Post-Neoadjuvant Treatment for Early Breast Cancer: What Happens When Cancer Remains After Chemotherapy?

Table of Contents

• Key Points
• Background: Why Treatment After Pre-Surgery Chemotherapy Matters
• Key Terms Explained
• How This Review Was Conducted
• How Often Does Treatment Clear the Tumor? Rates by Cancer Subtype
• Triple-Negative Breast Cancer: Chemotherapy, Targeted Drugs and Immunotherapy
• HER2-Positive Breast Cancer: T-DM1 and Beyond
• Hormone Receptor-Positive, HER2-Negative Breast Cancer: CDK 4/6 Inhibitors
• Ongoing Clinical Trials: What Is Being Tested Now
• Key Findings at a Glance
• Clinical Implications: What This Means for Patients
• Limitations: What This Research Cannot Tell Us
• Recommendations and Practical Advice
• Frequently Asked Questions
• Source Information

Key Points

• Patients with residual disease after chemotherapy before surgery have a higher risk of the cancer returning; those who reach pCR have lower recurrence and death rates.
• Capecitabine is standard for triple-negative breast cancer with residual disease; in CREATE-X's 286-patient triple-negative subgroup, it improved 5-year disease-free and overall survival.
• T-DM1 is standard for HER2-positive residual disease; in KATHERINE's 1,486 patients, 3-year invasive disease-free survival was 88.3% versus 77.0% with trastuzumab.
• One year of olaparib may be recommended for patients with germline BRCA mutations and high recurrence risk, based on a 3.4 percentage point absolute improvement in 4-year overall survival.
• More than twenty ongoing trials are testing new drugs, combinations and ctDNA-guided strategies; ask your oncology team whether you are eligible for one.

Background: Why Treatment After Pre-Surgery Chemotherapy Matters

Breast cancer is the most common cancer in women worldwide. More than 450,000 new cases are diagnosed every year in Europe alone. Most patients — about 65% — are diagnosed when the disease is still early-stage, which means it can potentially be cured with standard local treatments (surgery and radiotherapy) and systemic treatments (drugs that travel through the bloodstream).

Even so, up to 30% of patients experience the cancer coming back after surgery. The return can be local (near the original site) or distant (metastases, meaning spread to other organs).

Chemotherapy given before surgery is called neoadjuvant chemotherapy (NAC). It was first used for tumors that could not be removed by surgery, for locally advanced disease, or for inflammatory breast cancer. Today it is standard care for many forms of early breast cancer. The review lists three main reasons why doctors now use chemotherapy before rather than after surgery:

1. It may shrink the tumor (a process called downstaging), leading to better surgical results with less extensive breast surgery and less extensive removal of underarm lymph nodes (axillary surgery).
2. It lets doctors test how well new drugs work in a living patient by watching tumor size change during treatment.
3. It allows doctors to increase or decrease further drug treatment depending on how the tumor responded.

The largest evidence for this approach comes from a meta-analysis by the Collaborative Trials in Neoadjuvant Breast Cancer group. A meta-analysis is a study that pools results from many trials. The group was led by Cortazar and colleagues. That analysis included 11,955 patients. It found that patients who achieved a pathological complete response after neoadjuvant chemotherapy had better long-term survival than patients with leftover tumor. The link was even stronger in the more aggressive cancer subtypes — triple-negative breast cancer (TNBC) and HER2-positive, hormone receptor-negative tumors.

This creates two very different groups of patients after surgery. Patients whose tumor has disappeared may be candidates for de-escalation (reducing treatment). Patients with tumor still present are at higher risk and may benefit from additional treatment after the neoadjuvant phase — the focus of this review.

Key Terms Explained

Understanding the review requires a few definitions. Each term below is used repeatedly in the studies described.

