Preoperative partial breast radiation for favorable early-stage breast cancer: a narrative review
Review Article

Preoperative partial breast radiation for favorable early-stage breast cancer: a narrative review

Susan G. R. McDuff1, Sarah Jo Stephens1, Colin E. Champ2, Rachel C. Blitzblau1

1Department of Radiation Oncology, Duke Cancer Center, Durham, NC, USA; 2Department of Radiation Oncology, Allegheny Health Network, Pittsburgh, PA, USA

Contributions: (I) Conception and design: All authors; (II) Administrative support: SGR McDuff, RC Blitzblau; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Susan G. R. McDuff, MD, PhD. Department of Radiation Oncology, Duke Cancer Center, 30 Duke Medicine Circle, Box 3085, Durham, NC 27710, USA. Email: susan.mcduff@duke.edu.

Background and Objective: Adjuvant partial breast irradiation (PBI) is a well-established treatment for appropriately selected women with early-stage breast cancer. Preoperative PBI is a newer approach with some advantages compared to post-operative PBI, including potential for decreased toxicity, tumor response assessment, treatment stratification, and prognostication. Here, we summarize emerging data from prospective studies demonstrating safety and efficacy of preoperative PBI and explore techniques for assessing tumor response. We further review ongoing studies and discuss the intriguing possibility of utilizing this technique to adopt a non-operative approach for select patients with early-stage breast cancer.

Methods: We conducted a comprehensive literature search utilizing PubMed and ClinicalTrials.gov prior to August 01, 2024 to identify prospective studies in English documenting outcomes for women treated with a neoadjuvant partial breast approach. We utilized keywords of “partial breast radiation”, “breast cancer radiation”, “breast cancer radiotherapy”, “partial breast radiotherapy for breast cancer”.

Key Content and Findings: A growing number of prospective studies demonstrate that preoperative PBI may be a safe and effective alternative to postoperative PBI for appropriately selected patients with early-stage breast cancer. A subset of women treated with preoperative PBI achieve a pathologic complete response (pCR) following treatment. However, careful preoperative evaluation is critical to select patients suitable for a partial breast approach to avoid overtreatment.

Conclusions: Preoperative PBI is a promising alternative to traditional postoperative radiotherapy for appropriately selected women with early-stage breast cancer. Further prospective studies are necessary to further refine understanding of the optimal selection criteria and clinical outcomes for patients treated with this approach.

Keywords: Breast cancer; radiotherapy; partial breast radiation

Received: 06 October 2024; Accepted: 28 February 2025; Published online: 27 April 2025.

doi: 10.21037/tbcr-24-43

Introduction

Background

Breast conserving therapy (BCT) consisting of lumpectomy followed by adjuvant radiotherapy is a well-established alternative to mastectomy for many patients with early stage breast cancer (1,2). In the landmark trials establishing BCT, patients received adjuvant radiation therapy (RT) delivered to the whole breast over 5–6 weeks (1-3). Over the past 40 years, local control and survival following treatment for breast cancer have improved dramatically for many reasons including earlier diagnosis, improved surgical and RT techniques, and improved systemic therapy. Thus, significant research efforts have focused on de-escalation of therapy for appropriately selected patients with early-stage breast cancer. Efforts to de-escalate radiotherapy range from offering fewer treatments (4-6), selective omission (7,8), and avoiding uninvolved breast tissue when appropriate (9,10).

The effort to reduce radiation toxicity by decreasing the volume of breast tissue irradiated is termed partial breast irradiation (PBI) (9-13). Many studies now show comparable efficacy of PBI compared to whole breast irradiation (WBI) for women with low-risk, early-stage breast cancer and national and international guidelines support the use of PBI outside of a clinical trial for appropriately selected patients (14-18). Most studies investigating outcomes associated with PBI involve delivery of post-operative (i.e., adjuvant) RT with either external beam radiation [via three-dimensional (3D)-conformal or intensity-modulated radiation therapy (IMRT)] or brachytherapy (9,10,19). However, soft tissue fibrosis and cosmetic outcomes may be suboptimal with adjuvant accelerated external beam PBI, potentially due to the large volume of tissue treated in the postoperative setting (20-22). Data also exist supporting intraoperative adjuvant PBI for selected patients (11,13), although this technique requires specialized equipment and increases time in the operating room. Additionally, some series of intraoperative radiotherapy have shown higher rates of local recurrence compared to adjuvant external beam PBI and WBI (23,24).

Rationale and knowledge gap

Use of PBI in the preoperative (i.e., neoadjuvant) setting has been less well studied but has some potential advantages. First, delivering preoperative radiation to an intact tumor allows for more accurate target delineation and irradiation of a smaller volume of tissue (25-27). Smaller treatment volumes spare more normal breast tissue and local organs at risk especially when conformal stereotactic techniques are employed. Whereas intraoperative radiation requires specialized equipment, preoperative linear accelerator-based radiation can be delivered at most modern radiation facilities. Second, neoadjuvant partial breast regimens enable assessment of tumor response to RT. Response to neoadjuvant radiation could potentially be used for tailoring adjuvant treatment recommendations [such that patients with a poor response to neoadjuvant RT could potentially be selected for escalation of adjuvant therapy in a similar vein to the KATHERINE (28) and CREATE-X (29) trials, while those with a very favorable response could potentially be selected for de-escalation]. Finally, a subset of patients treated with preoperative techniques have been shown to achieve a pathologic complete response (pCR), raising the intriguing possibility of adopting a non-operative approach for select patients.

