Candidates for neoadjuvant chemo therapy or combination treatment if they have molecularly high risk disease according to one of the available molecular assays.
The use of preoperative chemotherapy is standard of care for patients with early-stage breast cancer.
No difference in disease free survival or overall survival based on timing of chemotherapy relative to surgery for breast cancer.
Almost all triple negative and HER2 positive tumors are molecularly high risk.
In patients with triple negative breast cancer and HER2 positive breast cancer, rates of pathological complete response to neoadjuvant chemotherapy is reported to be approximately 60 to 80%:suggesting that some patients who receive neoadjuvant systemic therapy might not require breast and Notal surgery.
High risk tumors include those that measure at least 2.5 cm on examination or 2 cm by imaging.
Tumors that are clinically high risk but molecularly low risk are often offered neoadjuvant endocrine therapy.
Preoperative endocrine therapy may be offered to those with strong hormone responsive positive tumors based on comorbidities or low risk luminal biology based on clinical characteristics and/or genomic signatures.
Preoperative endocrine therapy is effective in reducing residual disease and enabling breast conserving surgery for many patients with low rates of local regional recurrence post surgery.
Endocrine therapy options include an aromatase inhibitor, with ovarian function suppression for premenopausal patients, or tamoxifen with or without ovarian function suppression for premenopausal patients.
The preferred endocrine therapy option for postmenopausal patients is an aromatase inhibitor.
Neoadjuvant chemotherapy has resulted in DFS and OS rates equivalent to those achieved with adjuvant chemotherapy, while yielding a 10% to 30% increase in eligibility for breast conservation treatment.
Neoadjuvant therapy increasingly popular.
Neoadjuvant therapy has expanded beyond initial role in downstaging of tumors to accomplish surgery in patients with locally advanced breast cancer.
Neoadjuvant therapy allows for early evaluation of response or resistance to therapy, in terms of reduction of the proliferation index or the achievement of complete pathological response.
Neoadjuvant therapy provides for real-time examination of tumor tissue, imaging results, an biomarkers in response to systemic therapy.
While neoadjuvant therapy has equivalent efficacy to adjuvant therapy, and it has some additional benefits that include increasing breast conservation, assessing tumor response, establishing prognosis based on the pathological response, and providing a second opportunity for nonresponding patients.
NAT is now the preferred approach for the majority of patients with early TNBC at least 2 cm in diameter or node positive, where is upfront surgery is generally reserved for smaller, node negative tumors.
Pathological complete response to neoadjuvant therapy is important prognostic factor in locally advanced breast cancer, but such prognostic information is primarily relevant in triple negative breast cancer and HER2 positive subtypes.
The residual cancer burden index and pathological complete response are highly prognostic in patients with TNBC and post neoadjuvant treatment escalation improves long-term outcomes for patients with TNBC with residual following NAT.
Neoadjuvant therapy has proven to be cost‐effective by reducing nondrug costs, avoiding radical surgery, and reducing hospital stays when compared with other treatment approaches.
The neoadjuvant setting is a powerful model for the development of new drugs and the identification of prognostic markers.
When delivering cancer chemotherapy while of breast tumor is still intact allows the opportunity to observe in vivo rresponsiveness of the lesion before surgical resection and 2 also therapy if appropriate responses is not found.
Permits a response-guided approach that results in longer disease free survival, particularly in hormone receptor positive tumors.
Neoadjuvant therapy allows assessment of drug efficacy rapidly.
Patients with hormone receptor negative, high grade, or HER2 positive tumors are more likely to respond to neoadjuvant chemo therapy.
Achieving pathological complete remission because of neoadjuvant therapy has been correlated with long‐term clinical benefit, particularly in HER2‐positive and triple‐negative breast cancer.
The addition of trastuzumab to chemotherapy in neoadjuvant therapy for patients with HER-2 positive disease improves pathological complete remission rates, disease-free survival, event free survival, and overall survival.
Pathologic complete remissions (pCR) correlate with long-term outcomes, and indicate that in patients with the most aggressive tumor subtypes it provides the best prognostic value.
pCR indicates eradication of tumor from the breast and axillary lymph nodes with or without residual carcinoma in situ.
pCR has a strong association with improved event-free survival and overall survival than tumor eradication from breast alone.
pCR Has long-term benefits for patients, with the strongest association observed for more aggressive breast cancer subtypes such as triple negative breast cancer and HER2 positive disease.
With pCR selected patients can avoid surgery.
Tumor infiltrating lymphocytes associated with a higher rate of pathologic complete remission in the neoadjuvant setting.
Patients who attain pCR have a 64% reduction in the risk of death compared with patients who have residual tumor at the time of surgery.
I-SPY Trial three year outcome showed that regardless of subtype and/or treatment regimen achieving a pathologic complete response after neoadjuvant therapy implies approximately 80% reduction in recurrence rate.
Patients with breast cancer who a complete clinical remission following neoadjuvant chemotherapy who do not undergo surgery have no significant difference in five-year overall survival compared to patients with the pathologic CR following surgery.