• Pathological complete response (pCR) — no detectable invasive cancer cells found in the tissue removed at surgery. Patients who reach pCR have a lower risk of the cancer returning.
• Residual disease (RD) — cancer cells still present in the surgical specimen.
• Adjuvant treatment — treatment given after surgery.
• Post-neoadjuvant setting — the window after neoadjuvant therapy and surgery, when extra treatment may be given to patients with residual disease.
• Hazard ratio (HR) — a number comparing risk between two groups. An HR below 1.0 means the treatment group did better. For example, an HR of 0.50 means the risk of an event was cut roughly in half.
• Residual Cancer Burden (RCB) index — a scoring system that combines measurements of the main tumor (its size and how densely packed with cancer cells it is) and lymph node metastases (how many nodes are involved and how large the deposits are). It sorts specimens into four classes: RCB 0 (which is the same as pCR), RCB I, RCB II and RCB III. A higher RCB score means more residual disease and a higher risk of recurrence.

The review also notes that residual disease can be assessed using various biomarkers for risk evaluation. Biomarkers are biological measurements. These biomarkers include Ki67, a marker of how fast cells divide. They also include TILs, which are tumor-infiltrating lymphocytes, immune cells found inside the tumor. Other biomarkers are the RCB index, gene expression patterns and genetic alterations.

How This Review Was Conducted

This is a narrative review — a structured summary of existing evidence rather than a new experiment. The authors searched major scientific databases, including PubMed, along with conference proceedings from the main oncology conferences.

The search covered data available up to 1 August 2022. The review describes two categories of treatment: strategies already approved for clinical use, and strategies still under investigation in clinical trials. The authors include summary tables of completed practice-changing trials and of ongoing phase II and phase III studies.

How Often Does Treatment Clear the Tumor? Rates by Cancer Subtype

The likelihood of reaching pCR after neoadjuvant therapy differs sharply by cancer subtype. Understanding these numbers helps explain why some patients need more treatment after surgery and others may need less.

• Hormone receptor-positive, HER2-negative (HR+/HER2−) is the most common subtype, occurring in about 70% of patients. Its pCR rate is the lowest: 8.3%.
• HER2-positive and hormone receptor-positive (HER2+/HR+) accounts for roughly 20% of cases overall. Its pCR rate is 18.7%.
• HER2-positive and hormone receptor-negative (HER2+/HR−) has a pCR rate of 38.9%.
• Triple-negative breast cancer (TNBC) occurs in about 10% of patients and has a pCR rate of 31.1%.

These figures come from a meta-analysis by Houssami and colleagues published in the European Journal of Cancer in 2012. The pattern is clear: the more aggressive subtypes respond better to chemotherapy in terms of clearing the tumor. But the patients who do not reach pCR in those subtypes are the ones at highest risk of relapse.

Triple-Negative Breast Cancer: Chemotherapy, Targeted Drugs and Immunotherapy

TNBC is an aggressive subtype of breast cancer with limited treatment options. Neoadjuvant combination chemotherapy remains the standard of care for early-stage TNBC larger than 2 cm or with positive lymph nodes.

Only rare histological subtypes — such as secretory or adenoid cystic carcinomas, which carry a low risk of recurrence — or very early-stage tumors classified as T1aN0 may avoid chemotherapy.

pCR rates in TNBC have improved steadily over the past decades thanks to new treatment strategies. Two additions stand out:

• Adding carboplatin to the neoadjuvant regimen significantly improved pCR rates: 37% with a regimen not containing carboplatin versus 52% with one containing carboplatin.
• Adding pembrolizumab (an immune checkpoint inhibitor) to neoadjuvant chemotherapy pushed the pCR rate as high as 65%.

Despite these improvements, a substantial proportion of patients with TNBC still do not reach pCR after finishing neoadjuvant chemotherapy, and those patients face a higher risk of relapse. Several drugs have therefore been tested in the post-neoadjuvant setting.

