Preoperative Radiotherapy (Preop-RT) Improves Pathological Complete Response Rates in Partial Responders (PR) to Primary Systemic Chemotherapy (PST) in Locally Advanced Breast Cancers (LABC)

Abstract

Introduction

Preoperative radiotherapy (preop-RT) can be used as one strategy to improve pathological complete response rates in locally advanced breast cancer. Hence, we conducted a pilot study of preop-RT in partial responders to primary systemic chemotherapy (PST).

Methods

Standard PST comprising of four cycles of Adriamycin/cyclophosphamide followed by four cycles of taxanes (along with trastuzumab in Her2-neu enriched) was initiated. After two cycles of taxanes, partial responders (PRs) were enrolled onto preop-RT (40 Gy/15#/3 weeks to whole breast followed by boost dose of 10 Gy/4#/1 week to gross tumor with 5 mm margin [clinical target volume] and 10 mm margin [planning target volume] by three-dimensional conformal radiation therapy. Field-in-field technique was used whenever the need to correct dose heterogeneity arose. The remaining two cycles of taxanes were completed 3 weeks after the completion of RT. Surgical intervention was initiated 6 weeks after the completion of PST. The intention of such a strategy was to keep an interval of 12 weeks between completion of RT and surgery to achieve maximum downstaging. The primary endpoint was pathological complete response rate (ypCR).

Results

Twenty-one women were enrolled (median age 47 years, 35% premenopausal, 50% upper outer quadrant, 65% T4, 85% node positive, 40% luminal A, 10% luminal B, 15% Her-2-neu enriched, and 35% triple-negative breast cancer [TNBC]). Twenty-eight percent underwent breast conservation and the rest modified radical mastectomy (n = 13) and 2 did not undergo surgery (elderly [n = 1], lost to follow-up [n = 1]). ypCR(T) rate was 53% and ypCR(N) was 59%. ypCR(T) rate was 50% in Her-2 positive and 25% in TNBC, and 33.3% in luminal A. At a median follow-up of 24 months, the median overall survival is 41 months and 2 (both TNBC, ypCR, and ypPR) developed distant metastasis (in lung and soft tissue).

Conclusion

This pilot study reveals encouraging results in high-risk subsets and this potential of preop-RT should be explored further in larger studies.

Keywords

locally advanced breast cancer - neoadjuvant chemotherapy - preoperative radiotherapy - pathological complete response

Sushma Agrawal

Introduction

Locally advanced breast cancer (LABC) presents as a heterogeneous disease, which consists of extensive disease in the breast and/or regional lymph nodes, without evidence of distant metastases (DMs) (M0). It represents only 2 to 5% of all breast cancers (BCs) in western countries but its incidence can be as high as 80% in developing countries. This could be because the incidence of advanced stage disease is high in young women in whom the disease is aggressive and the incidence has been found to be high in young women in developing countries. Second, women from rural areas have a tendency to hide their disease and are ignorant about the nature of disease, which results in late reporting. Other causes of advanced disease presentation in developing countries are lack of organized BC screening programs, the paucity of diagnostic aids, and general indifference toward the health of women in the predominantly patriarchal society.[1] In our country, 25% women with BC are of young age (< 40 years) and 45% are premenopausal. Young women with BC present as LABC in 80% cases and 90% have node-positive disease.[2] Long-term survival in such cases has been greatly improved with aggressive trimodality treatment. Anthracycline- and taxane-based chemotherapy (CT) regimens are appropriate as induction CT along with trastuzumab in Her 2-enriched disease. The vast majority of patients will have clinical response to therapy, but only 25 to 35% experience a pathological complete response (pCR).[3] As with other experiences using neoadjuvant CT (NACT), complete pathologic eradication of the tumor is associated with superior outcomes among women with LABC.[4] The other advantage of induction therapy is downstaging of disease to allow breast conservation (BCS) in large tumors and increase resectability of inoperable disease to allow modified radical mastectomy (MRM). After primary systemic chemotherapy (PST) patients more frequently require oncoplastic volume displacement or replacement surgery if BCS is attempted.[5] [6] The 5-year survival with PST, mastectomy, and radiotherapy (RT) has been reported as 90% in node-negative (ypN0) and 75% in node-positive disease (ypN + ) in developed countries, while in developing countries, the 5-year overall survival (OS) is 40% in such patients.[7] [8] Therefore, there is clearly a need for intensifying therapy in partial responders to enhance pathological response rates, which may be achieved with preoperative RT (preop-RT).[9] This downstaging may also increase BCS rates in operable BC.[10] Patients with luminal A subtype have less response to standard PST, and neoadjuvant endocrine therapy is usually reserved for unfit patients with short life expectancies.[11] Preop-RT may improve response rates in such cases also. This could also be considered as salvage treatment for those who have responded less than anticipated or are refractory or progress on PST.[12] It has been shown that the partial breast clinical target volume may be increased by the presence of postoperative seroma, and seroma size was an independent predictor of poor cosmesis in the RAPID trial.[13] [14] Preoperative partial breast RT would avoid this issue as well. Treatment volumes in the PAPBI trial of preoperative accelerated partial breast RT were significantly smaller (mean PTV 122 cm³) than those in postoperative partial breast RT studies with comparable mean tumor size.

