The prognosis for many women with small, early-detected cancers receiving standard multi-disciplinary therapy has become so favorable that new, active treatments contribute only marginally to further reductions in the risk of recurrence and rarely affect overall survival.
Treatment guidelines are no longer based exclusively by the anatomic stage of the tumor or the histological subset of breast cancer.
Surgical, radiation therapy and medical approaches are increasingly tailored based on the initial response to neoadjuvant systemic therapy.
Systemic therapy lowers the risk of local-regional tumor recurrence, which enables less surgery of the breast and axilla in many cases.
Cancers that are highly sensitive to effective systemic therapy, such as HER2-positive tumors treated with anti-HER2 regimens, have different approaches or durations of local-regional treatment than cancers not as responsive to systemic interventions.
ACOSOG Z0011 trail evaluate the patient with T1/T2 clinically no negative disease and one or two positive sentinel nodes: sentinel lymph node biopsy alone or sentinel lymph node biopsy plus complete axial lymph node dissection resulted in acceptable nodal recurrence rate of 1 1/2 and 0.5% respectively, and no difference in disease free survival or overall survival between the approaches.
For some patients, there is a clear move to escalate therapy, such as longer durations of anti-estrogen treatment, more utilization of ovarian function suppression, treatment of residual tumor after neoadjuvant therapy, and dual targeting with anti-HER2 drugs.
There is a movement to de-escalate treatment, including the shortening or omission of adjuvant chemotherapy, the avoidance of axillary surgery, and shortened courses of radiation treatment.
There remains a need for improved treatment of patients at high risk of cancer recurrence.
Early-stage breast cancer is a heterogeneous disease.
Treatment depends on pathological and molecular characterization of the tumor subset to classify tumors as estrogen receptor (ER) positive or negative, HER2-positive or negative, or triple negative.
Endocrine therapy in tumors with low ER expression (<10%) that have a less favorable prognosis than tumors with higher levels of ER expression.
The benefits of endocrine therapy are lower or possibly absent when ER staining is 1%–10%, but no threshold for withholding endocrine therapy exists and adjuvant endocrine therapy for tumors with ≥1% ER expression is recommended.
Tumor-infiltrating lymphocytes (TILs) should be routinely characterized in triple-negative breast cancer (TNBC) because of their prognostic value.
Tumor PD-L1 or immune-cell PD-1 expression are recognized as markers that may predict benefit from immunotherapy treatment in advanced breast cancer.
Recommendations against routine PD-L1 tumor or PD-1 immune cell testing in early-stage TNBC, as current treatment algorithms are not based on such testing.
Genomic assays are valuable for determining whether or not to recommend adjuvant chemotherapy in T1/T2 N0 ER-positive breast cancers, and recognized the value of such tests in patients with ER-positive tumors and limited nodal involvement.
Pathology review including determination of grade, ER/PR levels, and proliferation likely serves as a surrogate for broad classification of ER-positive tumors into more favorable luminal A-like or less favorable luminal B-like cancers.
An increasing percentage of women with stage 2 or 3 breast cancer are receiving primary systemic therapy,an inversion of the historical patterns of practice which is surgery first followed by systemic therapy.
The use of primary systemic therapy is employed regardless of tumor histology (lobular versus ductal carcinoma) or the presence of an extensive intraductal component, and irrespective of tumor histological grade.
For women undergoing post neoadjuvant therapy optimal resection remains removal of all known residual as opposed to original tumor lesions with a margin goal of ‘no ink on tumor’ regardless of the presence of unifocal or multi-focal disease.
Wider margins are no longer recommended as long as the residual tumor bed and areas of persistent abnormal imaging have been excised with careful pathological review of the specimen.
A similar no ink on tumor margins for women undergoing skin-sparing and/or nipple-sparing mastectomy, particularly when radiation therapy is planned, ie recommended.
With focally positive margins at breast conserving surgery, re-excision is preferred.
Recent studies suggest that limited, focal positive margins in the setting of breast conserving therapy and radiation therapy with a boost to the primary tumor bed may be associated with acceptably low risks of local recurrence, even if still numerically higher, 2.9% versus 1.1%, at 5 years following re-excision than when there is no ink on tumor.
This may inform clinical practice especially when re-excision would have deleterious cosmetic impact or necessitate a mastectomy.
Sentinel node biopsy is the standard approach for patients presenting with a clinically negative axilla and undergoing breast conserving surgery.