Given the significant potential advantages of preoperative partial breast radiotherapy compared to postoperative partial breast radiotherapy and a newer body of literature supporting this novel approach, we sought to conduct a modern review of evolving data highlighting available studies investigating this novel approach.

Objective

In this review, we discuss data from prospective studies demonstrating the safety and efficacy of preoperative partial breast RT. We also review data regarding tumor response to preoperative radiation and investigate the prospect of omission of radiation for select patients. We will also discuss limitations of this approach and review ongoing prospective trials. We present this article in accordance with the Narrative Review reporting checklist (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-43/rc).

Methods

A literature review was conducted to survey available prospective studies investigating the use of preoperative partial breast radiotherapy for early-stage breast cancer. The literature search was conducted in English utilizing PubMed and ClinicalTrials.gov with keywords “partial breast radiation”, “breast cancer radiation”, “breast cancer radiotherapy”, and “partial breast radiotherapy for breast cancer”. Articles were included if they were published up to August 01, 2024. The search strategy is summarized in Table 1.

Table 1

The search strategy summary

Items Specification
Date of search August 01, 2024
Databases and other sources searched PubMed; Clinicaltrials.gov
Search terms used Partial breast radiation, breast cancer radiation, breast cancer radiotherapy, partial breast radiotherapy for breast cancer
Timeframe Prior to August 01, 2024
Inclusion criteria Prospective studies written in English
Selection process All authors conducted the literature search and reviewed appropriateness of articles

Results

Safety and efficacy of preoperative partial breast radiation for early-stage breast cancer

Historically, preoperative radiation for breast cancer has most often been utilized for treatment of locally advanced (and frequently inoperable) disease (30-33). In the setting of locally advanced disease, preoperative radiation most commonly utilizes whole breast and regional lymph node RT either alone (34,35) or in combination with systemic therapy (36-40). More recently, there has been interest in the combination of preoperative RT and immunotherapy for patients with localized high-risk disease, and trials utilizing the combination of immunotherapy and preoperative radiation are ongoing and in development (41,42).

Utilization of preoperative PBI is less well-studied but has gained interest in recent years. Bondiau et al. was one of the earliest prospective investigations of preoperative PBI, combining partial breast stereotactic body radiotherapy (SBRT) with concurrent neoadjuvant chemotherapy between 2007 and 2010 for 26 women with unifocal breast cancer who were not suitable for breast-conserving therapy at diagnosis (43). Patients received 19.5–31.5 Gy in 3 fractions concurrently with the second cycle of chemotherapy followed by surgery (lumpectomy or mastectomy with axillary dissection). Surgery was performed 4–8 weeks after the last cycle of chemotherapy, and conventional adjuvant radiation was given 4–6 weeks after surgery. After neoadjuvant treatment, 92% were able to undergo breast conserving surgery, and 36% exhibited a pCR (43).

Subsequent prospective studies investigated preoperative PBI alone for patients with favorable, early-stage disease, and initial reports from these studies demonstrated the feasibility and efficacy of preoperative partial breast radiation. In a phase 1 dose-finding study conducted at Duke Cancer Center between 2010 and 2013, 32 women with estrogen receptor positive (ER+), invasive or preinvasive tumors 2 cm or less were enrolled on a protocol to evaluate safety of preoperative SBRT and to investigate imaging and genomic markers of radiation response (25,44-46). Patients received 15, 18, or 21 Gy in a single fraction to the intact breast tumor with 1.5 cm margin using SBRT, followed by surgery within 10 days. After a median follow-up of 23 months, no local recurrences were reported and cosmetic outcomes were good/excellent with no grade 3 long-term toxicity (44). A larger trial investigating delivery of 21 Gy to the gross tumor volume [GTV, consisting of enhancing tumor on magnetic resonance imaging (MRI)] and 15 Gy to the clinical target volume (CTV, 1.5 cm anatomically constrained expansion of GTV) recently completed accrual (NCT02482376).

Researchers at the University of Maryland conducted a prospective trial between 2010 and 2013 investigating feasibility of neoadjuvant accelerated PBI (APBI) for women with early stage, clinically node negative breast cancer with tumors less than 3 cm (47). Twenty-seven patients were treated with 38.5 Gy delivered in ten 3.85 Gy fractions twice daily, followed by surgical resection after a minimum of 21 days. After a median follow-up of 3.6 years, no patients experienced local recurrence, and 79% had good-to-excellent cosmesis at 1 year (47). Fifteen percent of patients had a pCR, and median Ki-67 was 14% prior to RT and 4.2% post-radiation (47).