With the above anticipated advantages of preop-RT and the high proportion of PR in LABC in our setup, we conducted this pilot study of preop-RT in LABC who achieve PR with PST.

Materials and Methods

After obtaining an Institutional Ethics clearance, this study was conducted during the period of January 2020 to July 2022. After a diagnostic and metastatic workup (trucut biopsy from tumor, mammogram, fine-needle aspiration cytology from palpable axillary nodes, chest X-ray posterior-anterior, ultrasound abdomen, and bone scan) and histopathologic proof of malignancy, patients ≥ 18 years of age, with tumor stage IIB, IIIA, and IIIB, and unilateral disease, were offered standard NACT (PST, 4 cycles of anthracycline-based CT followed by either weekly 12 cycles of paclitaxel-based CT or 4 cycles of docetaxel-based CT). Patients with Her-2-neu disease were also administered trastuzumab along with taxanes. Since our intention was to keep the interval between completion of RT and surgery to be 3 months, we initiated preop-RT after six cycles of weekly paclitaxel or two cycles of docetaxel-based CT. The rest of CT was administered after the completion of RT ([Fig. 1], Consolidated Standards of Reporting Trials diagram). Patients were simulated either on wing board or breast board. Whole breast RT along with supraclavicular fossa (SCF) was treated to a dose of 40 Gy in 15 fractions over 3 weeks by three-dimensional (3D) conformal radiation therapy technique. Thereafter, a sequential boost of 10 Gy infour4 fractions to the tumor bed was delivered. The definition of the gross tumor volume was driven by the visible mass on planning computed tomography. The sequential boost clinical target volume was generated by adding a 0.5mm isotropic margin around the visible mass. 10 mm planning target volume was used for the boost. Axillary RT was offered only to those patients in whom enlarged axillary nodes were visible on treatment planning computed tomography scan. Following delineation, patients underwent 3D treatment planning using a single isocenter technique for the treatment of SCF and breast with 6 MV or combination of 6 MV and 15 MV X-rays. Organs at risk constraints for ipsilateral lung was V12 < 15% and heart was V2 < 30% and V10 < 5%. Treatment verification was done by portal imaging on the first day of treatment. Two to 3 weeks after completion of RT, the remaining CT was administered. Response assessment was done by clinical examination and mammogram using the Response Evaluation Criteria in Solid Tumors criteria before RT and before surgery. Patients then underwent surgical excision (BCS or MRM depending upon the extent of downstaging) 1.5 months after completion of CT. pCR rates were ascertained from the histopathological report of the excised specimen. After surgery and wound healing, patients with estrogen receptor + , progesterone receptor+ were kept on endocrine therapy while patients with partial response (Her2+ and triple-negative) were offered maintenance trastuzumab or capecitabine @ 2.4 g/m² per day, respectively, according to the standard guidelines. Patients considered too frail for CT, whatever their age, unilateral or bilateral inflammatory (T4d) BC, previous malignancy (except nonmelanoma skin cancer, thyroid carcinoma, noninvasive cancers outside the breast, and patients with previous cancer in remission since more > 5 years), pregnancy, active connective tissue disease involving the skin, and concurrent severe and/or uncontrolled medical conditions, which could compromise participation in the study, were excluded.

