Treatment of residual disease following neoadjuvant therapy in breast cancer

Substantial advances have been made in the systemic treatment of breast cancer with residual disease following neoadjuvant therapy. We reviewed recent and ongoing studies informing the standard clinical management of residual disease by subtype: HER2+, TNBC, and HR+/HER2‐, as well as strategies for BRCA+ disease. We conclude with a discussion of ongoing clinical trials and current controversies regarding the treatment of residual disease in breast cancer.


| RESIDUAL DISEASE
RCB is a continuous score which classifies the degree of residual disease after NAC. 3 RCB score is calculated from the dimensions of residual disease in the breast, cancer cellularity, %DCIS in the breast, number of positive lymph nodes, and diameter of largest metastasis.
RCB score is stratified into four classes: RCB-0, which is equivalent to pCR; RCB-I (scores 0.01-1.36,classified as minimal residual disease); RCB-II (scores 1.37-3.28,classified as moderate residual disease); and RCB-III (scores >3.28, classified as extensive residual disease). 2,3B is prognostic for EFS in each subtype, even when adjusted for age, grade, tumor size, and nodal status at baseline. 3

| Management of HER2+ residual disease
Approximately 15% of breast cancers overexpress HER2. 10 Patients with HER2+ tumors <2 cm without lymph node involvement generally undergo surgical resection first.Patients not meeting these criteria commonly undergo neoadjuvant therapy with docetaxel, carboplatin, trastuzumab, and pertuzumab followed by surgery.The rate of achieving pCR has risen substantially with the advent of dual anti-HER2 therapy in the neoadjuvant setting.
For patients with RCB >0, maintenance trastuzumab, with or without pertuzumab, for 1 year was the previous standard of care.Now, novel agents such as antibody-drug conjugates (ADCs) offer new therapeutic options.ADCs are constructed with cytotoxic agents bound to a targeting monoclonal antibody, allowing the cytotoxic agents to be delivered specifically to antigen-expressing tumor cells and sparing other benign, metabolically active cells.Adotrastuzumab-emtansine (T-DM1) was the first ADC utilized in breast cancer, 11 and is now preferred treatment in patients with HER2+ residual disease based on the phase III KATHERINE trial. 12e KATHERINE trial enrolled 1486 patients with HER2+, earlystage breast cancer with residual disease, postneoadjuvant taxane-based chemotherapy with or without anthracyclines in addition to trastuzumab, with or without pertuzumab.HER2 status was based on pretreatment biopsy rather than surgical sample.Additionally, 72% of patients had HR + disease.Patients were randomized 1:1 to receive T-DM1 or trastuzumab every 3 weeks for 14 cycles.The trial was stopped early for benefit of T-DM1, with estimated 3-year invasive disease-free survival (iDFS) of 88.3% versus 77.0% for those receiving trastuzumab.This effect was observed regardless of HR status, extent of residual disease at surgery, or single versus dual anti-HER2 neoadjuvant therapy.
Risk of recurrence or death was 50% lower with T-DM1 than with trastuzumab.OS data is not yet mature.Grade 3 or higher adverse events were more prevalent in patients on T-DM1 (25.7% vs. 15.4%) with the most common being thrombocytopenia (5.7%), radiation-related skin injury (1.4%), and peripheral neuropathy (1.4%). 12Limitations of KATHERINE included relying on pretreatment biopsy to determine HER2 status, as an estimated 1/3 of patients experience loss of HER2 positivity after neoadjuvant therapy. 13A small subset of patients in the trial were found to have HER2-negative residual disease, but these patients also benefited from TDM-1.
The ExteNET trial investigated the role of adjuvant neratinib, an oral anti-HER2 tyrosine-kinase inhibitor, in 2840 women with stage I-III HER2+ disease who received neoadjuvant and adjuvant chemotherapy with trastuzumab.Patients were randomized 1:1 to either 1 year of neratinib or placebo after completing 1 year of adjuvant trastuzumab.
| 19 trastuzumab (HR 1.00 [0.51-1.91]).Patients receiving neoadjuvant therapy who did not achieve a pCR and within a year of completing trastuzumab had the greatest benefit from neratinib (iDFS advantage of 7.4% and OS advantage of 9.1%).Neratinib can be challenging for some patients with the following grade 3 adverse effects: diarrhea (40%), vomiting (3%) and nausea, fatigue, or abdominal pain (2%). 15Overall, neratinib can be considered in patients with HR+, node-positive disease, particularly those not achieving pCR after neoadjuvant therapy and within 1 year of trastuzumab completion.
Ongoing trials in patients with HER2+ residual disease are studying trastuzumab deruxtecan (T-DXd), a second-generation ADC that has shown markedly improved progression-free survival (PFS) versus T-DM1 as second-line therapy in the metastatic setting (PFS 28.8 vs. 6.8 months). 17DESTINY-Breast 05 is a phase III trial of postneoadjuvant T-DXd versus T-DM1 in patients with residual disease following neoadjuvant therapy, with results expected in 2025. 18portantly, ongoing studies aim to identify which patients truly benefit from adjuvant chemotherapy, with the goal of de-escalating adjuvant chemotherapy for patients who may not benefit.The CompassHER2 trial is a phase II trial in patients with stage II-IIIa disease who undergo neoadjuvant therapy with paclitaxel, trastuzumab, and pertuzumab × four cycles (12 weeks).Patients who achieve pCR will receive standard adjuvant trastuzumab and pertuzumab, while patients with RCB will be randomized to T-DM1 with tucatinib or placebo (A011801).First data from this trial is expected in 2026. 19The DECRESCENDO trial in Europe is evaluating patients with HR-/ HER2+, N0, early-stage breast cancer.Patients receive neoadjuvant trastuzumab, pertuzumab with either paclitaxel or docetaxel.Patients achieving pCR will receive postoperative trastuzumab and pertuzumab without additional chemotherapy.Patients with RCB ≥1 will receive adjuvant T-DM1 without chemotherapy while patients with RCB ≥2 will receive T-DM1 and anthracycline-based chemotherapy.Initial data is expected in 2027. 20nally, de-escalation strategies are being extended from the adjuvant to neoadjuvant setting.A multiparameter molecular classifier is being used to identify patients with HER2+ disease who may achieve pCR without the need for chemotherapy in the neoadjuvant setting. 21Future prospective studies are needed to validate these findings.

