Omission of breast surgery in exceptional responders after neoadjuvant chemotherapy—what are future possibilities?—a narrative review

Introduction

Breast cancer treatment requires a combination of local and regional therapy via surgery and radiation, and systemic therapy. Treatment algorithms are evolving quickly in each discipline, and when advances occur, they often impact one another. For example, NSABP B-18 demonstrated that chemotherapy, given in the neoadjuvant or adjuvant setting, results in equivalent oncologic outcomes including disease free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS); however, receiving neoadjuvant chemotherapy (NAC) did allow for increased breast conservation therapy (BCT) rates (1). For high-risk lesions such as triple negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive (HER2+) cancers, chemotherapy has become an integral component of the treatment regimen and is often given in the neoadjuvant setting. In this population of patients specifically, NAC is advantageous because it allows for “in vivo” assessment of tumor response to risk-stratify patients and administer additional adjuvant therapies to those who did not experience a pathological complete response (pCR) (2,3). In addition to increasing rates of BCT, it also helps to control micrometastatic disease, de-escalate axillary surgery and decrease the risk of recurrence (4).

Leveraging NAC and potential pCR, there have been numerous studies published on surgical de-escalation in the breast and axilla, even omission. Because of their high pCR rates, the focus has mainly been on patients with TNBC and HER2+ disease, referred to as “exceptional responders”. Rates of breast and nodal pCR ranges from 30–68.9% (breast), 44–64.8% (nodal) in TNBC patients and 50–70% (breast), 53–68% (nodal) for HER2+ patients respectively (5-9). These high pCR rates have allowed for the omission of axillary lymph node dissection among cN1 patients (10) for example, and may allow for omission of breast surgery in the future.

In this narrative review, we aim to provide a comprehensive discussion on the relevant literature pertaining to the omission of breast surgery in early stage breast cancer. We also aim to discuss the idea of surgical de-escalation in multifocal/multicentric (MF/MC) TNBC/HER2+ tumors after NAC. We present this article in accordance with the Narrative Review reporting checklist (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-65/rc).

Methods

A literature search was performed on the PubMed database with the following keywords: “neoadjuvant chemotherapy”, “triple negative breast cancer”, “HER2+ breast cancer”, “omission of surgery”, “exceptional responders”, “vacuum assisted biopsy”, “false negative rate”, “multifocal”, “multicentric”, “locoregional therapy”, “breast conservation”, “adjuvant chemotherapy”, “omission of surgery”, “immunotherapy”, “trastuzumab”, “pembrolizumab”. The University of Rochester Edward Miner Library was also accessed for procurement of articles utilized in this review. Types of studies included review articles, clinical trials and retrospective studies, ranging from 1989–2024. A total of 49 studies were reviewed and summarized in this narrative review. The search strategy is detailed in Table 1.

Discussion

Systemic therapy and contemporary BCT rates for HER2+ and TNBCs

The utility of systemic therapy for breast cancer has been greatly expanded from its inception. A regimen consisting of cyclophosphamide, methotrexate and fluorouracil was introduced during the 1980s by Bonadonna et al. demonstrating reduced breast cancer recurrence when given adjuvantly (after surgery) (11). Studies giving systemic therapy neoadjuvantly were conducted around the same time, uniformly showing a reduction in tumor size; however, OS remained unaffected (1). Thus, NAC was historically used for downstaging locally advanced and inoperable breast cancers, potentially allowing for surgery and BCT (12).

The use of trastuzumab, an anti-HER2-directed antibody, started in 1998 when it was approved by the Food and Drug Administration based on a Phase 3 clinical trial by Slamon et al. that demonstrated superior efficacy of trastuzumab in addition to chemotherapy for patients with metastatic HER2+ breast cancer, showing a 20% reduction in risk of death (13). The NOAH trial, an international randomized placebo-controlled trial for women with locally advanced or inflammatory HER2+ breast cancer, then established the role of neoadjuvant trastuzumab, showing the addition of trastuzumab to NAC improved the event free survival (EFS) from 56% to 71% (14). Next, landmark neoadjuvant trials tested the efficacy of dual HER2-targeted agents, and in Neosphere, the addition of pertuzumab to trastuzumab increased pCR rates from 29% to 45.8%, leading to the approval of neoadjuvant trastuzumab and pertuzumab plus taxane-based chemotherapy as the mainstay of treatment for HER2+ patients (15). The TRYPHAENA trial, while designed to evaluate cardiac tolerability of concurrent trastuzumab and pertuzumab, showed increased BCT rates from 47% to 68.8% and decreased mastectomy rates from 52.8% to 31% with dual HER2 directed therapy (8). Finally, the KRISTINE trial demonstrated the superior efficacy of neoadjuvant taxane, carboplatin, trastuzumab plus pertuzumab with pCR and BCT rates of 56% and 70%, respectively, compared to trastuzumab emtansine (T-DM1) plus pertuzumab at 44% and 66%, respectively (16).