Fig. 1 Consolidated Standards of Reporting Trials (CONSORT) diagram.

Endpoints

The primary endpoint of this study was incidence of pCR (overall), ypCR (T), and ypCR (N), defined by the absence of invasive residual primary tumor in the breast (T) and lymph node (N). The secondary endpoint of this study was to evaluate the incidence of postoperative complications. The pCR rate was compared with the departmental database (standard of care [SOC]) (n = 206 patients of LABC [2007–2012]) treated by conventional PST (but without trastuzumab due to its prohibitive cost during that period). SPSS v 20 was used for computing the results.

Results

Twenty-one patients were enrolled in this study, while the SOC database included 206 patients of LABC. Patients' characteristics ([Table 1]) were comparable in both arms, except that there were more T4 (62% vs. 45%) and N1 (52% vs. 42%), postmenopausal (67% vs. 53%), and luminal A (33% vs. 26%) in the preop-RT arm. The median T size in preop-RT was 5 cm (interquartile range [IQR] 4–7) while that in SOC was 3 cm (IQR 3–5 cm). All had intraductal carcinoma. The most common histological subtypes were triple-negative BC (TNBC) (43%) and luminal A (33%). All patients received the prescribed CT and RT. Though the study was to enroll PR in preop-RT, 5 patients of TNBC with progressive disease (PD) on standard PST had to be enrolled and the CT regime was changed to cisplatin–gemcitabine combination and thereafter all attained PR. Trastuzumab was prescribed to all three patients with Her-2-neu enriched disease in the study arm while it was not received by SOC. All luminal A and B patients received endocrine therapy as per the standard guidelines. Regarding surgical intervention, 28% underwent BCS and the rest MRM in the study arm (two did not undergo surgery: one was 72 years old and had clinical CR and was unwilling for surgery, the second patient had large tumor [15 cm] with TNBC, who attained PR and was later lost to follow-up [FU]). The rate of either surgical intervention was comparable with the SOC arm. All patients in the study arm underwent surgery 12 weeks after completion of RT. The surgical margin was uninvolved in all patients.

Table 1 Demographic features

Demographic parameters	Experimental arm, N = 22 (%)	SOC, N = 206 (%)
1. Age in years (median)
< 40  > 40	5 (24) 16 (76)	61 (30) 145 (70)
2. Menopausal status
Premenopausal  Postmenopausal	7 (33) 14 (67)	96 (47) 110 (53)
3. Laterality
Right  Left	12 (57) 9 (43)	88 (43) 118 (58)
4. T status
T2  T3  T4	2 (9) 6 (29) 13 (62)	33 (16) 80 (39) 93 (45)
5. N status
N0  N1  N2  N3	3 (14) 11 (52) 5 (24) 2 (9)	17 (8) 83 (42) 80 (40) 23 (10)
6. Intrinsic subtype
Luminal A  Luminal B  Her2 type  Triple-negative	7 (33) 2 (10) 3 (14) 9 (43)	54 (26) 26 (11) 48 (23) 78 (40)
7. Type of surgery
MRM  BCS  None	13 (62) 6 (28) 2 (10)	143 (70) 63 (30) -

Abbreviations: BCS, breast conservation; MRM, modified radical mastectomy; SOC, standard of care.

All patients responded to preop-RT ([Figs. 2] and [3]). The ypCR (T) rate in the preop-RT cohort versus SOC was 53% versus 38% and ypCR (N) was 59% versus 40% ([Table 2]). The proportion of ypCR (T) was comparable in both arms in T2 and less for T4 (47% vs. 57%, since 38% of T4 patients in the study arm had PD). The proportion of ypCR (N) was 54% versus 60% (cN1), 60% versus 29% (cN2), and 100% versus 26% (cN3). The proportion of overall ypCR rate was 33.3% versus 10% in luminal A, 0% (n = 1) versus 17% in luminal B, 50% versus 27% in Her-2-neu enriched, and 25% versus 28% in TNBC subtypes, respectively, for experimental versus SOC. [Fig. 3] illustrates that at baseline 62% patients were T4, which downstaged to 24% after PST, 9.5% after preop-RT, and 0% after surgery (incremental gain of 14%). Similarly, at baseline 28.5% patients were T3, which downstaged to 9.5% after PST, remained 9.5% after preop-RT, and turned out 0% after surgery (incremental gain of 9.5%). Similarly, at baseline 52% patients were N1, which downstaged to 28.6% after PST, 19% after preop-RT, and 9.5% after surgery (incremental gain of 9.5%), but for N2 (23.8% at baseline), which downstaged to 9.5% after PST and 0% after preop-RT, turned out to be 19% on histopathology.