ACOSOG Z11 trial: study of women with cT1–2, cN0 cancers and tumor involvement of one or two sentinel lymph nodes, completion of axillary dissection is not indicated when patients will be receiving post-lumpectomy radiation therapy and appropriate systemic adjuvant therapy.
Women undergoing mastectomy who have positive sentinel lymph nodes warrant additional therapy to the axilla, either completion axillary dissection or regional radiation therapy.
Axlillary dissection after mastectomy could be omitted in patients with one to two positive sentinel lymph nodes provided that regional nodal irradiation is planned.
When no radiation is planned, or when chest wall-only radiation is planned, completion axillary dissection after mastectomy in women with positive sentinel lymph nodes is recommended.
Elderly patients presenting with clinical stage 1 disease and tumors with favorable biology may not need sentinel node biopsy if it is unlikely to change treatment.
Sentinel Lymph Node Biopsy after neoadjuvant systemic therapy (NST)
is a common treatment of women with clinically involved axillary nodes.
Patients with clinically positive nodes after neoadjuvant systemic therapy are advised to have a completion axillary dissection.
Patients who present with a clinically positive axillary node and received NST that downstaged the axilla to clinically negative, sentinel node biopsy instead of axillary dissection, an be performed.
Women with residual nodal disease after NST on sentinel node biopsy generally warrant completion axillary dissection.
Patients who present with cN2 axillary disease should undergo completion axillary dissection regardless of response to neoadjuvant therapy and receive regional nodal irradiation.
Hypofractionated radiation treatment schedules as preferred for most patients after breast conservation.
Equally low risks of local recurrence are obtained in selected women with low-risk breast cancer undergoing accelerated partial breast irradiation (APBI) compared with whole breast irradiation.
Regional nodal irradiation improves survival in node-positive breast cancer, in cases of involvement of four or more axillary lymph nodes.
In cases of one to three positive lymph nodes, regardless of mastectomy or breast conserving surgery, and in cases with adverse prognostic factors such as triple-negative, HER2, and luminal B cancers, and in women with residual disease after NST regional nodal post radiation is recommended.
Postmastectomy radiation therapy to the chest wall and regional lymph nodes in cases of four or more positive nodes, or one to three positive nodes with triple-negative histology is recommended.
Whether women should receive postmastectomy radiation in cancers that are HER2-positive and/or ER-positive with one to three involved lymph nodes, and in cases of larger (>5 cm) node-negative tumors is debated.
Postmastectomy radiation is not recommended for T2N0 cancers.
Postmastectomy radiation therapy recommendations are the same for women undergoing immediate reconstruction.
PMRT is recommended in women with one to three residual involved lymph nodes after NST.
Older women might avoid radiation therapy after breast conserving surgery for stage 1 breast cancer as randomized trials have shown that post-surgical radiation therapy does not improve overall survival.
Radiation is favored after breast conserving surgery in women age 70 years who were otherwise in good health with substantial life-expectancy, as radiation therapy meaningfully lowers the risk of in-breast recurrence.
Radiation in the oldest elderly, age 80 years or greater, is not recommended after breast conserving surgery,
Long-term follow-up of studies comparing tamoxifen and AI therapy showing small (2%–3%) reductions in 10-year recurrence risk with AI treatment.
Because of overall risk, more clinical benefit with AI-based therapy may be realized in: stage II/III cancers; tumors with higher grade or with high Ki-67 labeling index; lobular breast cancers, which show sensitivity to AI therapy, and cancers that are both ER-positive and HER2-positive.
Multiple trials have now suggested that extended therapy for up to a total of 10 years of treatment can reduce recurrence risk by several percentage points in high risk patients.
Women with higher risk cancers, with involved lymph nodes at diagnosis and higher risk genomic signature scores—are at greater risk for late recurrence and thus derive more absolute numerical benefit from extended therapy.
For higher risk stage 3 cancers and node-positive stage 2 cancers, extended adjuvant endocrine therapy is recommended for stage 1 cancers, generally for treatment at 5 years.
For stage 2, node-negative cancers, the recommendation is for extended adjuvant endocrine therapy, especially in women who received tamoxifen as their initial treatment.
It is preferred that a duration of therapy of 10 years for women receiving extended adjuvant treatment.
Treating very high risk individuals (e.g. more than 10 positive lymph nodes) for longer durations, and conversely, that the marginal benefits of treatment beyond 7–8 years are likely to be very modest.
ER-positive Tumors in Premenopausal Women:
Long-term data show that ovarian function suppression (OFS) paired with either tamoxifen or an AI can reduce recurrence compared with tamoxifen alone in premenopausal women with early-stage breast cancer.