Chemotherapy remains the mainstay of treatment for TNBC, with most TNBC patients being treated with NAC. The discovery of pembrolizumab has been monumental, and has led to drastic change in the NAC regimen for these patients. Pembrolizumab was first proven effective for patients with metastatic TNBC expressing programmed cell death ligand 1 (PD-L1) (17), and was moved into the NAC setting based on results from the Phase 3 KEYNOTE 522 trial, which showed higher pCR rates and EFS in both PDL-1 positive and negative TNBC patients, with the addition of pembrolizumab to NAC (9). Although locoregional outcomes from KEYNOTE 522 are awaited, one can assume this neoadjuvant chemo-immunotherapy regimen can lead to higher BCT rates given the higher pCR rates. In the BrighTNess trial, which treated TNBC patients with NAC, BCT eligibility rate increased to 83.8% (from 76.5%) with the addition of carboplatin (18). As tumor burden decreases after NAC, more patients are candidates for breast/axillary surgery de-escalation and as pCR rates improve, the topic of surgical omission becomes even more relevant.

In addition to increasing BCT rates, administering NAC provides critical prognostic information. The CTNeoBC pooled analysis evaluated 11,955 patients from 12 NAC breast cancer trials and demonstrated that achieving pCR after NAC was a significant indicator of survival, especially within TNBC and HER2+ populations (19). In contrast, patients with TNBC and HER2+ residual disease after NAC have a worse prognosis (2,3). These populations were then a critical target for drug development, to help augment their survival despite their poor prognosis as a result of therapy resistance. The KATHERINE trial compared T-DM1 to then standard trastuzumab as adjuvant treatment for HER2+ patients with residual disease after NAC and HER2-directed therapy and found that adjuvant T-DM1 reduced the risk of recurrence or death by 50% (2). Similarly, the CREATE-X trial demonstrated improved DFS and OS by administering adjuvant capecitabine to TNBC patients with residual disease after NAC, improving outcomes for these high-risk patients (3). Because of this treatment algorithm, using NAC to assess response and adding adjuvant therapies, improves survival, it is likely that novel agents will be developed to further increase pCR rates, and NAC use will continue to increase for these populations.

In summary, TNBC and HER2+ tumors belong to a biologically aggressive subtype of breast cancer historically associated with a poor prognosis. However, in part because of their aggressive nature, they respond well to systemic therapy with high rates of pCR. Utilizing these high rates, omitting surgery in these subtypes of breast cancer patients may be safe and feasible, and has been a hot topic of discussion recently.

Minimally invasive ways to evaluate pCR to NAC

In order to entertain the possibility of breast surgery omission, it is important to ensure that we can accurately predict pCR using imaging or minimally invasive techniques. Current assessment of treatment response is via physical exam and breast imaging. Unfortunately, the accuracy of physical exam is poor—measuring at 57% with a positive predictive value (PPV) of 91% and negative predictive value (NPV) of 31% in a literature review of six series (20). Breast imaging is only somewhat better. It is routinely performed after NAC to assess tumor response and operative planning, but the available imaging modalities are not accurate enough to detect pathologic response as seen across several studies (21,22). In a retrospective analysis of 143 patients led by Schaefgen et al., magnetic resonance imaging (MRI) performed well for TNBC with a NPV of 94% and false negative rate (FNR) of 5%, but it did not fare as well for HER2+ tumors and hormone receptor positive (HR+) tumors with a NPV of 60.7% and FNR of 35.5%, and NPV of 36.4% and FNR of 27.5%, respectively. Mammography (MMG) and ultrasound (US) did not perform well across all subtypes with a NPV of 48% and FNR of 30%, and NPV of 51% and FNR of 24%, respectively (21). A more recent retrospective single-institution analysis of 167 patients analyzed the accuracy of imaging-detected pCR rates in different tumor subtypes, showing MRI had the highest accuracy (87.5%) for patients with TNBC, however lowest accuracy (45.8%) for HER2+ (22). A large cooperative group trial was done to study the use of tri-modality (MMG, US, MRI) imaging in combination with stereotactic multiple core biopsies (NRG BR 005) to identify patients who experienced a pCR via minimally invasive methods. Authors found that, despite use of trimodality imaging to identify patients eligible for inclusion, 37% of the patients with radiologic complete response (rCR) or near-rCR still had residual disease overall (23).