Fig. 2 (A) Picture of a right breast tumor in upper inner quadrant prior to radiotherapy (RT). (B) Picture of the same patient in (A) with right breast tumor in upper inner quadrant after RT.

Fig. 3 (A) Proportion of patients in various T stages at baseline, post-primary systemic chemotherapy (PST), post-radiotherapy (RT), and after surgery. (B) Proportion of patients in various N stages at baseline, post-PST, post-RT, and after surgery.

Table 2 Pathological complete response (ypCR) according to T, N, and histological subtype

Variable	Preop-RT ( n  = 21) (ypCR rate %)	SOC ( n  = 206) (ypCR rate %)
ypCR (T)	48	30
ypCR (N)	63	48
ypCR (overall)	31	20
T2 T3 T4	50 33 47	45 26 57
N1 N2 N3	54 60 100	60 29 26
Luminal A Luminal B Her-2-enriched TNBC	33 0 50 25	12 17 27 28

Abbreviations: preop-RT, preoperative radiotherapy; SOC, standard of care; TNBC, triple-negative breast cancer.

The proportion of ypCR (T), ypCR (N), and ypCR (overall) rates was higher in the preop-RT than SOC arm ([Fig. 4A], [Table 2]). Similarly, the proportion of ypCR (T1, T2) and ypCR (N2) was higher in the preop-RT arm ([Fig. 4B, C]). A comparison of ypCR (overall) rates based on histological subtype in both arms revealed that it was significantly higher in luminal B and Her-2-enriched subtypes in the preop-RT arm ([Fig. 4D], [Table 2]).

Fig. 4 (A) Comparison of pathologic complete response (ypCR) (T), ypCR (N) and ypCR (overall) rates between preoperative radiotherapy (preop-RT) (cyan) and standard of care (SOC) (orange). (B) Comparison of ypCR (T) rates between preop-RT (blue) and SOC (orange). Proportion of various ypCR (T stage) rates in preop-RT (blue) and SOC arms (orange). (C) Proportion of ypCR (N) rates in preop-RT(blue) and SOC arms (orange). (D) Proportion of ypCR (overall) rates based on histological subtype in preop-RT (blue) and SOC arms (orange).

At a median FU of 24 months, 1 (4.7%) patient had locoregional recurrence (with heavy nodal burden) versus 11% with SOC. Four patients (three TNBC who had PD to PST and one Her-2-neu-enriched disease who could not complete adjuvant trastuzumab due to development of cardiac toxicity) had DMs (19%) as compared with 30% incidence with SOC. The 2-year OS is 85% versus 75% with preop-RT versus SOC (p = 0.6) ([Fig. 5]) and the 2-year disease-free survival is 78% versus 72% (p = 0.7).

Fig. 5 Comparison of overall survival between both arms.

Postoperative Complications

Preop-RT was associated with longer duration of surgery in all patients due to increased vascularity and tissue edema. It was also associated with prolonged duration of axillary drain in 20% patients. Mean time for removal of flap drain was 3.6 days. Since initial patients (20%) faced marginal flap necrosis with the usual thickness of flaps, it was successfully corrected with minor increase in the thickness of the flaps without compromising the oncological principles. The mean duration of hospital stay was 8.5 days. Treatment was well tolerated with no grade 3 or 4 events.