| Management of TN residual disease
TNBC is an aggressive subtype of breast cancer seen in 12%-15% of all cases in the United States. 10Because TNBC lacks both hormone receptor targets and HER2 overexpression, chemotherapy has historically been the mainstay of treatment.Anthracycline, cyclophosphamide, and paclitaxel-based regimens with the addition of carboplatin is associated with pCR of up to 60%. 22Recently, immunotherapy has become integrated into neoadjuvant and adjuvant regimens.
The KEYNOTE-522 trial included 602 patients with stage II-III TNBC with the goal of evaluating the efficacy of neoadjuvant and adjuvant pembrolizumab, a humanized antibody that targets the programmed cell death protein 1, known as a PD-1 inhibitor within the class of checkpoint inhibitors.Unlike the metastatic setting, pembrolizumab use and efficacy is not dependent on PDL-1 expression.Patients were randomized 2:1 to receive NAC with paclitaxel and carboplatin followed by an anthracycline and cyclophosphamide, along with pembrolizumab or placebo.Patients receiving pembrolizumab achieved pCR at a rate of 64.8% versus 51.2% in the placebo group (p < 0.001). 23In the adjuvant setting, patients received up to nine cycles of pembrolizumab or placebo.
Disease progression precluding definitive surgery, recurrence, a second primary tumor, and death from any cause were more common in the placebo group, suggesting a clinical benefit for those receiving pembrolizumab.Updated 3-year EFS was 84.5% versus 76.8% (p < 0.001) for pembrolizumab and placebo groups, respectively. 24Pembrolizumab is now utilized in neoadjuvant and adjuvant regimens for high-risk TNBC. 25 The GeparNuevo trial evaluated another immune checkpoint inhibitor, durvalumab (an anti-PD-1 monoclonal antibody) in combination with standard NAC in patients with nonmetastatic TNBC.
Patients were randomized 1:1 to receive nab-paclitaxel followed by epirubicin-cyclophosphamide plus either durvalumab or placebo.This trial initially included a window phase in which patients received one injection of durvalumab or placebo 2 weeks before the start of chemotherapy, however, the window phase was discontinued after 117 patients were recruited due to concerns that the time period before starting chemotherapy was too long.The window cohort included more patients with ≥stage IIA disease and more nodal involvement.Of the 174 total patients, 53% from the durvalumab group achieved pCR versus 44.2% in the placebo group (OR 1.45 [0.80-2.63]). 26Three-year DFS was 85.6% for patients receiving durvalumab versus 77.2% in the placebo group (HR 0.48, [0.24-0.97].A DFS survival benefit was seen for all patients receiving durvalumab, regardless of pCR status. 27As this trial did not include postoperative treatment with durvalumab, it raises the question of how much benefit would be derived from a checkpoint inhibitor in the adjuvant setting, particularly if a pCR had been achieved, or if patients with RCB had predictably inferior prognosis compared with those achieving pCR.How much added benefit is derived from adjuvant durvalumab in those with RCB is an open question. The 2017 Phase III Create-X trial assessed the use of adjuvant capecitabine versus placebo in 910 patients with residual HER2-negative disease after NAC (with anthracycline, taxane, or both).Thirty-two percent of the patients had TNBC.Patients in the treatment arm received capecitabine 2500 mg/m 2 D1-14 every 21 days for eight cycles.
In patients with TNBC, the 5-year DFS was 69.8% in the capecitabine group compared with 56.1% in the control group, HR 0.58 [0.39-0.87]. 28tients receiving capecitabine also had a 5-year OS benefit (78.8% vs. 70.3%,HR 0.52 [0.30-0.90]).The most common adverse effect on capecitabine was hand-foot syndrome, seen in 73% of patients, with 11% experiencing grade 3 toxicity.Most other adverse events were grade 1 or 2. Based on the results of Create-X, NCCN guidelines have included adjuvant capecitabine since 2017 as an option for patients with TNBC with residual disease after NAC. 25 Though the safety of capecitabine plus pembrolizumab has been established, the added benefit of the doublet versus either of these agents alone in this setting has not been clearly delineated.
Following Create-X, the 2021 ECOG-ACRIN EA1131 trial compared adjuvant platinum chemotherapy with cisplatin or carboplatin to capecitabine in 308 patients with stage II-III basal subtype TNBC (determined by PAM50 gene expression) with >1 cm residual disease in the breast after NAC.Patients received either capecitabine 1000 mg/m 2 D1-14 every 21 days for six cycles or platinum-based chemotherapy (88% carboplatin and 12% cisplatin) every 21 days for four cycles.The trial was stopped prematurely as the rate of disease progression on platinum chemotherapy was higher than predicted and patients in the platinum chemotherapy group had an unfavorable toxicity profile compared with those receiving capecitabine. 29Patients treated with platinum chemotherapy had 3-year iDFS of 42% versus 49% in the capecitabine group.RFS (46% vs. 49%) and OS (58% vs. 66%) also favored capecitabine.Moreover, grade 3 and 4 toxicities, primarily hematologic, were more common in the chemotherapy group (26% vs. 15%).The disappointing results in EA1131 compared with Create-X are likely due to several factors.For example, patients in EA1131 were higher-risk (with a basal subtype and higher RCB score), and also received a lower dose of capecitabine (1000 vs. 2500 mg/m 2 ).
The efficacy of maintenance capecitabine therapy after standard adjuvant chemotherapy was evaluated in the SYSUCC-001 trial of 434 patients with early-stage TNBC.This trial was not designed to capture patients with residual disease after neoadjuvant therapy, but rather if capecitabine maintenance following standard adjuvant chemotherapy offers any improvement in outcome.Patients were randomized 1:1 to low dose, high frequency capecitabine therapy (650 mg/m 2 twice daily) or observation for 1 year, with 82% of patients in the treatment group completing the full year of treatment.