Instead of physical exam and imaging, numerous single-institution studies have investigated alternative minimally invasive techniques to obtain a reliable diagnosis of pCR, such as vacuum assisted biopsy (VAB) (5,23-30). In 2015, Heil et al. published one of the first studies to determine the accuracy of minimal invasive biopsy in diagnosing pCR. They performed a multicenter prospective analysis of 164 patients with any breast cancer subtype (HR+, HER2+, TNBC) who had a clinical complete response (cCR), defined as no signs of residual disease by physical exam or multi-modal imaging including US, MMG, MRI, after NAC between 2009 and 2013. Patients underwent a core cut or VAB after NAC followed by surgery to determine true pathologic findings, resulting in a NPV of 71.3% and FNR of 49.3% for these biopsy techniques. Interestingly, VAB performed mammographically had a NPV of 100% and FNR of 0%, but the overall NPV of 71.3% was deemed too low to accurately predict pCR (5).

The same group continued their efforts by performing a prospective single institutional study of 50 patients with clinical partial (cPR) or cCR, and radiologic partial (rPR) or rCR between 2014 and 2015. Ultrasound-guided VAB was performed after NAC and prior to surgery, but this time to minimize sampling error, the physician performing the VAB quantified the representativeness of the sample and obtained post biopsy specimen radiography to analyze if the lesion/clip was captured by the VAB. The VAB was performed by experienced physicians using 9 gauge (G) needles and at least 6 samples were taken (up to 12 was allowed per physician discretion). An overall NPV of 76.7% and FNR of 25.9% was reported. When narrowed to a histopathological representative VAB sample (cases of VAB specimen with residual tumor), the NPV was 94.4% and FNR 4.8%. With these findings, the authors conclude that VAB may be able to accurately diagnose pCR provided that the evaluation is representative of the lesion, but there is a need for further research (24).

Another group studied the accuracy of combining VAB and FNA. Kuerer et al. enrolled patients with biopsy confirmed TNBC or HER2+, clinical T1–4, N0–3 breast cancer after NAC between 2015 and 2016 to study the accuracy of FNA and VAB after NAC at a single center. Imaging (US and MMG) performed before and after NAC was carefully reviewed to determine radiologic response and guide the percutaneous biopsies. FNA was performed with 2 passes and VAB was performed with 9G needles. After NAC and prior to surgery, 40 patients with rPR or rCR underwent combined FNA and VAB of the site, revealing pCR in 50% of TNBC and 42.9% of HER2+ patients. Interestingly, 12 of 19 (63.2%) patients with breast pCR did not have a rCR in the breast further reinforcing that imaging is not a reliable modality for predicting pCR. The median number of cores removed was 12 (range, 4–14), performed via stereotactic-guidance in 62.5% and US-guidance in 37.5%, resulting in 98% accuracy with a FNR of 5%, PPV of 100%, and NPV of 95% for the combination of FNA plus VAB, indicating it may be feasible to identify patients who are excellent responders to NAC via percutaneous methods (25).

