic Therapy Regimens for Recurrent or Stage IV (M1) Disease (BINV-Q).
rrr See Systemic Therapy for ER- and/or PR-Positive Recurrent or Stage IV (M1) Disease (BINV-P).
ttt See Principles of Monitoring Metastatic Disease (BINV-S).
xxx Fam-trastuzumab deruxtecan-nxki is indicated following two or more lines of prior HER2-targeted therapy in the metastatic setting. This agent is contraindicated for patients with pneumonitis or interstitial lung disease (ILD).
Progression on first-line endocrine therapy
No clinical benefit after up to 3 sequential endocrine therapy regimens ± HER2- targeted therapyttt orSymptomatic visceral disease Progression
on systemic therapy + HER2- targeted therapy
Continue HER2- targeted therapy until progressionttt,yyy,bbbb,cccc
Systemic therapy + HER2-targeted therapy until
progressionqqq,rrr,ttt,yyy Consider no further HER2-targeted
therapy and continue supportive caredddd See NCCN Guidelines for Palliative Care and NCCN Guidelines for Supportive Care Most patients will
be candidates for multiple lines of systemic therapy to palliate advanced breast cancer. At each reassessment clinicians should assess value of ongoing treatment, the risks and benefits of an additional line of systemic therapy, patient performance status, and patient preferences through a shared decision- making process.
yyy Trastuzumab given in combination with an anthracycline is associated with significant cardiac toxicity. Concurrent use of trastuzumab and pertuzumab with an anthracycline should be avoided.
bbbb Patients previously treated with chemotherapy plus trastuzumab in the absence of pertuzumab may be considered for one line of therapy including both trastuzumab plus pertuzumab in combination with or without cytotoxic therapy (such as vinorelbine or taxane). Further research is needed to determine the ideal sequencing strategy for anti-HER2 therapy.
cccc Continue HER2-targeted therapy following progression on first-line HER2- targeted chemotherapy for metastatic breast cancer. The optimal duration of trastuzumab in patients with long-term control of disease is unknown.
dddd The potential side effects of additional HER2-targeted therapy may outweigh any clinical benefit in a patient who has a compromised performance status.
Patient preference must be taken into account.
Progression Another line of systemic therapy + HER2-targeted therapyqqq,ttt,xxx,yyy,bbbb,cccc
Consider no further HER2-targeted therapydddd and continue supportive care
See NCCN Guidelines for Palliative Care
and NCCN Guidelines for Supportive Care Continue
therapy until progressionttt or unacceptable toxicity
Systemic therapy + HER2-targeted therapy with:
• Pertuzumab +
trastuzumab + taxane (preferred)qqq
• Ado-trastuzumab or emtansine (T-DM1)qqq
• Fam-trastuzumab or deruxtecan-nxkiqqq,xxx
• Trastuzumab + or chemotherapyqqq,yyy
• Other HER2-targeted or therapiesqqq,yyy
d See Principles of Biomarker Testing (BINV-A).
qqq See Systemic Therapy Regimens for Recurrent or Stage IV (M1) Disease (BINV-Q).
ttt See Principles of Monitoring Metastatic Disease (BINV-S).
xxx Fam-trastuzumab deruxtecan-nxki is indicated following two or more lines of prior HER2-targeted therapy in the metastatic setting. This agent is contraindicated for patients with pneumonitis or interstitial lung disease (ILD).
yyy Trastuzumab given in combination with an anthracycline is associated with significant cardiac toxicity. Concurrent use of trastuzumab and pertuzumab with an anthracycline should be avoided.