Discussion

This pilot study of preop-RT in LABC shows that RT is an effective modality for further downstaging in partial responders, stable disease, and nonresponders. Similar findings of 75% response have been reported in chemo-sensitive and chemo-refractory patients.[15] The incremental gain in downstaging (overall ypCR) after PST was 10 to 14% in both tumor and nodes in spite of the median T size (> 5 cm) as compared with 3 cm in SOC. The rates of ypCR (T) was higher (48%) versus 30% in SOC, nodal ypCR rates were 63% versus 48%, more so in N2 (60% vs. 29%) than in N1 (54% vs. 60%). This finding holds importance because PST adequately downstages cN1 while preop-RT adds to the downstaging in N2 subset as well. This finding is important as nodal clearance has been shown to be more prognostic than tumor downstaging and is used for stratification in clinical trials.[16] Collectively, we achieved a gain of 10% in overall ypCR, which is comparable to literature of operable BC and LABC.[10] [17] Though we achieved 10% enhancement in the endpoint of ypCR, it may have been higher if dual anti-Her-2-neu blockers were used in Her-2-neu-enriched disease. We could not use pertuzumab along with trastuzumab due to cost constraints in a developing country. Studies that used concurrent CT with RT reported higher ypCR rates of 45% in LABC. Perhaps, if we had used concurrent CT our ypCR rate would have been higher.

Some of the studies used conventional preop-RT, and some ablative doses. We used hypofractionated schedule of 40 Gy/15# followed by boost dose of 10 Gy/4 #. Riet et al used hypofractionated schedule of 45 to 55 Gy at 2.5 Gy/# and achieved 10% pCR only (a reflection of gap between preop-RT and surgery), but the local control rate was 89% at 30 years.[18] In our series too, the local control rate was 90%. Dose escalation beyond 55 Gy has been used in chemo-refractory and unresectable patients only. Stereotactic ablative RT combined with NACT has delivered promising results in terms of the pCR rate (36%), BCS percentages (92%), very low recurrence rates, only grade 1 to 2 toxicities, and good to excellent cosmetic outcomes in small series of early BC. [19] [20] Most of the reported studies have irradiated breast, axilla, and SCF as well as delivered a boost. This practice is likely to increase lymphedema rates. Lerouge et al reported 17% rate of lymphedema in his mature series of 120 patients.[21] Axilla should be addressed by only a single modality to avoid lymphedema. The other reported toxicity is seroma in 15%, shoulder capsulitis in 43%, and grade 3 dermatitis in 22% patients.[18] [22] [23] Our practice was also similar and we observed seroma and flap necrosis in initial 20% patients, which was thereafter taken care by thicker flaps. No other postoperative complications were observed. Our results are not mature enough for reporting late toxicity.

In spite of the fact that surgery followed by CT then followed by radiation is considered to be the more conventional approach to BC multidisciplinary treatment, the increasing use of neoadjuvant treatments has renewed the interest in exploring combined CT and radiation therapy in BC, especially in the most aggressive and unfavorable molecular subtypes. Corradini et al mentioned four strategies for scheduling of PST, preop-RT, and surgery: (1) preoperative RT → followed by surgery within 6 to 8 weeks; (2) preop-RT → NACT as bridging → surgery; (3) NACT → preop-RT → surgery; and (4) NACT → preop (chemo)-RT → NACT → surgery.[22] [23] [24] We adopted the fourth strategy to maximize the time interval between completion of RT and surgery to 12 weeks so that high pCR rates are observed. Most of the studies have used 4 to 8 weeks' interval between completion of RT to surgery. The ABLATIVE study used an 8-month interval between preop-partial breast irradiation (PBI) of single fraction of 20 Gy and surgery in early BC and achieved pCR in 42% of the patients.[25] Since the inclusion criteria and endpoints in various studies are different, it is difficult to conclude which interval is most optimal. Hence, further studies are needed to optimize this aspect.

The ypCR rates are low with PST in luminal A tumors. These women are less likely to undergo conservative surgery following CT.[26] Primary endocrine therapy may be an option for these patients, but this practice is still relatively uncommon and is usually reserved for unfit patients with short life expectancies. Coles proposed that an alternative strategy for women with large, hormone receptor positive and low-grade BCs could be preop-RT. In the index study the ypCR rate was high in luminal A (33%) versus 12% in SOC.[9] This higher ypCR facilitated BCS in 29% patients. Makai reported pCR rate of 24% in hormone receptor positive, 57% in patients with HER-2-enriched tumors, and 52% in patients with triple-negative tumors.[27] Some studies have reported incremental gain in BCS rates with preop-RT. BCS rates have been reported to be 69 to 100% in operable BC.[10] [28] In a study of preop-RT in LABC reported by Lerouge et al, 32% could be spared surgery, 27% underwent wide-excision, and the rest MRM. These rates are comparable to 30% BCS rates in index study. Preoperative PBI allows irradiation of less healthy breast tissue and tumor downstaging, which could reduce the surgical excision volumes or even omit surgery, both leading to improved toxicity and improved cosmetic outcome.[29] [30] The available literature on cosmesis (preop-PBI) scored by physicians and patients are excellent or good in 62 to 100% of the cases and improved significantly with longer FU after surgery.[31] Since our data are not mature, we cannot comment on the late effects and cosmesis.