A large, pooled analysis across 3 institutions internationally (Royal Marsden Hospital, London UK, Seoul National University Hospital, South Korea and MD Anderson Cancer Center, Houston, Texas) was published in 2020 by Tasoulis et al. A total of 166 patients with unifocal or MF/MC breast cancers were included with a primary endpoint of accuracy of image-guided biopsy in diagnosing residual cancer in the breast following NAC. Secondary endpoints were to identify any variables that would improve biopsy accuracy. The biopsy procedure involved removing the previously placed marker clip to ensure the tumor bed was adequately sampled and replacing it with a new clip. The median needle gauge was 10 (range, 7–14). The FNR in the whole cohort was 18.7% with a NPV of 84.3%, but in a subset analysis excluding patients with invasive lobular carcinoma, residual tumors >2 cm, or ≤6 cores obtained, the FNR was 3.2% with a NPV of 97.4%. These findings highlight the importance of patient selection and VAB technique (gauge of needles and number of cores performed) in improving accuracy (26).

In addition to single institution studies and multi-institutional analyses, several multicenter prospective studies were designed. The RESPONDER trial designed by Heil et al. enrolled 398 women with clinical stage 1–3 breast cancer of all subtypes with rPR or rCR to NAC across 21 sites in Germany, and required at least 6 VABs be performed with 7 to 10 G needles before surgical excision. Image-guided biopsy missed residual tumor in 37 of 208 women (an FNR of 17.8%). An exploratory analysis of the falsely negative cases revealed that 19 of 37 cases may have been avoidable due to technical difficulties and inadequate/missed sampling. A subgroup analysis revealed that the biopsies performed with a 7 G needle yielded a FNR of 0%; alternatively, imaging and VAB results combined in an “either positive” approach yielded a FNR of 6.2%. The authors concluded that image-guided VAB missed residual disease at a higher rate than expected and stated that refinements in technique and careful patient selection are needed (27). A further subgroup analysis by Koelbel et al. excluding patients with accompanying ductal carcinoma in situ (DCIS) on initial diagnostic biopsy and/or multicentric disease on pre-NAC imaging, including only patients whose previous biopsy marker clip was removed with the VAB revealed an adjusted FNR of 2.9% and NPV increased from 81.4% to 93.9%. While their findings further reinforce the importance of appropriate patient selection and technique, they significantly narrow the patient population that may be included in forthcoming trials (28).

Larger cooperative group trials may not be as successful as single institution studies due to quality control of biopsies, imaging and pathologic review on cooperative group studies. For example, the multi-institution cooperative group trial NRG BR005 was designed to test the accuracy of stereotactic tumor bed biopsy to determine pCR in post-NAC patients with cCR and rCR on tri-modality imaging. Patients must have completed NAC and achieved cCR and rCR or near-rCR (as defined by ≤1 cm and no malignant microcalcifications on MMG, ≤2 cm US, no mass with rapid rise or washout kinetics on MRI). Patients then received multiple marker-directed stereotactic core biopsies of the tumor bed with marker placement to facilitate breast conservation surgery. The primary endpoint was NPV. Among 98 evaluable patients with clinical T1–3 breast cancer of all subtypes, 36 had residual disease at the time of surgery and of those, 18 had a positive pre-operative stereotactic biopsy representing a sensitivity of 50%, indicating that disease was missed by percutaneous biopsy 50% of the time. The NPV of 77.5% did not reach the pre-specified threshold of 90% NPV to support the omission of surgery. The final manuscript of NRG BR 005 is pending at the time of this review (23). Another multicenter prospective study in the Netherlands assessed the accuracy of US-guided core needle biopsies in predicting pCR in 167 patients with rPR or rCR on post-treatment MRI (MICRA) between 2016 and 2019. They found an unacceptably high FNR rate of 37% and concluded that US-guided core biopsies are not accurate in predicting pCR, but did note that under sampling may be an issue with core biopsies compared with VAB (29).

Finally, there is a large scale international multicenter prospective feasibility trial being conducted across 26 sites studying the accuracy of VAB in TNBC/HER2+ patients who have achieved rCR or near rCR after NAC. US or mammographically guided VAB will be performed to detect residual tumor prior to surgery to determine its diagnostic accuracy in assessing pCR compared to surgery. The study is currently active and results are pending at the time of this review (30).

These trials (Table 2) show promise for the feasibility of minimally invasive percutaneous procedures to predict pCR reliably, and potentially avoid surgery; however, these procedures will be limited to specialized centers and only in the context of clinical trials, so will not have widespread applicability in the near future. In addition to the strict technical feasibility, there is also concern of how missing residual disease would impact systemic therapy recommendations, precluding eligible, high-risk patients from receiving adjuvant therapies such as capecitabine and T-DM1.