The recommended OFS based on clinical risk factors including patient age, and tumor stage and pathological features.
In general, OFS in young women (e.g. ≤35 years), node-positive cases (especially two or more lymph nodes), and tumors with high grade and/or adverse results of genomic signatures, though molecular tests were not routinely used in canonical trials of OFS.
In cases that warrant chemotherapy should additionally receive OFS, and either tamoxifen or an AI in addition to chemotherapy treatment.
Premenopausal women with low risk, node-negative cancers may be treated with adjuvant tamoxifen alone.
Standard treatment of women with ER-positive, HER2-negative breast cancer includes adjuvant endocrine therapy.
Some women with ER-positive tumors will gain additional benefit from chemotherapy, whereas many such patients can safely avoid chemotherapy.
In general, women with stage 3, ER-positive breast cancer warrant adjuvant chemotherapy.
Recommended chemotherapy in women with four or more affected lymph nodes, including those with lobular carcinoma and/or grade 1 or luminal A breast cancers.
In contrast, women with ER-positive, node-negative tumors <1 cm rarely warrant chemotherapy.
Recommendation for adjuvant chemotherapy is based upon consideration of: patient age, anatomic stage, tumor size, the presence of absence of lymphovascular invasion, the extent of nodal involvement, and tumor pathology including grade, proliferation assays such as Ki67 labeling index, and increasingly, the results of gene expression signature (genomic) assays.
Genomic assays are helpful for determining whether to recommend chemotherapy in T1/T2 N0 tumors, T3 N0 tumors, and TxN1.
In women with low-risk genomic signature tumors, there is no significant benefit to adding chemotherapy to endocrine therapy in node-negative cancers, nor—in all likelihood—cancers with limited nodal involvement when they are naturally or iatrogenically postmenopausal.
TailorX results: women with node-negative cancers and recurrence scores ≤25 do not need chemotherapy.
The management of premenopausal women with node-negative cancers where retrospective subset analyses have questioned whether there is a benefit for chemotherapy in a group of patients with tumors falling in the intermediate range of the OncotypeDX Recurrence Score.
There is no consensus whether to recommend chemotherapy in addition to endocrine therapy in such cases, with doctors split between favoring chemotherapy and endocrine therapy or preferring OFS plus either tamoxifen or an AI.
When multigene signature assays are not available, clinicians integrate traditional pathology (T size, grade, ER/PR, proliferation) to assign ER-positive, node-negative tumors to low- or high-risk, and largely on that basis, recommend adjuvant chemotherapy or not.
The preferred chemotherapy regimen for women receiving adjuvant chemotherapy for node negative ER-positive breast cancers included alkylator- and taxane-based regimens without inclusion of an anthracycline.
Traditionally, anthracycline-based regimens are for higher risk tumors.
Chemotherapy is the mainstay of neo/adjuvant treatment of TNBC.
Dose-dense’ treatment as the preferred approach for anthracycline- and taxane-based neo/adjuvant chemotherapy regimens.
Standard ‘dose-dense’ regimens typically include accelerated schedules of anthracycline- and alkylator-based therapy, followed sequentially by accelerated or weekly taxane treatments.
Neoadjuvant chemotherapy as the preferred approach to stage 2 or 3 TNBC, based on the opportunity to surgically downstage many patients, to deliver effective systemic therapy, to gain insights into the prognosis for a given patient, and to tailor both local and systemic therapy based on the extent of residual disease.
Anthracycline-, alkylator-, and taxane-based chemotherapy asthe preferred regimen for many women with stage T1cN0 disease and virtually all of those with higher stage TNBC.
Studies of neoadjuvant chemotherapy have consistently shown that adding platinum-based chemotherapy improves the rates of complete pathological response in TNBC, though the effect on long-term disease recurrence remains less certain, especially if a different alkylator (i.e. cyclophosphamide) has already been included in the treatment regimen.
The inclusion of platinum-based chemotherapy among women with known, deleterious germline BRCA1/2 mutations is recommended.’
Patients with TNBC who have residual invasive cancer following neoadjuvan chemotherapy have a higher risk of recurrence.
Patients with residual invasive cancer, especially those with nodal involvement and/or more than 1 cm of residual tumor in the breast, are offered adjuvant capecitabine after completing taxane-, anthracycline-, and alkylator-based chemotherapy.
Anti-HER2 therapy paired with chemotherapy is an essential component of neo/adjuvant treatment of HER2-positive breast cancer.