Roth et al reported significantly better 10-year relapse-free survival and OS with preop-RT as compared with SOC in patients with cT2 tumors.[29] Furthermore, this strategy was associated with low grades of fibrosis and a good to excellent long-term cosmetic outcome. Poleszczuk et al published their results based on an analysis of the large Surveillance, Epidemiology, and End Results database, showing that preop-RT is safe and results in similar OS as SOC. The authors pointed out that RT administered to a large tumor bulk activates robust antitumor immunity, and this could contribute to eliminating the primary tumor and microscopic foci present in the ipsilateral and contralateral breast, and also diminish the risk of distant micrometastasis, leading to an abscopal effect. The authors also specified that in more aggressive tumors, immunity induced by preop-RT would require potentiation with systemic agents, such as the concurrent administration of taxanes, to maximize effectiveness.[32] The ongoing studies to evaluate the efficacy of preop-RT and immunotherapy in BCs will give answers regarding the above hypothesis.

Usage of preop-RT is still in evolution. It facilitates a single-stage surgical procedure with mastectomy and immediate autologous breast reconstruction, eliminating the delay to reconstructive surgery. Thiruchelvam et al have presented the results of the PRADA study, which analyzed the incidence of complications in the form of suture dehiscence greater than 1 cm in 33 consecutive patients treated with PST and preop-RT with moderate hypofractionation followed by mastectomy 2 to 6 weeks after, with deep inferior epigastric perforator (DIEP) flap reconstruction. Four weeks after surgery, four patients (12.1%) suffered suture dehiscence greater than 1 cm. The authors concluded that reconstruction using DIEP after PST and preop-RT is feasible and safe, with surgical wound dehiscence rates similar to those of postmastectomy RT.[33] The dosimetric coverage of targets is more achievable when there are no reconstructive materials in place and this strategy also shortens a woman's BC journey.

Preop-RT is also being evaluated for accelerated PBI (APBI) in early BC to small and defined target volume. As regards target volume, definition is more precise before surgery and a substantial reduction in treatment volumes can be achieved with preoperative APBI, when compared with a postoperative approach. Nichols et al also reported limited toxicity and good to excellent cosmetic outcomes after a median FU of 3.6 years in 27 patients treated with preoperative APBI (38.5 Gy in 3.85 Gy fractions delivered twice daily), followed by breast conserving surgery after 21 days.[34] Guidolin et al did not identify any significant toxicity and demonstrated excellent cosmetic and quality-of-life outcomes with a single APBI dose.[35]

The limitations of our study are the small sample size, since it was a pilot study. The other limitation was that we did not use concurrent chemoradiotherapy and simultaneous integrated boost.

Conclusion

Based on our observations we can conclude that preop-RT is feasible and an effective modality for LABC who achieve partial response or stable disease to PST. It yields an incremental gain in pCR rates of 10% after PST. It is also effective in chemo-refractory patients. It yields encouraging results in hormone positive cancers, which usually do not respond well to PST. Hypofractionated RT to breast and SCF can be adopted for this strategy with acceptable side effects. To confirm the results achieved in the index study, this strategy should be evaluated in a randomized study in partial responders to PST.

Conflict of Interest

None declared.

Ethical Approval

This work has been approved by the institute's Ethics Committee.

Authors' Contributions

S.A. was involved in the study design, data collection and analysis, as well as manuscript writing. A.G. contributed to data analysis. G.C. facilitated patient recruitment, performed the surgeries, and analyzed postoperative complications.

This work has been presented in UP AROI, Breilly, 2022, and won the best paper award.

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Publication History

Received: 24 May 2023

Accepted: 18 April 2025

Article published online:
15 May 2025