In the European PAPBI trial, between 2010 and 2013, 133 women with favorable early breast cancer (unifocal, invasive ductal carcinoma, up to 3 cm, with negative sentinel node assessment) received neoadjuvant external beam radiotherapy (4 Gy ×10 daily fractions or 6 Gy ×5 daily fractions) followed by lumpectomy after 6 weeks (48,49). Outcome data for 70 patients from this cohort treated with 40 Gy in 10 fractions was first reported (48). At a median of 23 months, two patients experienced local recurrence (2.9%), postoperative infection rate was 11%, and cosmetic outcome was good-to-excellent in all patients after 3 years (48). A subsequent publication reported rates of tumor response for 63 evaluable patients (49). A near complete or complete pathologic response rate was seen in 6 patients (10%), a good response in 3 (5%), a partial response in 32 (51%), and 22 (34%) had no response (49).

The Canadian SIGNAL (Stereotactic Image-Guided Neoadjuvant Ablation then Lumpectomy) trial treated 27 women between 2014 and 2016 with a clinically negative axilla and ER+ tumors up to 3 cm with a single dose of 21 Gy, followed by surgical excision after 7 days (50). Fifty-two patients were initially enrolled on study, however, many were not able to be treated according to initial dosimetric constraints resulting in a protocol change with revised dosimetric constraints. No patients developed postoperative infection, no grade 2 or higher toxicity was observed, and physician-rated cosmetic outcome was good-to-excellent in 96% of the cohort at 1 year (recurrence data not reported) (50).

The Italian phase II ROCK trial (Preoperative Robotic Radiosurgery for Early Breast Cancer) treated 22 women between 2018 and 2021 who were over 50 years old with hormone-receptor positive, human epidermal growth factor receptor 2 (HER2) negative, clinically node negative breast cancers up to 2.5 cm (51). Patients received 21 Gy with Cyberknife (Accuray Incorporated, Sunnyvale, CA, USA) followed by lumpectomy and sentinel lymph node biopsy (SLNB) 2 weeks later. Pathologic positive axillary nodes were seen in 13.6% and two patients received postoperative whole breast radiation. No postoperative complications were reported, and acute toxicity was limited to grade 1–2. However, cosmetic outcomes were noted to worsen over time, with only 81.8% exhibiting a good/excellent cosmetic outcome at 18 months which is lower than other studies. No recurrences were noted at a median follow up of 18 months and pCR was observed in 9% (51).

Researchers in the Netherlands conducted a prospective single-arm (ABLATIVE) study of 36 patients between 2015 and 2018 of single-fraction MRI-guided preoperative SBRT for women with negative sentinel nodes and favorable non-lobular unifocal tumors up to 2 cm (age, 50–70 years) or up to 3 cm (for patients over 70 years) (52,53). The primary outcome was rate of pCR, and 36 patients received 20 Gy to the GTV and 15 Gy to the CTV followed by surgery 6 or 8 months after radiation. Neoadjuvant endocrine therapy was allowed, and 6 patients received this treatment. A pCR was seen in 15 patients [42%, 95% confidence interval (CI): 26–59%], and no patients experienced a local recurrence after a median follow-up of 21 months (52). All patients experienced grade 1 fibrosis in the treated breast, and transient grade 2 toxicity was observed in 31% of patients (52). Given these favorable results, the authors concluded that preoperative SBRT with or without endocrine therapy represents a feasible treatment approach and may even allow for omission of surgery in select patients if pCR can be accurately predicted.

More recently, researchers at UT Southwestern presented the interim analysis of a phase I dose escalation study, exploring feasibility of treatment to a higher dose with preoperative stereotactic PBI than previously studied (54). Eligible patients had hormone-receptor positive, HER2-negative, clinically node negative breast cancers up to 3 cm. Between 2019 and 2023, eleven patients received treatment with 30 Gy and fifteen patients received 34 Gy in a single fraction. Patients started endocrine therapy 2 weeks after radiation and proceeded to surgery 2–12 months after. Rates of pCR or near complete response (nCR) were 37.5% for patients receiving 30 Gy and 92.8% for patients receiving 34 Gy. Patients in the 34 Gy cohort had a longer time-to-surgery interval than those in the 30 Gy cohort (7.3 versus 4.3 months), and it is unclear whether increased dose or longer time-to-surgery interval could account for the difference in pCR/nCR rates. Nonetheless, this is a promising experience demonstrating the safety and efficacy of dose escalation to 30–34 Gy, with results that will pave the way for future studies exploring feasibility of non-surgical management for select patients with favorable early-stage breast cancers (54).