Omission of breast surgery

The concept of surgical omission after NAC is not new, with studies on the topic dating back to the 1980s, even predating receptor testing. For example, one of the earlier studies by Perloff et al. analyzed locoregional recurrence (LRR) among 87 evaluable patients who had received NAC between 1978 and 1983 and were randomized 1:1 to surgery or radiation therapy. A 19% and 27% LRR rate was reported for surgery and radiotherapy, respectively, with no difference in DFS or OS between the two groups (31). Another older retrospective analysis of a prospectively maintained database published by Ring et al. identified 136 breast cancer patients of any subtype treated with NAC between 1986–1999 who experienced a cCR (determined by physical exam) and 67 underwent surgery while 69 underwent radiotherapy. They found no significant difference in DFS or OS between the two groups, however there was a non-significant higher LRR rate (21% vs. 10%) in the nonsurgical group at 5 years (32).

Previous studies of surgery omission after NAC resulted in high rates of LRR for multiple reasons including the following: clinical response was typically determined via physical exam which is known to be inaccurate (20) and patient inclusion and treatment was not differentiated based on cancer subtype (33). Fortunately, the multidisciplinary treatment for breast cancer has vastly improved with more effective systemic therapy resulting in markedly improved overall oncologic outcomes, furthering the interest in local therapy de-escalation. In a more recent analysis, Clouth et al. performed a retrospective study of 101 patients with clinical T2–3, N0–1 breast cancer of any subtype who were not BCT candidates and underwent NAC between 2000 and 2005. Clinical exam and imaging were combined with core biopsies performed at the time of nodal surgery to determine response. If pathological core biopsies were negative (pCR), patients received radiotherapy and no further surgery. If the cores were positive, patients continued to receive surgery. Twenty six of 101 patients were identified to have both complete clinical and radiological response with 25/26 undergoing core needle biopsy. Sixteen of 25 patients had negative core needle biopsies and underwent radiotherapy without further surgery while 86 patients (9 core biopsy positive, 77 without complete clinical response) underwent surgery. Overall, there were 10 patients with LRR detected with a mean follow-up of 27.5 months, 12.5% in the radiotherapy group compared to 9.5% in the surgical group. There was, again, no difference in DFS and OS between groups (34). Synthesizing the information above, LRR rates were consistently higher in the non-surgical groups, however there were no differences seen in DFS and OS. These studies predate the introduction of immunotherapy (pembrolizumab) and HER-2 direct therapies which have contributed to higher pCR rates, making further trials attractive if patient selection and biopsy techniques could be improved.

With the feasibility trial demonstrating potential safety of image-guided VAB (FNR of 5%), a subsequent single-arm prospective clinical trial led by Kuerer et al. was designed to evaluate the LRR rate for TNBC and HER2+ patients undergoing VAB of the tumor bed revealing pCR after NAC and radiotherapy-alone. The study was conducted in 8 centers in the USA with a feasibility and an expansion phase, including patients with non-recurrent, unicentric, clinical T1–2, clinical N0–1 invasive breast cancers, excluding patients whose masses, density, microcalcifications or enhancement measured >2 cm. A minimum of 12 VAB cores were obtained with a 9G needle targeting the previous clip and circumferentially around the remaining mass, distortion or microcalcifications. A new marker was placed in the area to facilitate surgery (if residual disease was found) or for radiation planning (in patients with pCR determined by VAB). Patients with documented nodal involvement prior to NAC underwent a targeted axillary dissection and had to have a nodal pCR to remain eligible. Patients received external beam whole breast radiation (40 Gy in 15 fractions or 50 Gy in 25 fractions) followed by a mandatory boost, concordant with adjuvant radiotherapy recommendations post BCT. Of 50 patients enrolled, 31 were determined to have a pCR per minimally invasive means and underwent radiation only, and there were no ipsilateral breast tumor recurrences (IBTR) among them at 26.4 months of follow-up (35). Authors recently presented updated findings of 0 % IBTR, 100% DFS and OS at 38.4 months of follow-up (36). Longer follow-up information is anticipated upon study conclusion.