Capecitabine: The First Approved Post-Neoadjuvant Treatment

The CREATE-X trial was the first phase III study to show a benefit from giving extra capecitabine (an oral chemotherapy drug) after neoadjuvant chemotherapy was completed. In this trial, 910 patients with HER2-negative disease and residual tumor after neoadjuvant chemotherapy with anthracyclines and taxanes were randomly assigned to either observation (no further treatment) or six to eight cycles of adjuvant capecitabine.

Both disease-free survival and overall survival were significantly better in the capecitabine group, and the benefit was especially strong in the TNBC subgroup. Here are the detailed results:

• All HER2-negative patients (910): 5-year disease-free survival 74.1% with capecitabine versus 67.6% with no adjuvant therapy (HR 0.70); 5-year overall survival 89.2% versus 83.6% (HR 0.59).
• TNBC subgroup (286 patients): 5-year disease-free survival 69.8% versus 56.1% (HR 0.58, 95% confidence interval 0.39–0.87); 5-year overall survival 78.8% versus 70.3% (HR 0.52, 95% CI 0.30–0.90).
• Invasive disease-free survival in the overall population (1,836 patients): 4-year rate 82.7% versus 75.4% (HR 0.63).

Post-neoadjuvant capecitabine is now the standard of care for patients with TNBC who have residual disease after completing neoadjuvant chemotherapy.

Olaparib for Patients with Inherited BRCA Mutations

Among patients with TNBC, those carrying germline (inherited) BRCA1 or BRCA2 mutations form a distinct high-risk subgroup. The OlympiA trial tested one year of oral olaparib in patients with high-risk HER2-negative early breast cancer and a germline BRCA mutation. Olaparib is a PARP inhibitor, a drug that blocks a DNA repair enzyme cancer cells depend on. Olaparib was given either after surgery or after neoadjuvant treatment.

The second prespecified analysis of overall survival showed 4-year survival rates of 89.8% with olaparib versus 86.4% with placebo. That is an absolute improvement of 3.4 percentage points (HR 0.68, 98.5% CI 0.47–0.97; p=0.009).

The updated invasive disease-free survival and distant disease-free survival results matched earlier findings. Both favoured olaparib:

• Invasive disease-free survival: HR 0.63 (95% CI 0.50–0.78).
• Distant disease-free survival: HR 0.61 (95% CI 0.48–0.77).
• 3-year distant disease-free survival in the HER2-negative/TNBC group (1,509 patients): 86.5% with olaparib versus 79.1% with placebo (HR 0.61).

Approaches That Did Not Work

Not every strategy tested has succeeded, and the review documents these negative results clearly.

In the BRE12-158 trial, residual tumors after neoadjuvant chemotherapy were sequenced using a next-generation sequencing assay (a test that reads the tumor's genetic code). Patients were then randomly assigned to four cycles of genomically targeted therapy — treatment matched to the specific mutations found — versus the treatment of the physician's choice. The study failed to demonstrate that personalised therapy was superior to standard therapy.

A subsequent phase III trial by the ECOG-ACRIN group tested post-neoadjuvant carboplatin or cisplatin against capecitabine in TNBC patients with residual disease. This trial also failed to show superiority of the platinum drugs. In fact, the numbers favoured capecitabine: 3-year invasive disease-free survival was 42.8% with platinum versus 53.5% with capecitabine (HR 1.16, meaning a higher risk of events with platinum).

Immunotherapy in Early TNBC

Immunotherapy has transformed the treatment of several cancer types, including breast cancer. Several clinical trials in early TNBC have shown improvements in pCR rates when immunotherapy is added to standard chemotherapy.

KEYNOTE-522 evaluated adding pembrolizumab to neoadjuvant chemotherapy with carboplatin and paclitaxel, followed by doxorubicin-cyclophosphamide, in patients with stage II–III TNBC (1,174 patients enrolled).