Taken together, these experiences (summarized in Table 2) demonstrate the feasibility and safety of preoperative partial breast radiation for treatment of early-stage breast cancer, with longer follow-up and larger studies in process to confirm the efficacy of this approach. Ongoing prospective trials of preoperative PBI for early-stage breast cancer are summarized in Table 3. Newer trials investigating preoperative PBI are designed to elucidate the most effective dose for preoperative PBI, with many trials investigating the feasibility and safety of dose escalation. Additionally, rates of pCR and cosmesis are important endpoints under investigation. Most trials are prospective single-arm studies, but some are randomizing patients between receiving preoperative or postoperative partial breast radiation. The results of these ongoing prospective studies are eagerly awaited to enhance our understanding of the side effect profiles and oncologic outcomes associated with preoperative PBI.

Table 2

Prospective studies investigating preoperative partial external beam breast irradiation for women with early-stage breast cancer or DCIS

Study Inclusion criteria Years Intervention Outcomes N
Horton et al. [2015] Age ≥55 years with cN0, HR+, Her2− grade 1–2 IDC or DCIS ≤2 cm, no LVI; surgery within 10 days of RT 2010–2013 Dose escalation study: 15 Gy (N=8), 18 Gy (N=8), 21 Gy (N=16) to intact tumor with SBRT No dose-limiting toxicity observed 32
No local recurrence at median follow-up 23 months
G1–2 toxicity for patients treated only with neoadjuvant PBI
G3 toxicity observed in 2/3 patients who also received postoperative RT
Nichols et al. [2017] Age ≥18 years with invasive carcinoma <3 cm, HR+, Her2−; surgery >21 days after RT 2010–2013 Feasibility of preoperative PBI (38.5 Gy in 10 fractions delivered BID) with 3D-conformal RT No local recurrence at median follow-up 3.6 years 27
Good/excellent cosmetic outcome in 79%
15% with pCR
Median Ki-67 decrease following RT
van der Leij et al. [2015] Age ≥60 years with invasive ductal tumors ≤3 cm (not allowed: lobular, pN1–3 preoperative SLN performed) 2010–2013 PBI 40 Gy in 10 daily fractions via 3D-conformal or IMRT/VMAT followed by lumpectomy after 6 weeks Global cosmetic outcome good/excellent in 77% at 6 months and 100% at 3 years 70
Postoperative infection rate 11%
2.9% IBTR at median follow-up of 23 months
Near complete CR or pCR in 10% (Bosma et al., 2020)
Guidolin et al. [2019] Postmenopausal women with unifocal invasive carcinoma <3 cm, HR+ at least 2 cm from skin and chest wall 2014–2016 21 Gy in a single fraction PBI followed by surgery 1 week later with SBRT No differences in toxicity, patient- and physician-reported cosmesis and quality of life were observed 27
Meattini et al. [2022] Age ≥50 years with invasive carcinoma ≤2.5 cm, HR+, Her2−, cN0 2018–2021 21 Gy single-fraction PBI followed by surgery 2 weeks later with Cyberknife SBRT 13.6% with positive axillary nodes on final pathology and 2 received adjuvant whole breast radiation 22
9% pCR rate
No recurrences at a median follow up of 18 months
Cosmetic worsening over time: good/excellent cosmetic outcome in 81.8% at 18 months
Vasmel et al. [2020] Age ≥50 years with IDC <2 cm (≤3 cm if age >70 years), ER+, Her2−, grade 1–2 tumor, negative preop sentinel node 2015–2018 Single dose of 20 Gy to GTV and 15 Gy to CTV followed by surgery 6–8 months later pCR rate 42% 36
No local recurrences at median follow up of 21 months
Rahimi et al. [2023] <3 cm, HR+, Her2− invasive breast cancers, cN0 2019–2023 Single fraction PBI of 30 or 34 Gy via SBRT followed by surgery 2–12 months after Near CR/pCR 37.5% for patients treated with 30 Gy (median time to surgery 4.3 months) 26
Near CR/pCR 92.8% for patients treated with 34 Gy (median time to surgery 7.3 months)
Mean Ki-67 decrease from 12% preoperatively to 1.4% postoperatively

DCIS, ductal carcinoma in situ; 3D, three-dimensional; BID, twice a day; cN0, clinically node negative; CR, complete response; ER+, estrogen receptor positive; CTV, clinical target volume; GTV, gross tumor volume; Her2−, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive; IBTR, ipsilateral breast tumor recurrence; IDC, invasive ductal carcinoma; IMRT, intensity-modulated radiation therapy; LVI, lymphovascular invasion; N, number; PBI, partial breast irradiation; pCR, pathologic complete response; RT, radiation therapy; SBRT, stereotactic body radiotherapy; SLN, sentinel lymph node; VMAT, volumetric modulated arc therapy.