The use of NST as the preferred approach to stage 2 or 3 HER2-positive tumors for similar reasons as in TNBC: to improve surgical options, to deliver effective systemic treatment, to obtain prognostic information, and to tailor therapy based on the extent of residual disease.
Anthracycline-, alkylator-, and taxane-based chemotherapy in combination with trastuzumab- and pertuzumab-based treatment is the preferred approach for stage 2 or 3, HER2-positive tumors, in either the adjuvant or neoadjuvant setting, though many frequently prescribe non-anthracycline regimens such as docetaxel/carboplatin/trastuzumab/pertuzumab.
For stage 1, HER2-positive tumors, paclitaxel plus trastuzumab, without pertuzumab-based therapy, as adjuvant therapy.
Some panelists favor inclusion of pertuzumab when offering neoadjuvant therapy in HER2-positive, ER negative, and clinical stage 1 cancers.
Trials addressing the option using <12 months of adjuvant trastuzumab-based therapy in early stage, HER2-positive breast chave shown a narrow reduction in recurrence risk with 12 months of therapy compared with shorter (3 or 6 month) durations.
It is recommended 1 year of trastuzumab-based treatment as the preferred duration while acknowledging that the benefits of 12 months over 6 months is likely to be very modest based on results from those trials.
Extended anti-HER2 therapy with neratinib in the adjuvant setting after one year of trastuzumab may further reduce the likelihood of tumor recurrence.
Neratinib is recommended in cases of node-positive, ER-positive, HER2-positive breast cancers, especially those with four or more affected lymph nodes treated with trastuzumab-based therapy.
NST is the preferred approach for stage 2 or 3, HER2-positive tumors and achieves robust rates of pathological complete response.
In women with residual invasive HER2-positive breast cancer following NST, the introduction of adjuvant trastuzumab emtansine therapy substantially reduced the risk of recurrence, an absolute benefit of 8%–12% risk reduction.
Trastuzumab emtansine is recommended for women with residual invasive cancer following NST with trastuzumab- or with trastuzumab- and pertuzumab-based regimens.
For patients who achieve a pathological complete response with anti-HER2-based therapy do not require the addition of trastuzumab emtansine.
They should receive adjuvant trastuzumab or trastuzumab plus pertuzumab as originally offered in their initial NST regimen.
Adjuvant bone modifying therapy can reduce the risk of tumor recurrence in postmenopausal women.
It is recommended that routine use of adjuvant zoledronic acid or clodronate in postmenopausal women be given.
It is favored that the use of zoledronic acid in premenopausal women with ER-positive breast cancer receiving GnRH agonist therapy with either an AI or tamoxifen.
In these settings, bisphosphonate therapy contributes to a 4% to 8% reduction in cancer recurrence at 5 years without improving overall survival.
Ductal carcinoma in situ (DCIS) is a precancerous lesion frequently identified through screening mammography.
The historical standard treatments for DCIS have included surgery—either lumpectomy and radiation therapy in women undergoing breast conserving surgery, or mastectomy, in order to prevent the subsequent development of invasive breast cancer or recurrent DCIS.
DCIS is a relatively low-risk population of women with a recurrence risk of ~10% after breast conserving surgery through a decade of follow-up.
Randomized trials have shown that even such low-risk patients might still benefit from post-lumpectomy radiation therapy, reducing the risk of in-breast recurrence or invasive cancer.
Given the modest absolute benefits of radiation therapy in such cases, and lack of a survival impact for treatment of DCIS, It is believed that women with favorable prognostic features (low- or intermediate-grade, absence of comedonecrosis, age >50 years) and generous surgical margins—typically in excess of 0.5 cm—may forego radiation treatment and endocrine therapy if they were willing to accept a slightly greater risk of in-breast recurrence.
CDK4/6 plus aromatase inhibitors and patients with high risk, early stage, hormone receptor positive, HER2neu negative breast cancer has demonstrated efficacy.
Hereditary breast cancer accounts for 5%–10% of all breast cancers.
It is recommended genetic counseling and germline genetic testing using multigene panels for women with: strong family history of breast cancer, breast cancer onset younger than age 35, and women less than age 60 with TNBC.
Randomized trials have demonstrated that the use of GnRH agonist therapy during neo/adjuvant chemotherapy improves preservation of ovarian function and promotes the likelihood of subsequent pregnancy.
The use of OFS during chemotherapy as a strategy for fertility preservation in women with either ER-positive or ER negative cancer who seek to optimize long-term fertility.