• pCR rate: 64.8% with pembrolizumab versus 51.2% without (95% CI 5.4–21.8; p<0.001), which was the study's primary endpoint.
• Estimated event-free survival at 36 months: 84.5% in the pembrolizumab group versus 76.8% in the standard group (HR 0.63, 95% CI 0.48–0.82; p<0.001) — an absolute improvement of 7.7 percentage points.

Based on these results, the U.S. Food and Drug Administration approved pembrolizumab in combination with neoadjuvant chemotherapy, followed by pembrolizumab alone as adjuvant treatment, for high-risk early-stage TNBC. Notably, this is the only trial that included a platinum drug in the chemotherapy backbone.

IMpassion031 was also conducted in stage II–III TNBC (455 patients), but used a different immune checkpoint inhibitor, atezolizumab, with nab-paclitaxel and no carboplatin in the neoadjuvant phase. Atezolizumab was continued for one year after surgery. The addition of atezolizumab produced a statistically significant increase in pCR rate: 57.6% versus 41.1% (95% CI 5.9–27.1; p=0.0044). However, the trial was not designed, or not "powered", to evaluate event-free survival, disease-free survival or overall survival. Those results are still immature. The median values have not been reached for any of these endpoints.

Gepar-Nuevo tested a third immune checkpoint inhibitor, durvalumab, together with nab-paclitaxel followed by standard anthracycline-based chemotherapy in TNBC patients. The trial did not meet its primary endpoint of improving pCR. Still, the addition of durvalumab improved 3-year invasive disease-free survival from 76.9% to 84.9% and overall survival from 83.2% to 95.1%. Interestingly, the immunotherapy was not continued in the adjuvant phase. The authors caution that the study was not powered to detect a survival difference, so these results need further confirmation.

PD-L1 expression (a protein measured on tumor cells) is an established predictive biomarker in the advanced (metastatic) setting, but it does not separate responders from non-responders in early disease. Both patients with PD-L1-positive and PD-L1-negative tumors benefited from the addition of immune checkpoint inhibitors. The benefit of immunotherapy in early disease appears independent of PD-L1 status, although PD-L1-positive tumors are more likely to respond.

Three Open Questions in TNBC

The authors identify three major questions that future studies in the post-neoadjuvant setting must answer:

1. What is the best backbone chemotherapy to combine with immunotherapy?
2. How can capecitabine and olaparib be integrated with immune checkpoint inhibitors when residual disease is present after neoadjuvant chemotherapy?
3. Is it possible to de-escalate immunotherapy once pCR has been achieved?

The first question matters because the chemotherapy regimen could influence how well the immunotherapy works. In the phase II TONIC trial, patients with advanced TNBC were randomised to two weeks of induction therapy with either cyclophosphamide, doxorubicin, cisplatin or irradiation, followed by nivolumab. Patients who received doxorubicin and cisplatin as induction showed the highest overall response rates: 35% and 23% respectively. Consistent with this, in the NeoTRIP trial, which tested adding atezolizumab to an anthracycline-free chemotherapy regimen in the neoadjuvant phase, no increase in pCR was observed. These effects may be subtle and hard to assess from indirect comparisons between trials. But the data suggest the choice of chemotherapy backbone could have a major impact on immunotherapy efficacy.

For the second question, no data are yet available in the early setting. In current practice, adjuvant treatment of patients with residual disease can be tailored according to residual cancer burden, overall recurrence risk and BRCA germline status:

• In patients at high risk of recurrence, it may be appropriate to give adjuvant capecitabine if residual disease is present and to continue pembrolizumab if it was started during neoadjuvant treatment.
• In BRCA-mutated patients, olaparib is recommended for one year if the risk of recurrence is high.
• In patients with low residual cancer burden and low overall recurrence risk, continuing pembrolizumab alone could be a reasonable option if no immune-related side effects occurred during the neoadjuvant phase.

The unresolved question is whether a PARP inhibitor should be added to pembrolizumab when pembrolizumab is used in the neoadjuvant phase. The potential side effects of this combination need to be carefully weighed, as no robust data exist in the early setting yet.