Table 3

Ongoing clinical trials of preoperative partial external beam breast irradiation for women with early-stage breast cancer or DCIS (recruiting and not yet recruiting)

Study title Eligibility criteria Intervention Primary outcome NCT number Sponsor Status Ph Est. N
Non-randomized
   SPORT: Single Pre-Operative Radiation Therapy for Low-Risk BC Age ≥60 years with IDC <2 cm, cN0, ER+, Her2−, grade 1–2 Dose escalation study: 15 Gy (N=3), 18 Gy (N=3), 20 Gy (N=4) Acute toxicity NCT01717261 Maisonneuve-Rosemont Hospital; Canada Recruiting 1 10
   Single Pre-Operative Radiation Therapy With Delayed Surgery (SPORT-DS) for Low Risk BC: A Phase 1 Study Age ≥65 years with IDC <2 cm, cN0, ER+, Her2−, grade 1–2 with planned lumpectomy/SLNB Preoperative radiation with surgery after 3 months Rate of pCR NCT03917498 Maisonneuve-Rosemont Hospital; Canada Recruiting 1 20
   A Phase 1 Dose Escalation Study of Single Fraction Preoperative Partial Breast (S-PBI) for Early-Stage BC Age ≥18 years with invasive carcinoma <3 cm, HR+, Her2− 3 preoperative single-fraction dose levels: 30, 34, 38 Gy with surgery up to 12 months after Maximum tolerated dose NCT04040569 UT Southwestern Medical Center, USA Active, not recruiting 1 60
   Feasibility Study of the Role of SBRT for the Treatment of Early-Stage Breast Cancer (ARTEMIS) Age ≥70 years, grade 1–2, HR+, cT1N0M0 invasive carcinoma SBRT (40 Gy in 5 fractions) preoperatively Feasibility NCT02065960 Juravinski Cancer Centre, Canada Recruiting 1 32
   Phase Ib Dose Escalation of Single Fraction Preoperative Stereotactic PBI for Early-Stage BC Age ≥45 years with IDC <3 cm, cN0, ER+, Her2−, no LVI GammaPod delivery of preoperative 21, 24, 27, and 30 Gy prior to lumpectomy Maximum tolerated dose NCT04234386 University of Maryland, USA Not yet recruiting 1 50
   Phase 1 Study to Evaluate the Safety and Feasibility of Preoperative Ablative Breast Radiotherapy (SABER) for Selected Early-Stage BC Age ≥50 years cT1N0M0 HR+, Her2− BC 4 preoperative dose levels: 35 Gy (7 Gy ×5), 40 Gy (8 Gy ×5), 45 Gy (9 Gy ×5), 50 Gy (10 Gy ×5) with lumpectomy/SLNB 4–6 weeks after Maximum tolerated dose NCT04360330 University of Miami, USA Not yet recruiting 1 18
   Precision Medicine in Action: Phase II Trial of Response Adaptive Ablative Pre-operative SPBI and Non-operative Sentinel Lymph Node Biopsy in Patients with Early-stage ER+ Breast Cancer: RAPS Trial Age ≥18 years with invasive carcinoma ≤3 cm, HR+, Her2−, cN0 Single fraction 30 Gy with response assessment at 9 months. Responders: surgery at 10–15 months. Non-responders: 2nd fraction of PULSAR radiation 8 Gy and surgery at 12–15 months Efficacy, rate of pCR NCT06444269 UT Southwestern Medical Center, USA Recruiting 2 53
   Phase II Study of MRI-Based Preoperative Accelerated Partial Breast Irradiation Age ≥50 years with IDC <3 cm, cN0, ER+ Accelerated MRI-based PBI in 5–8 fractions and lumpectomy +/− SLNB 5–8 weeks after Postop complication rates NCT02728076 Medical College of Wisconsin, USA Recruiting 2 40
   MRI-guided Single Dose Preoperative Radiotherapy in Low-Risk
   BC (ABLATIVE-2)		 Age ≥50 years with IDC <2 cm (≤3 cm if age >70 years), ER+, Her2−, grade 1–2, tumor negative sentinel node Single dose of 20 Gy to GTV and 15 Gy to CTV Rate of pCR NCT03863301 UMC Utrecht, Netherlands Recruiting 2 70
   A Phase II Study of Preoperative Single Fraction SBRT to the Intact Breast in Early-Stage Low Risk BC: Analysis of Radiation Response Age ≥50 years with IDC, cT1N0, HR+, Her2−, postmenopausal Single dose of 21 Gy preoperatively Rate of pCR NCT03043794 Johns Hopkins, USA Recruiting 2 40
   Preoperative Single-Fraction Partial Breast Radiotherapy in Early-Stage BC: Analysis of Pathologic Response Age ≥50 years with invasive or in situ BC, <2 cm, low oncotype score (0–17) for age 50–59 years, ER+, Her2− Single fraction of 21 Gy SBRT Cosmesis NCT02482376 Duke Cancer Center, USA Recruiting 2 100
   Single fraction ablative preoperative radiation treatment for early-stage breast cancer (CRYSTAL) Age ≥18 years with unifocal cT1–cT2 cN0 breast cancer 3 preoperative single-fraction dose levels: 18, 21, 24 Gy followed by surgery within 8 weeks Maximum tolerated dose (ph 1 endpoint); pCR (ph II endpoint) NCT04679454 European Institute of Oncology; Milan, Italy Recruiting 1/2 79
Randomized
   Pre- Versus Postoperative Accelerated Partial Breast Irradiation in Early-Stage Breast Cancer Patients (PAPBI-2) Age ≥51 years with grade 1–2 IDC tumors ≤3 cm (not allowed: LVI, grade 3, triple negative, Her2+, pN1–3) Randomized to preoperative or postoperative APBI (5.7 Gy ×5) Cosmetic outcome NCT02913729 Netherlands Cancer Institute, Netherlands Recruiting 2/3 500
   A Randomized Phase II Study Comparing Surgical Excision Versus Neoadjuvant Radiotherapy Followed by Delayed Surgical Excision of Ductal Carcinoma In Situ (NORDIS) Age ≥18 years with unifocal DCIS, ≤3 cm Randomized to lumpectomy alone or preoperative PBI (6 Gy ×5) followed by lumpectomy pCR NCT03909282 Stanford University Recruiting 2 50