Most patients will be candidates for multiple lines of systemic therapy to palliate advanced breast cancer. At each reassessment clinicians should assess value of ongoing treatment, the risks and benefits of an additional line of systemic therapy, patient performance status, and patient preferences
through a shared decision-making process.
bbbb Patients previously treated with chemotherapy plus trastuzumab in the absence of pertuzumab may be considered for one line of therapy including both trastuzumab plus pertuzumab in combination with or without cytotoxic therapy (such as vinorelbine or taxane). Further research is needed to determine the ideal sequencing strategy for anti-HER2 therapy.
cccc Continue HER2-targeted therapy following progression on first-line HER2- targeted chemotherapy for metastatic breast cancer. The optimal duration of trastuzumab in patients with long-term control of disease is unknown.
dddd The potential side effects of additional HER2-targeted therapy may outweigh any clinical benefit in a patient who has a compromised performance status. Patient preference must be taken into account.
Systemic therapy until progression or unacceptable toxicityqqq,ttt,eeee
Another line of systemic therapy
d See Principles of Biomarker Testing (BINV-A).
qqq See Systemic Therapy Regimens for Recurrent or Stage IV (M1) Disease (BINV-Q).
ttt See Principles of Monitoring Metastatic Disease (BINV-S).
dddd The potential side effects of additional chemotherapy may outweigh any clinical benefit in a patient who has a compromised performance status. Patient preference must be taken into account.
eeee See Additional Targeted Therapies and Associated Biomarker Testing for Recurrent or Stage IV (M1) Disease (BINV-R).
Consider no further cytotoxic therapydddd and continue supportive care See NCCN Guidelines for Palliative Care
and NCCN Guidelines for Supportive Care Most patients will be candidates for
multiple lines of systemic therapy to palliate advanced breast cancer.
At each reassessment clinicians should assess value of ongoing treatment, the risks and benefits of an additional line of systemic therapy, patient performance status, and patient preferences through a shared decision-making process.
• HER2 testing should be performed on all new primary or newly metastatic breast cancers using methodology outlined in the ASCO/CAP HER2 testing guideline.a
• A re-review of the pathology with consideration for repeat or consultative HER2 testing should be made if a Grade 1 (any histologic type), pure mucinous, pure tubular, or pure cribriform carcinoma tests HER2-positive.a
• After a negative HER2 test result on initial biopsy sample, consider retesting on subsequent surgical or other additional sample if the initial sample was suboptimal (eg, minimal invasive cancer was present, cold ischemic time or fixation was suboptimal), testing error is expected, additional samples contain higher grade morphologically distinct cancer from the biopsy, to rule out heterogeneity in a high grade cancer, or if it will otherwise aid in clinical decision-making.a
HER2 testing by validated IHC assayb,c
IHC 0,1+
IHC 2+
IHC 3+
HER2 (-)
Equivocal result HER2 (+)
Must reflex test with ISH (if same specimen), or order new test with IHC or dual probe ISH (if new specimen available).
HER2 testing by validated dual-probed ISH assayb,c
HER2-Negative:
(Group 5: HER2/CEP17 ratio <2.0 AND average HER2 copy number <4.0 signals/cell) HER2-Negativee (Determined by concurrent IHC and ISH results):
• (Group 2) HER2/CEP17 ratio ≥2.0 AND average HER2 copy number <4.0 signals/cell and concurrent IHC 0-1+ or 2+
• (Group 3) HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥6.0 signals/cell and concurrent IHC 0-1+
• (Group 4) HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥4.0 and <6.0 signals/cell and concurrent IHC 0-1+ or 2+
HER2-Positivee (Determined by concurrent IHC and ISH results):
• (Group 2) HER2/CEP17 ratio ≥2.0 AND average HER2 copy number <4.0 signals/cell and concurrent IHC 3+
• (Group 3) HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥6.0 signals/cell and concurrent IHC 2+ or 3+
• (Group 4) HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥4.0 and <6.0 signals/cell and concurrent IHC 3+
HER2-Positive:
(Group 1: HER2/CEP17 ratio ≥2.0 AND average HER2 copy number ≥ 4.0 signals/cell) a NCCN endorses the ASCO/CAP HER2 testing guideline. “Principles of HER2
Testing” modified with permission from Wolff AC, Hammond EH, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 2018;36:2105-2122.