On the third question, KEYNOTE-522 showed that adding pembrolizumab for patients who achieved pCR was associated with only a 2% improvement in 3-year event-free survival, whereas a 10% difference was observed in patients who did not achieve pCR. This has raised the question of whether adjuvant treatment could be reduced for patients who reach pCR with chemo-immunotherapy. However, in the absence of prospective evidence, pembrolizumab in adjuvant treatment should still be considered the standard therapy even in patients with pCR.

HER2-Positive Breast Cancer: T-DM1 and Beyond

For patients with HER2-positive breast cancer who have residual disease after neoadjuvant chemotherapy, the established post-neoadjuvant standard is T-DM1 (trastuzumab emtansine), an antibody-drug conjugate (a drug that links a chemotherapy payload to an antibody that seeks out HER2-positive cancer cells).

The KATHERINE trial enrolled 1,486 patients with residual invasive disease after neoadjuvant treatment and compared T-DM1 with trastuzumab alone. Three-year invasive disease-free survival was 88.3% with T-DM1 versus 77.0% with trastuzumab (HR 0.50) — one of the largest treatment effects reported in this setting.

The ExteNET trial tested extended adjuvant neratinib (an oral HER2-targeted drug) versus placebo. In the overall population of 2,840 patients:

• 5-year invasive disease-free survival: 90.8% versus 85.7% (HR 0.58).
• 8-year overall survival: 91.5% versus 89.4% (HR 0.79).

The benefit signal was strongest among the 1,334 patients with hormone receptor-positive disease who started neratinib within one year of finishing trastuzumab.

Multiple ongoing trials are now pushing this field further. DESTINY-Breast05 compares the next-generation antibody-drug conjugate T-DXd (trastuzumab deruxtecan) with T-DM1 in patients with residual disease after neoadjuvant treatment, with invasive disease-free survival as the endpoint. DESTINY-Breast11 tests T-DXd in the neoadjuvant setting. CompassHER2-RD adds tucatinib (an oral HER2 inhibitor) to T-DM1, while Astefania combines T-DM1 with the immunotherapy atezolizumab.

De-escalation is also under study. DECRESCENDO assigns treatment based on how much residual disease remains — patients with RCB 0 receive pertuzumab and trastuzumab, those with RCB 1 receive T-DM1, and those with RCB 2 or higher receive anthracycline-based chemotherapy followed by T-DM1. PHERGAIN-2 tests a chemotherapy-free, pCR-guided strategy. Other trials are testing the oral HER2 drug pyrotinib in the post-neoadjuvant setting (ATP and NCT04973319).

Hormone Receptor-Positive, HER2-Negative Breast Cancer: CDK 4/6 Inhibitors

Hormone receptor-positive, HER2-negative disease is the most common subtype, and its post-neoadjuvant options have expanded recently. The main drug class studied is the CDK 4/6 inhibitor — a drug that blocks two proteins (CDK 4 and CDK 6) that help cancer cells divide.

Two trials tested palbociclib, and neither showed a clear benefit:

• PALLAS (5,796 patients): palbociclib plus endocrine therapy versus endocrine therapy alone. 4-year invasive disease-free survival: 84.2% versus 84.5% (HR 0.96).
• PENELOPE-B (1,250 patients): palbociclib versus placebo. 3-year invasive disease-free survival: 81.2% versus 77.7% (HR 0.93).

By contrast, abemaciclib — a different CDK 4/6 inhibitor — did show benefit in the MonarchE trial:

• Overall population (5,637 patients): 3-year invasive disease-free survival 88.8% with abemaciclib plus endocrine therapy versus 83.4% with endocrine therapy alone (HR 0.69); 3-year distant relapse-free survival 90.3% versus 86.1% (HR 0.68).
• Patients who had received prior neoadjuvant chemotherapy (2,087 patients): 3-year invasive disease-free survival HR 0.69.