DCIS, ductal carcinoma in situ; IDC, invasive ductal carcinoma; APBI, accelerated partial-breast irradiation; BC, breast cancer; cN0, clinically node negative; CTV, clinical target volume; ER+, estrogen receptor positive; Est., estimated; GTV, gross tumor volume; Her2−, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive; LVI, lymphovascular invasion; MRI, magnetic resonance imaging; N, number; NCT, National Clinical Trial; PBI, partial breast irradiation; pCR, pathologic complete response; Ph, phase; postop, postoperative; PULSAR, personalized ultra-fractionated stereotactic adaptive radiotherapy; SBRT, stereotactic body radiotherapy; SLNB, sentinel lymph node biopsy.

Techniques for assessing tumor response

The efficacy of neoadjuvant partial breast radiation in a subset of patients raises the intriguing possibility of avoiding surgery in select women who might achieve a pCR following preoperative radiation. Among patients with favorable early-stage breast cancer treated with neoadjuvant radiation alone, existing studies report rates of pCR ranging from 10% to 42% at timepoints ranging from 6 weeks to 8 months after RT as described above. However, widespread adoption of non-operative management for early breast cancer would require very reliable methods for identifying those who would have a pCR following neoadjuvant radiation in addition to carefully conducted, prospective studies monitoring outcomes associated with a non-operative approach.

Methods for assessing treatment response prior to surgery include clinical breast exam, radiographic imaging, serial biopsy, and circulating tumor assessment either alone or in combination. The optimal timepoint at which to assess clinical and/or pathologic treatment response is unknown. The investigators of the ABLATIVE study initially allowed an interval from radiation to surgery of 6 months, but increased this time to 8 months after the first 15 patients to improve the likelihood of inducing a pCR (52). Though limited by small numbers, they noted that 33% of the patients who went to surgery after 6 months achieved a pCR, compared to 48% of the group that underwent surgery at 8 months. However, further study is needed to determine the ideal timepoint to assess treatment response after neoadjuvant radiation.

Imaging

Imaging evaluation with mammography, ultrasound, and MRI are commonly used to assess response following neoadjuvant breast cancer treatment (55-58). MRI has been utilized in several neoadjuvant PBI trials to assess tumor response with promising results (44,59). In the Duke preoperative SBRT trial, pre- and post-treatment MRI were obtained to investigate radiographic markers associated with radiation. After RT, area under the contrast concentration versus time curve [initial area under the curve (iAUC)] decreased significantly in the treated volume, suggesting an increase in the post-radiation vascular permeability, and extravascular-extracellular space fraction (ve) significantly increased after RT, consistent with decreased cellular density (44,60). In the ABLATIVE study, pre- and post-treatment MRIs were obtained to try to correlate radiographic change with final pathology (52). Radiologic complete response was seen in 15 patients (42%), and 10 of these patients had a pCR, while 5 of 21 patients with residual disease on MRI had a pCR (52). Thus, the positive predictive value (PPV) of MRI to predict pCR was 67%, and the negative predictive value (NPV) of MRI to predict pCR was 76% (52). Unfortunately, efforts to utilize MRI as a single modality to determine those who may harbor no residual disease have not shown adequate PPV/NPV for utilizing MRI as a single modality to screen those for a non-operative approach.

Minimally invasive biopsy

Repeat biopsy following neoadjuvant treatment has also been studied as a method for identifying patients who may be suitable for a non-operative approach. Initial proof-of-concept single-center prospective feasibility studies showed promise for minimally invasive mammogram or ultrasound-guided biopsy to identify patients who may achieve a pCR (61-63). However, larger multi-center prospective confirmatory trials such as the RESPONDER (64), MICRA (65), and NRG-BR005 (66) and trials have not shown that repeat minimally invasive biopsy can reliably identify patients suitable for a non-operative approach. For example, in the RESPONDER trial, 398 women with clinical stage I–III breast cancer underwent neoadjuvant treatment followed by image-guided vacuum-assisted biopsy (VAB) prior to surgical resection (64). In this trial, image-guided VAB was associated with a false-negative rate (FNR) of 17.8% (64). The Minimally Invasive Complete Response Assessment (MICRA) trial similarly enrolled 219 patients treated with neoadjuvant therapy followed by repeat biopsy prior to surgical resection and reported an overall FNR rate of 37% (65). A multi-institutional analysis of 166 patients from Royal Marsden Hospital, Seoul National University Hospital, and MD Anderson Cancer center reported a FNR of 18.7% (67). Finally, in NRG-BR005, 105 women were accrued to undergo repeat biopsy following neoadjuvant treatment with an unacceptable NPV associated with repeat biopsy (66).