b Laboratory must participate in a quality assurance accreditation program for HER2 testing. Otherwise, tissue specimen should be sent to an accredited laboratory for testing. Health care systems and providers must cooperate to ensure the highest quality testing.
c Evidence from trastuzumab adjuvant trials show that HER2 testing by ISH or IHC have similar utility to predict clinical benefit from HER2-targeted therapy.
d Single-probe ISH assays are not preferentially recommended but if used, cases with average HER2 copy number ≥4.0 and <6.0 signals/cell should base final results on concurrent IHC and if 2+ reflexed to dual probe ISH testing.
e For ISH Groups 2–4 final ISH results are based on review of concurrent IHC, with recounting of the ISH test by a second reviewer if IHC is 2+ (per 2018 CAP/ASCO Update recommendations). Additional report comments are recommended for negative final results in these ISH Groups.
• Hormone receptor testing (ER and PR) by IHC should be performed on any new primary or newly metastatic breast cancer using methodology outlined in the latest ASCO/CAP hormone receptor testing guideline.1 DCIS should be tested for ER (PR not required).
• ER testing should be used to determine if a patient is a candidate for endocrine therapies.
Cancers with 1%–100% of cells positive for ER expression are considered ER-positive. Patients with these results are considered eligible for endocrine therapies (applies to DCIS and invasive cancers).
Invasive cancers with between 1%–10% ER positivity are considered ER-low–positive. There are more limited data on the benefit of endocrine therapies in this group, but they suggest possible benefit from endocrine treatment, so patients are considered eligible for this treatment (as above).
However, this group is noted to be heterogeneous and the biologic behavior of ER-low–positive cancers may be more similar to ER-negative cancers.
This should be considered in decision-making for other adjuvant therapy and overall treatment pathway.
Cancers with <1% staining are considered ER-negative. Patients with cancers with these results have not been shown to benefit from endocrine therapies.
• Laboratories should have standard operating procedures to maximize accuracy and reproducibility of results for cases with <10% ER staining or weak intensity staining (to avoid false negatives). The status of controls should be reported for cases with these results.
• PR testing by IHC on invasive cancers can aid in the prognostic classification of cancers and serve as a control for possible false-negative ER results.
Patients with ER-negative, PR-positive cancers may be considered for endocrine therapies, but the data on this group are noted to be limited. The same overall interpretation principles apply but PR should be interpreted as either positive (if 1%–100% of cells have nuclear staining) or negative (if
<1% or 0% of cells have nuclear staining).
• Interpretation of any ER result by pathology should include evaluation of the concordance with the histologic findings of each case. Clinicians should be aware of when results are unusual and work with pathologists to attempt to resolve (eg, repeat testing, consultative review) or explain atypical reported findings. See table below.
Results
(following ER testing by validated IHC assay)
Interpretation/
Report As:
0% – <1% of nuclei stain ER-negative
1%–100% of nuclei stain
1%–10% of nuclei stain
ER-low–positive (with recommended comment)
>10% of nuclei stain ER-positive
Highly Unusual ER-Negative Results Highly Unusual ER-Positive Results Low-grade invasive carcinomas of no
special type (also known as invasive ductal carcinoma)
Metaplastic carcinomas of all subtypes
Lobular carcinomas (classic type) Adenoid cystic carcinomas and other salivary gland-like carcinomas of the breast Pure tubular, cribriform, or mucinous
carcinomas Secretory carcinoma
Encapsulated papillary and solid
papillary carcinomas Carcinomas with apocrine differentiation Correlation of ER and Histology: Highly Unusual Results
Summary of ER IHC Scoring/Interpretation
1 Allison KH, Hammond ME, Dowsett M. et al. Estrogen and progesterone receptor testing in breast cancer. American Society of Clinical Oncology/College of American Pathologists Guideline Update. Arch Pathol Lab Med. doi: 10.5858/arpa.2019-0904-SA.