Secondary endpoint analysis of the Kuerer trial by Johnson et al. evaluated patient reported outcomes of surgical omission and found an overall positive experience for trial participants. By decisional regret scores (DRS) declined over time then stabilized, indicating high decisional comfort. By the breast cancer treatment outcomes scale, which assesses function, pain, cosmesis and edema in both breasts (scale of 1 to 4, 1 indicating no difference and 4 indicating large difference), differences between breasts were low at 1.05 at baseline and 1.36 at 36 months. By FACT-B+4, which is a quality of life scale, scored 1–148, scores were high at baseline [121], increased to 133 at 12 months and finally 129 at 36 months, indicating high quality of life. Taken together, omission of breast surgery in highly selected patients may provide quality of life benefits, but more work needs to be done in this area. Complete 5-year data for the entire cohort is anticipated (37).

There is another clinical trial currently accruing at 17 Korean sites studying omission of breast and axillary surgery after NAC. The OPTIMIST trial is a prospective multicenter, single-arm trial enrolling patients with clinical T1–2, N0–2 TNBC and HER2+ breast cancer, with strict post-treatment MRI criteria including lesions ≤1 cm and lesion to background signal enhancement ratios ≤1.6. Patients with clinical nodal disease will undergo nodal surgery post-NAC (sentinel lymph node biopsy with or without axillary lymph node dissection). The primary endpoint is 5-year DFS, and secondary endpoints are 5-year ipsilateral breast tumor recurrence-free survival, OS, DFS, rate of residual axillary lymph node metastasis and quality of life scores (38).

While preliminary results may be promising, there are several important issues to consider before adopting omission of surgery into practice, such as differing physician and patient preferences. A questionnaire conducted in Japan assessed the preferences of patients with TNBC and HER2+ tumors and good clinical response after NAC and found that a low proportion of patients (23.7%) were willing to omit surgery, and 38.7% preferred surgery (39). It is important to keep in mind that this is the very beginning of ground breaking research. Currently, most patients are expecting surgery to be part of their treatment plan. Significant emotional distress often accompanies a diagnosis of breast cancer and can be the driver of decisions and it would take a fairly large paradigm shift with extensive education to change patients’ perspectives about surgery. The potential need for future percutaneous biopsies and testing anxiety may also discourage a patient from omitting surgery.

In contrast, a recent study by Gharzai et al. investigated physician attitudes and most expressed interest in omission of surgery (17/18, 94.4%). There was a general positive attitude towards breast cancer treatment de-escalation and towards performing additional research to refine patient selection for safe surgical omission; however, there were reservations about availability of biopsy equipment and expertise, adoption into community practice, the ability to enroll patients to clinical trials, and the loss of prognostic information impacting adjuvant treatments with omission of surgery. Perception is that lumpectomy is a fairly minimally invasive procedure without significant morbidities that may not warrant further de-escalation (40). Additional challenges include establishing proper imaging and biopsy follow-up regimens for patients who omit surgery, and a continued need for axillary surgery for patients with clinically involved nodes during which time a lumpectomy could easily be performed.

BCT after NAC for patients with MF/MC tumors—a potential application of surgery omission?

Historically, BCT has been advised against for patients with MF/MC tumors due to published LRR rates as high as 40% (23–40%), necessitating mastectomy (41-43). The recently published Alliance/American College of Surgeons Oncology Group Z11102 trial showed a LRR of 3.1% in patients with MF/MC tumors undergoing BCT, but patients receiving NAC were excluded (44), leaving unanswered questions about BCT safety in this population.