Circulating biomarkers

Analysis of circulating tumor DNA (ctDNA) via a “liquid biopsy” has emerged as a promising method for assessing disease burden for many patients with localized and metastatic cancers (68,69). This technique is rapidly gaining traction as a means to assess disease burden and response to treatment. Among patients with localized breast cancer, ctDNA levels following definitive treatment were recently shown to be highly correlated with subsequent relapse (70). In a cohort of 101 women who underwent definitive treatment for localized breast cancer, detection of ctDNA during follow-up was significantly associated with subsequent relapse (hazard ratio, 25.5, P<0.01); median relapse-free survival (RFS) was 38 months among patients with detectable post-treatment ctDNA versus a median RFS not reached among those with undetectable post-treatment ctDNA (70). In a similar vein, McDonald et al. [2019] investigated response to neoadjuvant systemic therapy for a group of 33 women with stage I–III breast cancer (71). They observed that ctDNA concentrations after neoadjuvant chemotherapy were lower in patients who achieved a pCR compared to those with residual disease, and patients achieving a pCR had a larger decrease in ctDNA concentrations during neoadjuvant therapy (71).

To summarize, further study is needed to refine methods for assessing treatment response to delineate the optimal method for identifying candidates for a non-operative approach. Likely a combination of radiographic assessment with pre- and post-radiation biopsy and circulating biomarkers will yield the highest predictive power for selecting patients for a non-operative approach. Finally, pCR will require validation in this setting as a surrogate endpoint, as interventions that result in improvements in pCR do not necessarily translate into increased disease free and overall survival (72). As methods improve for selecting patients for a non-operative approach, randomized studies with long-term follow-up will be necessary to compare overall survival of patients treated with operative and non-operative approaches.

Limitations of preoperative partial breast radiation

Preoperative PBI has the potential to reduce radiotoxicity for early-stage breast cancer and may allow for important understanding about tumor response to radiation, tailoring of adjuvant therapy, prognostication, and potentially avoidance of surgery for some patients. However, this technique is not without limitations. First, patient selection is critical when considering preoperative PBI to avoid compromising oncologic outcomes. The absence of final surgical pathology preoperatively can result in a subset of patients who may need additional adjuvant radiation and thus potential for increased toxicity. In the Duke study, 3 of 32 patients treated with neoadjuvant RT required additional postoperative RT due to final pathology warranting additional treatment per protocol (tumor size larger than 2 cm, mixed ductal/metaplastic histology, and a positive lymph node), and these patients had fair/poor cosmetic outcomes (44). In the University of Maryland experience, 3 of 27 patients were found to have disease on SLNB, and 2 required additional adjuvant radiation after surgery (47). Similarly, in the ROCK study, 2 patients also required postoperative radiotherapy given adverse features seen on final pathology (51). Performing a lymph node assessment preoperatively as done in the PAPBI and ABLATIVE trials could improve patient selection and minimize risk of treating patients with preoperative partial breast radiation who may also require adjuvant regional nodal irradiation.

Second, patients treated with neoadjuvant PBI and surgery may have different and more robust post-treatment changes seen on surveillance imaging compared to patients treated with conventional adjuvant radiation (73). Additional research is necessary to characterize these expected changes and avoid unnecessary further workup and post-treatment biopsies in patients treated with preoperative PBI. Third, adopting longer intervals between preoperative radiation and surgery with the hope of obtaining a pCR could potentially result in progression for inappropriately selected patients with higher-risk disease. This limitation could potentially be mitigated by frequent imaging assessment during this interval.

Finally, and most importantly, currently available data are based on small patient series with relatively short-term follow-up for a disease that can have a prolonged timeline for toxicity and recurrence. Longer follow up and larger studies will further inform us regarding safety of adoption of preoperative PBI off clinical trial for selected patients. In order to adopt preoperative PBI as an ablative approach, future studies must show that appropriately selected patients treated with a non-operative approach experience equivalent long-term local control and survival compared to those treated with surgery.

Future directions

In conclusion, a growing body of research shows that preoperative PBI may be a safe and effective alternative to postoperative PBI for early-stage breast cancer and provides a unique platform to assess tumor response to RT. Additionally, early data suggests preoperative RT may result in a pCR in a subset of patients. This finding raises the intriguing possibility of utilizing preoperative SBRT as an ablative approach, potentially allowing for the avoidance of breast cancer surgery for select patients. However, many important questions remain before the omission of surgery for favorable early-stage patients may be widely adopted. Critical questions include determining optimal criteria for patient selection, delineating the optimal dose/fractionation and design (74) of preoperative radiation, and defining optimal surveillance method(s) to allow patients who receive a non-operative approach to be safely followed without undergoing surgery.