Assessments of combination chemotherapy and immunotherapy
have yielded mixed results in the metastatic setting.A phase II, single-arm study of 30 patients with metastatic HR+, HER2endocrine resistant breast cancer (14 patients), or TNBC (16 patients)   was conducted to evaluate the response rate of combined chemotherapy and immunotherapy.Patients received pembrolizumab on D1 and capecitabine 100 mg/m 2 on D1-14 of a 21-day cycle.
The median PFS for patients with TNBC was 4.0 months [1.9-12.7],not reaching the preset clinically significant compared with historic controls with median PFS of 3 months. 31The objective response rate was 13% with a clinical benefit rate of 27%.Patients with PD-L1 positive disease did not have significantly improved outcomes.
Atezolizumab, a humanized antibody targeting programmed cell death-ligand 1 (PD-L1) inhibitor, found initial success as first-line treatment of mTNBC in combination with chemotherapy, 32 however, this benefit has not been seen in the adjuvant setting.ALEXANDRA/ IMpassion030, a phase III study of 2300 patients with stage II-III TNBC, investigated the effect of adjuvant atezolizumab and paclitaxel followed by atezolizumab with doxorubicin-cyclophosphamide or epirubicincyclophosphamide compared with the same chemotherapy regimen without atezolizumab.In April 2023, the study was halted after a futility analysis found the study was unlikely to meet its primary endpoint of improved iDFS versus chemotherapy alone. 33spite the disappointing results of adjuvant atezolizumab, two ongoing trials are evaluating other adjuvant immunotherapies in patients with early-stage, high-risk TNBC.Avelumab, another PD-L1 antibody, has shown clinical activity in mTNBC. 34A-BRAVE is a European phase III trial comparing 1 year of adjuvant avelumab to observation in patients with early-stage, high-risk TNBC. 35Enrolled patients had undergone either NAC without achieving pCR or surgery followed by adjuvant chemotherapy.Results for the primary endpoint of DFS are expected in 2023.Similarly, pembrolizumab has shown clinical efficacy in patients with advanced TNBC with high expression of PD-L1. 36The SWOG1418 trial is evaluating the effect of adjuvant pembrolizumab in patients with stage II-III TNBC with >1 cm residual invasive cancer or positive lymph nodes after NAC. 37Patients are randomized to receive 1 year of adjuvant pembrolizumab or observation.The primary endpoint is iDFS, with a planned subgroup analysis for a PD-L1 positive subset.Results are expected in 2026.
Another focus of ongoing clinical trials in TNBC is on ADCs.The German Breast Group's phase III SASCIA trial is evaluating postneoadjuvant sacituzumab govitecan (SG), which targets Trop-2, in HER2-early breast cancer, including patients with TNBC.Patients are randomized to receive either eight cycles of SG or treatment of physician's choice, with a primary endpoint of iDFS.The trial plans to enroll approximately 1200 patients with results expected in 2026. 38e ASCENT-05/OptimICE-RD trial is evaluating adjuvant SG with pembrolizumab versus treatment of physicians choice of chemotherapy in patients with stage I-III TNBC not achieving pCR. 39Results for the primary endpoint of iDFS are expected in 2027.A second ADC of interest in patients with residual disease is Datopotamab Deruxtecan (Dato-DXd), a novel humanized anti-trophoblast cell surface protein 2 (TROP2) IgG1 monoclonal antibody attached via a stable, cleavable linker to a topoisomerase I inhibitor (deruxtecan).
TROPION-Breast-03 will investigate the efficacy and safety of Dato-DXd with or without durvalumab versus treatment of physician's choice of chemotherapy in patients with TNBC with residual disease postneoadjuvant therapy.Results are expected in 2027. 403 | Management of early-stage HR+, HER2-at high risk of recurrence HR+/HER2-is the most common subtype of breast cancer, affecting 70%-75% of patients.10 Patients with HR+/HER2-disease typically undergo surgery followed by adjuvant endocrine-based therapy, with or without adjuvant chemotherapy.Many patients with ER+/HER2disease undergo preoperative chemotherapy to achieve downstaging, possibly avoiding an axillary dissection and converting some mastectomy patients into breast conservation candidates.The adjuvant treatment of HR+/HER2-disease is based on risk of recurrence, which persists up to 20 years after diagnosis with 50% of all recurrences occurring in year 5 or later.41 Adjuvant endocrine therapy is the foundation of postoperative treatment, with a rising role for targeted treatments such as CDK4/6 inhibitors (CDK4/6i), particularly in high-risk patients.
Unlike the success seen with abemaciclib, the use of adjuvant palbociclib, another CDK-4/6i, was not beneficial for patients with high-risk, early-stage breast cancer with residual disease when used in combination with endocrine therapy. 45Though the reason for these discrepant results is uncertain, it is postulated that differences in dosing schedule or potency may have led to lower levels of CDK4/ 6 inhibition in patients receiving palbociclib.
Ongoing studies of CDK 4/6i in HR+/HER2-early breast cancer include the phase III NATALEE study of 5100 patients with HR+/HER2-stage II-III at risk for recurrence (including patients with N0 disease) treated with endocrine therapy with or without ribociclib for 36 months. 46This trial included patients receiving neoadjuvant therapy who remained at high risk for recurrence based on presence of residual disease or because of high-risk features at diagnosis.Patients receiving endocrine therapy with ribociclib had improved 3-year iDFS (90.4% vs. 87.1%)versus endocrine therapy alone. 46Though promising, longer follow-up is required to confirm long-term outcomes and whether particular subsets of patients benefit most.