The highest pCR rates are found in aggressive tumors subtypes such as triple-negative breast cancer with a rate of 33.6%, HER-2 positive/hormone receptor-negative breast cancer treated with trastuzumab at 50.3%, or without trastuzumab 30.2%, and grade 3 hormone receptor positive/HER-2 negative breast cancer 16.2%.
The prognostic value of pathologic complete response is greatest in patients with aggressive subtype tumors, with the risk of death reduced by 84% in T NBC, 92%, in HER-2 positive/hormone receptor negative breast cancer treated with trastuzumab, 71% in those that did not receive trastuzumab, and 71% and high-grade hormone receptor-positive/HER-2 negative breast cancer.
Pathologic complete response associated with improved event free survival and overall survival, and this is especially true in human epidermal growth factor receptor 2-positive (HER-2+)/hormone receptor negative tumors and triple negative tumors.
Among patients with TNBC, the percentage of patients with pathological complete response is significantly higher among patients who receive pembrolizumab plus neoadjuvant chemo therapy than among those who receive placebo plus neoadjuvant chemo therapy ( Schmidt P).
Neoadjuvant therapy is currently the preferred management for the majority of patients with early TNBC of at least 2 cm in diameter or node positive, whereas upfront surgery is reserved for smaller, node negative tumors.
The pathological complete response rate is highly prognostic in patients with TNBC.
Postneoadjuvant treatment escalation improves long-term outcomes for patients with TNBC with residual disease following neoadjuvant therapy.
Cytotoxic chemotherapy remains the mainstay of neoadjuvant therapy for early TNBC.
Anthracyclines and taxanes regimens remains standard for most patients with localized TNBC.
The addition of carboplatinum to anthracycline in taxing base regimens increases the pathological response rate.
The addition of checkpoint inhibitors added to chemotherapy significantly improves pathological complete response rates by greater than 70% and is approved; pembrolizumab is approved for the treatment of high risk early TNBC.
In neoadjuvant therapy the primary endpoint, pCR, may be achieved in a much shorter period of time than traditional endpoints of disease-free survival or overall survival.
NeoSphere study added pertuzumab for locally advanced, inflammatory, or early stage HER2 positive breast cancer to doctaxel and trastuzumab resulting in 18% improvement in pathologic complete response rate.
NeoAltto randomized trial evaluating neoadjuvant lapatinib and trastuzumab combination therapy in her 2 positive operable breast cancer: pCR was significantly higher in the combination group, particularly in hormonal receptor-negative tumors.
The addition of Durvalumab and Parp inhibitors to standard paclitaxel neoadjuvant chemotherapy increases pathological complete remission rates in stage II or III HER2 negative breast cancer.
ICIs Improve pCR Rates in Early ER+/HER2– Breast Cancer
Evidence for the benefit of adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early high-risk estrogen receptor–positive, HER2-negative (HR+/HER2–) breast cancer comes from results of two randomized trials.
In the KEYNOTE-756 trial, adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy resulted in an 8.5% increase in pathologic complete response (pCR) rates, compared with chemotherapy alone, regardless of the patients’ programmed death ligand-1 (PD-L1) status.
In the Checkmate 7FL trial the addition of nivolumab (Opdivo) to neoadjuvant chemotherapy resulted in a 10.5% absolute increase in pCR rates, compared with chemotherapy alone.
The prognosis for many women with small, early-detected breast 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 node 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 NST
NST is a common treatment of women with clinically involved axillary nodes.
Patients with clinically positive nodes after NST are advised to have a completion axillary dissection.
In patients who present with a clinically positive (cN1) axillary node and received NST that downstaged the axilla to clinically negative.
In such instances, the sentinel node biopsy is acceptable instead of axillary dissection, provided that three or more sentinel nodes were identified and all were negative.
Women with residual nodal disease after NST on sentinel node biopsy generally warrant completion axillary dissection.
Even in the setting of micrometastatic residual cancer at sentinel node biopsy after NST, completion axillary dissection unless RNI was planned is recommended.
Patients who present with cN2 axillary disease should undergo completion axillary dissection regardless of response to NST, and receive RNI.
Following breast conserving surgery, whole breast irradiation remains the standard treatment recommendation for optimal outcomes.
Hypofractionated radiation treatment schedules is preferred for most patients after breast conservation.
Evidence exists that 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.
Less favorable cosmetic outcomes were seen after accelerated partial breast irradiation in the RAPID trial.
Accelerated partial breast irradiation may be appropriate for carefully selected patients at low risk of local recurrence as defined by international guidelines.
Regional nodal irradiation improves survival in node-positive breast cancer.
Regional nodal irradiation (RNI) is endorsed in cases of involvement of four or more axillary lymph nodes.
In cases of one to three positive lymph nodes, RNI is recommended regardless of mastectomy or breast conserving surgery, in cases with adverse prognostic factors such as triple-negative, HER2, and luminal B cancers, and in women with residual disease after neoadjuvant systemic therapy.
Postmastectomy radiation therapy is recommended 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.
It is not resolved 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.
Postmastectomy radiation is not recommended for T2N0 cancers.
Post-mastectomy radiation therapy recommendations are the same for women undergoing immediate reconstruction.