For patients with higher-risk (e.g., triple negative, HER2+) or more locally advanced disease, preoperative PBI may be a useful addition to neoadjuvant treatment algorithms utilizing chemotherapy or immunotherapy. Ongoing prospective trials of preoperative PBI combined with systemic therapy for higher-risk disease are summarized in Table 4. Many important questions for these patients remain unanswered, including understanding whether preoperative radiation can elicit a more robust immune response compared to neoadjuvant immunotherapy alone, defining the optimal treatment volume, dose and fractionation for preoperative radiation for patients with locally advanced disease who may also need adjuvant radiation, and delineating the optimal sequencing of radiation in conjunction with neoadjuvant systemic agents for increasing rates of pCR. Further, if the addition of neoadjuvant radiation to neoadjuvant systemic therapy results in higher pCR rates, it is unclear whether this will also translate to improved survival for these patients and will be important to determine if response to preoperative radiation can be used for treatment stratification (i.e., escalation or de-escalation of adjuvant therapy).

Table 4

Ongoing clinical trials of preoperative partial external beam breast irradiation combined with systemic therapy for women with more advanced breast cancer (recruiting and not yet recruiting)

Study title Eligibility criteria Intervention Primary outcome NCT number Sponsor Status Ph Est. N
Non-randomized
   Preoperative Combination of Pembrolizumab and Radiation Therapy in Patients with Operable BC Age ≥18 years with high-risk ER+/Her2− or TNBC, with operable tumors ≥2 cm Neoadjuvant pembrolizumab with RT boost (8 Gy ×3 fractions, given with second dose of pembrolizumab) Safety, changes in TIL NCT03366844 Cedars-Sinai Medical Center, USA Recruiting 1–2 60
Randomized
   Neo-CheckRay: Neo-adjuvant Chemotherapy Combined with Stereotactic Body Radiotherapy to the Primary Tumor +/- Durvalumab, +/- Oleclumab in Luminal B Breast Cancer Age ≥18 years, with tumors ≥1.5 cm, cN0 or N1, ER+/Her2−, with high-risk Mammaprint score Randomized to: (I) preop chemotherapy (weekly paclitaxel → ddAC) with SBRT (8 Gy ×3 at week 5); (II) preop chemo/SBRT with durvalumab; (III) preop chemo/SBRT with durvalumab and oleclumab Safety run-in, tumor response NCT03875573 Jules Bordet Institute, Belgium Recruiting 2 147
   PANDORA: A Randomized Study Evaluating Pathologic Response Rates Following Pre-operAtive Non-Anthracycline Chemotherapy, Durvalumab, +/- RAdiation Therapy in TNBC Male/female patients age ≥18 years with clinical stage II–III TNBC Randomized to (I) preoperative carboplatin, paclitaxel and durvalumab; (II) chemotherapy + durvalumab + RT boost (8 Gy ×3 fractions) pCR NCT03872505 Cedars-Sinai Medical Center, USA Not yet recruiting 2 140
   P-RAD: Preop Pembro and Radiation Therapy in Breast Cancer Age ≥18 years with TNBC or high-risk ER+/Her2−, cT1–2N1–3M0; surgically resectable Randomized to receive preoperative boost radiation: (I) none; (II) low dose (9 Gy); or (III) high dose (24 Gy) with neoadjuvant pembrolizumab followed by neoadjuvant chemoimmunotherapy TIL; pCR in lymph nodes NCT04443348 Multicenter Recruiting 2 120

BC, breast cancer; cN0, clinically node negative; ddAC, dose-sense doxorubicin-cyclophosphamide; ER+, estrogen receptor positive; Est., estimated; Her2−, human epidermal growth factor receptor 2 negative; N, number; NCT, National Clinical Trial; pCR, pathologic complete response; Ph, phase; preop, preoperative; RT, radiation therapy; SBRT, stereotactic body radiotherapy; TIL, tumor-infiltrating lymphocytes; TNBC, triple negative breast cancer.

Conclusions

In conclusion, preoperative PBI is a promising treatment approach with potential applications for a variety of patients, including providing tumor response assessment, treatment stratification, immune modulation, and possibly even enabling omission of surgery for select favorable patients. However, careful preoperative evaluation is essential to selecting patients who may be suitable for a partial breast approach. We eagerly await the results of current ongoing trials and those in development to continue to delineate the optimal uses of neoadjuvant PBI in breast cancer.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-43/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-43/coif). R.C.B. reports funding from Gateway for Cancer Research. C.E.C. reports serving as a scientific advisor to Simply Good Foods and receiving royalties for books on exercise and nutrition. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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doi: 10.21037/tbcr-24-43
Cite this article as: McDuff SGR, Stephens SJ, Champ CE, Blitzblau RC. Preoperative partial breast radiation for favorable early-stage breast cancer: a narrative review. Transl Breast Cancer Res 2025;6:17.

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