Olaparib also has a role in this subtype. In the hormone receptor-positive subgroup of the OlympiA trial (325 patients), 3-year invasive disease-free survival was 83.5% with olaparib versus 77.2% with placebo (HR 0.70).

Immunotherapy is being explored here too. CheckMate 7FL (NCT04109066) is testing nivolumab added to chemotherapy in high-risk early-stage disease, before and after surgery, with endocrine therapy afterwards. A parallel study (NCT03725059) evaluates pembrolizumab in the same population. The RSBNAT trial stratifies treatment according to recurrence risk levels calculated from multiple genes.

Ongoing Clinical Trials: What Is Being Tested Now

The review catalogues more than twenty ongoing phase II and phase III trials in the post-neoadjuvant setting. Highlights include:

• SASCIA (NCT04595565, phase III): compares the antibody-drug conjugate sacituzumab govitecan against the physician's choice of capecitabine or platinum-based chemotherapy in HER2-negative and TNBC patients with residual disease after neoadjuvant chemotherapy.
• SWOG S1418/BR006 (NCT02954874, phase III): observation versus pembrolizumab in high-risk patients after neoadjuvant chemotherapy.
• A-Brave (NCT02926196, phase III): the immunotherapy avelumab versus observation in high-risk patients after neoadjuvant chemotherapy.
• ASPRIA (NCT04434040, phase II): sacituzumab plus atezolizumab in patients with residual disease and detectable circulating tumor DNA after neoadjuvant chemotherapy. The endpoint is the rate of undetectable ctDNA after six cycles.
• BreastImmune03 (NCT03818685, phase II): radiotherapy plus nivolumab and ipilimumab versus radiotherapy plus capecitabine in residual disease.
• PERSEVERE (NCT04849364, phase II): assigns treatment by genomic pathway based on ctDNA results, using talazoparib, atezolizumab, inavolisib or capecitabine in various combinations.
• PHOENIX (NCT03740893, phase IIa): tests the ATR kinase inhibitor AZD6738, olaparib and durvalumab in residual disease, with change in the Ki67 proliferation index as the endpoint.
• APOLLO (NCT04501523, phase II): uses ctDNA to guide treatment with the anti-PD-1 antibody tislelizumab plus capecitabine, capecitabine alone, or follow-up.
• OXEL (NCT03487666, phase II): nivolumab, capecitabine, or the combination.
• ZEST (NCT04915755, phase III): niraparib versus placebo in patients with ctDNA detected after surgery or adjuvant therapy, including those with BRCA mutations.
• COGNITION-GUIDE (NCT05332561, phase II): a seven-arm "umbrella" trial using genomics-guided therapy — including immunotherapy, PARP inhibitors, antibody-drug conjugates, PI3K inhibitors, AKT inhibitors and anti-HER2 therapy — in high-risk patients with residual disease.

Additional smaller studies are testing atorvastatin with or without capecitabine, measuring circulating tumor cells at six months. Other studies are testing T-DM1 combined with a vaccine (TPIV100) and sargramostim. More studies are testing epirubicin or pirarubicin versus cyclophosphamide, and platinum-based chemotherapy versus capecitabine. Further studies are testing vitamin D supplementation in patients who are vitamin D deficient before and after neoadjuvant treatment.