| Management of BRCA+ residual disease
Poly(adenosine diphosphate-ribose) polymerase inhibitors target the homologous recombination defect in patients with BRCA 1/2+ F I G U R E 1 Treatment paradigm for residual disease postneoadjuvant chemotherapy.cancers, and have been shown to express activity against BRCA 1/ 2+ ovarian, breast, prostate, and pancreatic cancers. 47OlympiA evaluated 1836 patients with high-risk HER2-, BRCA1/2+ breast cancer with residual disease after neoadjuvant (50%) or adjuvant (50%) chemotherapy with anthracycline and/or taxane-based regimens in a phase III trial.Seventy-two percent of patients carried a BRCA1 germline mutation, while 27% of patients were BRCA2+.Patients with HR+ disease (18%) were required to have a CPS + EG score (staging system incorporating pretreatment clinical stage, posttreated pathologic stage, ER status, and tumor grade) of 3 or higher to meet the study's definition of high-risk.

| CONCLUSIONS
Substantial advances have been made in the treatment of breast cancer with residual disease following neoadjuvant therapy.Recent updates to NCCN guidelines include the addition of T-DM1 for HER2+ residual disease, capecitabine and pembrolizumab for TNBC, and abemaciclib for patients with HR+ disease.Ongoing trials will bring new therapeutic options to improve outcomes for patients with residual disease.