It is recommended that women with one to three residual involved lymph nodes receive post-mastectomy RT after NST.
WITH cT3cN0 TNBC with a complete pathological response to NST postmastectomy radiation treatment is favored.
After breast conserving surgery for stage 1 breast cancer randomized trials have shown that post-surgical radiation therapy does not improve overall survival.
Adjuvant endocrine therapy is the standard for women with ER-positive breast cancer.
In postmenopausal women, the options include either tamoxifen or an aromatase inhibitor (AI).
AI therapy can be administered either as initial endocrine therapy or after 2–5 years of tamoxifen.
Based on long-term follow-up of studies comparing tamoxifen and AI therapy showing small (2%–3%) reductions in 10-year recurrence risk with AI treatment: most patients consider AI therapy at some point during their course of adjuvant treatment.
More meaningful 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.
Initial therapy with tamoxifen followed in sequence by an AI, especially in lower risk cancers, though most specialists opt for initial treatment with an AI.
Five years of treatment has been the historical duration of adjuvant endocrine treatment therapy but many recurrences happen after 5 years.
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, the adjuvant endocrine therapy treatment for 5 years is recommended.
For stage 2, node-negative cancers, extended adjuvant endocrine therapy is recommended especially in women who received tamoxifen as their initial treatment.
Long-term data show that ovarian function suppression paired with either tamoxifen or an AI can reduce recurrence compared with tamoxifen alone in premenopausal women with early-stage breast cancer.
Ovarian function suppression is preferred in women 35 years or younger, node positive cases, and in tumors with high-grade and/or adverse genomics/molecular findings.
Patients who would warrant chemotherapy should additionally receive ovarian function suppression.
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.
Stage remains an important determinant of recurrence risk and hence the need for chemotherapy.
In general, women with stage 3, ER-positive breast cancer warrant adjuvant chemotherapy.
Chemotherapy is recommended 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.
Between those extremes of stage, the 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 assays, particularly among cases when Ki67 testing is not available or where results are ambiguous or unreliable.
Genomic assays help determine whether to recommend chemotherapy in T1/T2 N0 tumors, T3 N0 tumors, and TxN1 (one to three positive LN).
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 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.
It is recommended against chemotherapy in lobular breast cancers and low-grade, luminal A breast cancers that are node-negative and/or affecting one to three axillary nodes.
For node-negative, ER-positive cancers, the recommended alkylator- and taxane-based regimens without inclusion of an anthracycline.
Anthracycline-based regimens are favored for higher risk tumors.
Chemotherapy is the mainstay of neo/adjuvant treatment of TNBC.
Dose-dense treatment is the preferred approach for anthracycline- and taxane-based neo/adjuvant chemotherapy regimens.
NST (Neoadjuvant systemic therapy) is the preferred approach to stage 2 or 3 TNBC: provides 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 as the preferred regimen for many women with stage T1cN0 disease and virtually all of those with higher stage TNBC.
Studies of NST have consistently shown that adding platinum-based chemotherapy improves the rates of complete pathological response in TNBC.
Patients with TNBC who have residual invasive cancer following NST have a higher risk of recurrence.
It is recommended that 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.
NST is 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 as the preferred approach for stage 2 or 3, HER2-positive tumors, in either the adjuvant or neoadjuvant setting, though non-anthracycline regimens such as docetaxel/carboplatin/trastuzumab/pertuzumab can be used.
For stage 1, HER2-positive tumors, paclitaxel plus trastuzumab, without pertuzumab-based therapy, as adjuvant therapy.
Some favor inclusion of pertuzumab when offering neoadjuvant therapy in HER2-positive, ER negative, and clinical stage 1 cancers.
Several trials have addressed the option using <12 months of adjuvant trastuzumab-based therapy in early stage, HER2-positive breast cancer.
These studies have shown a narrow reduction in recurrence risk with 12 months of therapy compared with shorter (3 or 6 month) durations.
It is ecommended 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.
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.
Randomized trials supported by a meta-analysis have suggested that adjuvant bone modifying therapy can reduce the risk of tumor recurrence in postmenopausal women.
Bisphosphonate therapy can help reduce osteopenia or osteoporosis, common problems in women with breast cancer treated with ovarian suppression or with estrogen deprivation strategies.
Routine use of adjuvant zoledronic acid or clodronate in postmenopausal women is recommended.
The use of zoledronic acid in premenopausal women with ER-positive breast cancer receiving GnRH agonist therapy with either an AI or tamoxifen is recommended.
Bisphosphonate therapy contributes to a 4% to 8% reduction in cancer recurrence at 5 years without improving overall survival.
In the KEYNOTE-522 trial which was a double-blind, placebo controlled trial comparing preoperative carboplatinum and paclitaxel followed by doxirubicin or epirubicin and cyclophosphamide in combination with either Pembrolizumab or placebo followed byPembrolizumab or placebo every three weeks for nine cycles after surgery in patient with previously untreated stage TI or II TNBC: Significant improvement and free survival was seen with the addition ofPembrolizumab compared with placebo plus chemotherapy (three year event free survival rates were 84.5 and 76.8%, respectively.