Key Findings at a Glance

• Patients who reach pCR after neoadjuvant chemotherapy have lower recurrence and death rates; those with residual disease are the target group for extra treatment.
• Capecitabine is approved for TNBC patients with residual disease after neoadjuvant chemotherapy. In the TNBC subgroup of CREATE-X, it cut 5-year disease-free survival risk by 42% (HR 0.58) and overall survival risk by 48% (HR 0.52).
• T-DM1 is approved for HER2-positive patients with residual disease. KATHERINE showed 3-year invasive disease-free survival of 88.3% versus 77.0% (HR 0.50).
• Olaparib for one year benefits patients with germline BRCA mutations, with a 3.4 percentage point absolute improvement in 4-year overall survival (89.8% vs 86.4%).
• Pembrolizumab improved pCR (64.8% vs 51.2%) and 36-month event-free survival (84.5% vs 76.8%) in high-risk early TNBC.
• Abemaciclib improved 3-year invasive disease-free survival in hormone receptor-positive disease (88.8% vs 83.4%, HR 0.69), while palbociclib did not.
• Platinum chemotherapy and genomic matching failed to beat capecitabine or standard therapy in TNBC with residual disease.

Clinical Implications: What This Means for Patients

The post-neoadjuvant setting has become one of the fastest-moving areas in breast cancer care. For patients, the practical meaning is direct: the amount of tumor left at surgery is now used to decide whether extra treatment is added.

If you have TNBC and tumor remains after pre-surgery chemotherapy, you may be offered capecitabine. If you carry a BRCA1 or BRCA2 mutation, one year of olaparib may be recommended. If you have HER2-positive disease with residual tumor, T-DM1 is the standard. If your cancer is hormone receptor-positive and HER2-negative with high-risk features such as positive lymph nodes, abemaciclib plus endocrine therapy may be discussed.

Patients who achieve pCR face a different conversation. Their risk is lower, and treatment reduction (de-escalation) may be raised — but the review stresses caution. The management of a patient with pCR is multifactorial and requires multidisciplinary discussion. Removing too many treatment components could be harmful.

The review also highlights the growing role of biomarkers for tailoring decisions. These include Ki67, TILs, the RCB index, gene expression profiles, genetic alterations, and circulating tumor DNA — fragments of tumor DNA detectable in the blood. Several ongoing trials are designed specifically to use ctDNA to guide who receives more treatment and who can safely receive less.

Limitations: What This Research Cannot Tell Us

Several important gaps remain.

First, many of the immunotherapy survival results are immature. In IMpassion031, the authors state explicitly that the trial was not powered to evaluate event-free survival, disease-free survival or overall survival. No median values have been reached for those endpoints yet.

Second, some encouraging results come from studies not designed to prove a survival benefit. The Gepar-Nuevo findings came from a trial that did not meet its primary endpoint of improving pCR. The trial was not powered to detect a survival difference. The findings were improved 3-year invasive disease-free survival from 76.9% to 84.9% and overall survival from 83.2% to 95.1%. The authors call for further confirmation.

Third, PD-L1 testing, which guides immunotherapy decisions in advanced disease, does not identify who will benefit in early disease. This makes patient selection harder.

Fourth, comparisons between trials are indirect. The TONIC and NeoTRIP observations about which chemotherapy backbone works best with immunotherapy come from different studies rather than a head-to-head comparison. The review notes that extremely large studies would be needed to answer this question definitively.

Finally, for several key clinical questions — such as combining a PARP inhibitor with pembrolizumab — no robust data exist in the early setting. The review's authors also acknowledge that their review is based on literature and conference proceedings available up to 1 August 2022, so conclusions reflect the evidence at that time.

Recommendations and Practical Advice

1. Understand your residual disease status. Ask your oncology team whether you achieved pCR or whether residual disease was found, and what the RCB score was. This result drives the next treatment decision.
2. Ask about germline genetic testing if you have TNBC or another high-risk feature, since BRCA1/2 mutation status determines whether olaparib is an option.
3. Discuss your subtype-specific post-neoadjuvant options: capecitabine for TNBC with residual disease, T-DM1 for HER2-positive residual disease, abemaciclib plus endocrine therapy for high-risk hormone receptor-positive disease.
4. Ask whether you are eligible for a clinical trial. More than twenty studies are actively recruiting, testing new drugs, combinations and ctDNA-guided strategies.
5. Expect a multidisciplinary discussion if you achieved pCR, since the decision to reduce treatment is not straightforward and needs input from surgery, radiation oncology, pathology and medical oncology.
6. Report any immune-related side effects during immunotherapy, since these influence whether the drug can be continued after surgery.