1 Houssami N, Ciatto S, Macaskill P, et al. Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. J Clin Oncol 2008;26:3248-3258.
Personnel, Facility, and Equipment
• Breast MRI examinations are performed with IV contrast and should be performed and interpreted by an expert breast imaging team working in concert with the multidisciplinary treatment team.
• Breast MRI examinations require a dedicated breast coil and breast imaging radiologists familiar with the optimal timing sequences and other technical details for image interpretation. The imaging center should have the ability to perform MRI-guided needle sampling and/
or image-guided localization of MRI-detected findings.
Clinical Indications and Applications
• May be used for staging evaluation to define extent of cancer or presence of multifocal or multicentric cancer in the ipsilateral breast, or as screening of the contralateral breast cancer at time of initial diagnosis (category 2B). There are no high-level data to demonstrate that the use of MRI to facilitate local therapy decision- making improves local recurrence or survival.1
• May be helpful for breast cancer evaluation before and after
preoperative systemic therapy to define extent of disease, response to treatment, and potential for breast-conserving therapy.
• May be useful for identifying primary cancer in women with axillary nodal adenocarcinoma and occult (or unidentified) primary cancer, with Paget’s disease, or with invasive lobular carcinoma poorly (or inadequately) defined on mammography, ultrasound, or physical examination.
• False-positive findings on breast MRI are common. Surgical
decisions should not be based solely on the MRI findings. Additional tissue sampling of areas of concern identified by breast MRI is recommended.
• The utility of MRI in follow-up screening of women with prior breast cancer is undefined. It should generally be considered only in those whose lifetime risk of a second primary breast cancer is greater than 20% based on models largely dependent on family history, such as in those with the risk associated with inherited susceptibility to breast cancer.
See NCCN Guidelines for Breast Cancer Screening and Diagnosis for indications for screening MRI in women at increased breast cancer risk.
• All premenopausal patients should be informed about the potential impact of chemotherapy on fertility and asked about their desire for potential future pregnancies. Patients who may desire future pregnancies should be referred to fertility specialists before chemotherapy and/or endocrine therapy to discuss the options based on patient specifics, disease stage, and biology (which determine the urgency and type and sequence of treatment). Timing and duration allowed for fertility preservation, options inclusive of oocyte and embryo cryopreservation as well as evolving technologies, and the probability of successful pregnancies subsequent to completion of breast cancer therapy are also to be discussed.
• Although amenorrhea frequently occurs during or after
chemotherapy, it appears that the majority of women younger than 35 years resume menses within 2 years of finishing adjuvant chemotherapy.
• Menses and fertility are not necessarily linked. Absence of regular menses, particularly if the patient is taking tamoxifen, does
not necessarily imply lack of fertility. Conversely, the presence of menses does not guarantee fertility. There are limited data regarding continued fertility after chemotherapy.
• Patients should not become pregnant during treatment with RT, chemotherapy, endocrine therapy, or during or within 6 months of completing trastuzumab or pertuzumab.
• Although data are limited, hormone-based birth control is discouraged regardless of the hormone receptor status of the patient's cancer.
• Alternative methods of birth control include intrauterine devices (IUDs), barrier methods, or, for patients with no intent of future pregnancies, tubal ligation or vasectomy for the partner.
• Randomized trials have shown that ovarian suppression with GnRH agonist therapy administered during adjuvant chemotherapy in premenopausal women with breast tumors (regardless of hormone receptor status) may preserve ovarian function and diminish the likelihood of chemotherapy-induced amenorrhea.
• Breastfeeding following breast-conserving cancer treatment is not contraindicated. However, the quantity and quality of breast milk produced by the breast conserved may not be sufficient or may be lacking some of the nutrients needed. Breastfeeding is not recommended during active treatment with chemotherapy and endocrine therapy or within 6 months of completing trastuzumab or pertuzumab.
• Smaller historical experiences in patients with ER-positive disease have reported conflicting results with regard to the protective effect of GnRH agonist therapy on fertility.