More contemporary studies have reported lower IBTR/recurrence rates for patients with MF/MC tumors undergoing BCT after NAC (45-47). In a retrospective analysis of 97 patients with MF/MC disease treated with NAC between 1977 and 2003 by Oh et al., there were no significant differences in locoregional control of MF/MC tumors compared to unifocal tumors. Specifically after NAC and BCT, 5-year locoregional control rate was 89% for unifocal lesions and 94% for MF/MC tumors (45). Ataseven et al. analyzed data from the GeparTrio, GeparQuattro and GeparQuinto trials which were prospective, multicenter trials analyzing NAC for all subtypes of breast cancer, with a focus on outcomes for patients with MF/MC disease after NAC. Among 820 (13.4%) patients with multifocal and 581 (9.5%) with multicentric tumors, pCR rates were 16.5% and 14.4%, respectively, and there were no differences in local relapse-free survival for patients with MF/MC disease who underwent BCT compared to unifocal disease, if pCR or negative margins were achieved. Similarly, there was no difference in OS for MF/MC disease compared to unifocal disease if pCR or negative margins were achieved (46). Lastly, Di Lena et al. retrospectively reviewed 544 patients treated with NAC between 2012 and 2021, 106 of whom had MF/MC tumors, and found no significant difference in IBTR or survival between patients with MF/MC and unifocal tumors. A pCR was achieved in 41.1% of the patients with MF/MC tumors compared to 41.5% of the patients with unifocal tumors. Among those with a pCR, there was a 4.7% 5-year recurrence rate in the MF/MC group and a 4.8% rate in the unifocal group. The authors found margin status (negative) and receipt of radiotherapy protective against IBTR, but tumor focality had no statistically significant impact. Authors also reported a distant recurrence rate of 9.8% in the unifocal cohort and 5.7% in the MF/MC cohort at 55 months of follow-up (47). Together, these studies cautiously support BCT as a safe surgical option for MF/MC tumors.

Though BCT after NAC may be acceptable for patients with MF/MC tumors, thus far, patients with MF/MC tumors have been excluded from surgery omission studies. Additionally, for patients with MF/MC tumors that are scattered throughout the breast that may not be amenable to BCT, mastectomy is still required. In an exploratory analysis of a single-arm prospective trial of NAC for HER2+ breast cancer, 44% of patients with classic contraindications to BCT, including MF/MC disease, experienced a pCR (48). Obligatory mastectomy may be overtreatment for these patients, and this scenario presents a potential application of the research regarding omission of surgery. For example, image-guided VABs could be performed on satellite lesions while a single-site lumpectomy is performed on the main tumor, to determine if PCR has been achieved and render these patients BCT candidates, omitting mastectomy if the combination of VABs and single lumpectomy show pCR. This hypothesis would be further tested in a prospective clinical trial. Being able to use the primary tumor’s response as an indicator of the other sites’ responses will rely upon MF/MC tumors having similar biomarker statuses and morphologies, and future research should focus on MF/MC tumor concordance. For example, our group has performed a small retrospective review of MF/MC TNBC and HER2+ tumors, with pathologic re-review, and found a concordance rate of 91% (49). More studies like this are needed to determine the feasibility of surgical de-escalation in MF/MC patients, which would then support large scale clinical trials to test this approach.

Conclusions

The breast cancer treatment landscape has changed greatly in the past few decades. Global de-escalation is now the goal, with systemic therapy, surgery, and radiation therapy trials all aimed at de-escalating treatments. While not all patients would be candidates for surgical de-escalation in the form of omission, or would want surgery omitted, there are some patients for whom the risk of surgery would be prohibitive who may benefit from a non-operative approach, or some to whom this option may be attractive for other reasons. These studies also allow us to further customize treatment based on patient preferences and tumor biology with various methods of de-escalation. Patient preferences and attitudes will be important to take into consideration moving forward. Patient reported outcomes are important to assess the clinical meaningfulness of scientific findings. Johnson et al. demonstrated an overall positive experience for trial participants, indicating that there are a subset of patients who can stand to benefit from surgical de-escalation (37). The concern for widespread applicability of surgical omission remains relevant and its adoption may be limited to centers with more resources and expertise. Another very important point moving forward is how breast cancer treatment modalities impact one another, i.e., how new systemic therapies may allow for further surgical de-escalation, and vice versa how breast and axillary surgery de-escalation may impact adjuvant therapeutic strategies. Large scale studies with longer follow-up will need to be performed to assess the safety of surgical omission in this high-risk group of patients.

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-24-65/rc

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-65/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-65/coif). A.W. had received consulting fees from Merck and Myriad; She also received payment from OncLive (MJH Lifesciences), Empire State Hematology & Oncology Society, and Society of Breast Imaging; She is on the Advisory Board of Daiichi-Sankyo and Abbvie. The other author has 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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