Frequently Asked Questions

What does it mean if I still have tumor left after chemotherapy before surgery?

Cancer cells remaining in the tissue removed at surgery is called residual disease. Patients with residual disease have a higher risk of the cancer returning than those whose tumor disappeared completely. This is why extra treatment after surgery may be discussed. The amount of tumor left is now used to help decide whether more treatment is added.

What is a pathological complete response (pCR)?

A pathological complete response means no detectable invasive cancer cells were found in the tissue removed at surgery. Patients who reach pCR have a lower risk of the cancer returning. In a pooled analysis of 11,955 patients, those who achieved pCR after chemotherapy before surgery had better long-term survival than patients with leftover tumor.

What extra treatment might I be offered if I have triple-negative breast cancer with tumor left after pre-surgery chemotherapy?

Capecitabine, an oral chemotherapy drug, is now standard for triple-negative breast cancer patients with residual disease after chemotherapy before surgery. In the CREATE-X trial of 910 patients with HER2-negative disease, the triple-negative subgroup of 286 patients had better disease-free and overall survival with capecitabine than with no further treatment.

I have HER2-positive breast cancer and tumor remained at surgery. What is the standard extra treatment?

T-DM1 (trastuzumab emtansine) is the established treatment after surgery for HER2-positive patients with residual disease. In the KATHERINE trial of 1,486 patients, three-year invasive disease-free survival was 88.3% with T-DM1 versus 77.0% with trastuzumab alone. T-DM1 links a chemotherapy payload to an antibody that seeks out HER2-positive cancer cells.

Does a BRCA mutation change my treatment options after surgery?

Yes. If you carry an inherited BRCA1 or BRCA2 mutation, one year of the PARP inhibitor olaparib may be recommended when recurrence risk is high. In the OlympiA trial, four-year overall survival was 89.8% with olaparib versus 86.4% with placebo, an absolute improvement of 3.4 percentage points. Ask your team about germline genetic testing.

What does a hazard ratio below 1.0 mean in these trials?

A hazard ratio compares risk between two groups. A number below 1.0 means the treatment group did better. For example, a hazard ratio of 0.50 means the risk of an event was cut roughly in half. In the KATHERINE trial, the hazard ratio for invasive disease-free survival with T-DM1 versus trastuzumab was 0.50.

Can treatment after surgery be reduced if my tumor disappeared completely?

Treatment reduction may be discussed if you achieved pCR, because your risk is lower. However, the review stresses caution: managing a patient with pCR is multifactorial and needs multidisciplinary discussion, and removing too many treatment components could be harmful. In the absence of prospective evidence, continuing pembrolizumab after surgery is still considered standard even in patients with pCR.

If I still have tumor left after pre-surgery chemotherapy for early breast cancer, when should I get a second opinion on my post-surgery treatment?

When residual disease remains at surgery, the next step depends on subtype and risk. The options are capecitabine for triple-negative disease, T-DM1 for HER2-positive disease, abemaciclib plus endocrine therapy for high-risk hormone receptor-positive disease, and one year of olaparib for germline BRCA mutations. Because these options differ and more than twenty trials are recruiting, a second opinion can help confirm your residual disease status, RCB score and germline testing. A second opinion can also clarify which additional treatment fits. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Post-Neoadjuvant Treatment Strategies for Patients with Early Breast Cancer

Publication details: Published in Cancers (MDPI), 2022, volume 14, article 5467. DOI: 10.3390/cancers14215467. Published online 7 November 2022. This is an open-access article distributed under the Creative Commons Attribution (CC BY) license.

Note: This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and does not replace individual medical advice. Patients should discuss their own treatment options with their oncology team.