Professor Gianluca Franceschini on surgical de-escalation, response assessment, reconstruction and the evidence needed before omitting breast surgery
Neoadjuvant chemoimmunotherapy has improved outcomes in high-risk early-stage triple-negative breast cancer (TNBC). For breast surgeons, its success brings a consequential question: how much should an excellent response to systemic treatment change the operation that follows?
The phase III KEYNOTE-522 trial established the benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab, with estimated five-year overall survival of 86.6%, compared with 81.7% in the control group. However, definitive surgery remained part of treatment in both groups. The trial demonstrated the efficacy of a treatment pathway incorporating surgery; it did not establish when surgery could be reduced or omitted.
That distinction now sits at the intersection of immuno-oncology and breast surgery. Better responses create opportunities for breast conservation, but they also expose gaps in how residual disease is assessed, how breast and axillary treatment are coordinated, and how immune-related toxicity is incorporated into perioperative care.
OncoDaily IO spoke with Professor Gianluca Franceschini about five decisions shaping breast surgery in the immunotherapy era—and why the evidence required to perform less surgery must extend beyond tumour response.
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From Tumour Response to Response-Adapted Surgery
A major response to neoadjuvant treatment can change the anatomical possibilities for surgery. Whether it should change the extent of treatment depends on the original disease burden, the distribution of residual disease and the reliability of post-treatment assessment.
Professor Franceschini emphasizes that breast and axillary de-escalation require separate decisions, integrated within the broader locoregional treatment plan.
How should response to neoadjuvant chemoimmunotherapy inform breast and axillary surgical de-escalation?
Neoadjuvant chemoimmunotherapy, particularly the combination of pembrolizumab and chemotherapy in early-stage triple-negative breast cancer (TNBC), is changing the therapeutic landscape and creating important opportunities for surgical de-escalation.
The achievement of a pathological complete response (pCR), conventionally defined as the absence of residual invasive carcinoma in both the breast and axillary lymph nodes (ypT0/is ypN0), is associated with a favourable prognosis and represents an important endpoint of neoadjuvant treatment. However, pCR should be considered a prognostic biomarker rather than, by itself, an indication to omit surgery.
At the breast level, the most immediate opportunity is to increase the proportion of patients eligible for breast-conserving surgery rather than mastectomy. The decision should integrate the initial tumour extent, multifocality or multicentricity, the distribution of residual disease, the presence of associated ductal carcinoma in situ, the breast-to-tumour volume ratio and the patient’s preferences. Importantly, the original tumour bed must be accurately identified through appropriate clip placement before starting systemic treatment.
A major response should therefore translate into a smaller surgical excision whenever oncologically appropriate, with the objective of preserving breast shape and achieving negative margins.
Oncoplastic techniques can further facilitate this approach.
Beyond increasing breast-conserving surgery rates, a more ambitious approach is the potential omission of breast surgery in highly selected patients achieving a radiological complete response and biopsy-confirmed pathological complete response. Image-guided vacuum-assisted biopsy of the tumour bed is currently being investigated as a means of identifying patients who might safely avoid breast surgery. However, this strategy remains investigational and should currently be restricted to prospective clinical trials.
Axillary de-escalation requires a separate assessment. In patients initially presenting with clinically node-negative disease, sentinel lymph node biopsy remains an established approach.
In patients with biopsy-proven node-positive disease who convert to clinically node-negative status after neoadjuvant treatment, targeted axillary dissection (TAD), combining removal of the previously marked positive node with sentinel lymph node biopsy, represents an important strategy to improve staging accuracy, reduce the false-negative rate and avoid unnecessary axillary lymph node dissection.
The accuracy of TAD depends on appropriate pretreatment marking of the biopsy-proven metastatic lymph node, its successful retrieval after neoadjuvant therapy and an adequate sentinel lymph node assessment. The use of dual-tracer mapping and retrieval of at least three sentinel lymph nodes, whenever feasible, can further improve diagnostic accuracy. Importantly, the applicability of axillary de-escalation depends on the initial nodal burden, with the strongest evidence supporting this approach in patients presenting with limited cN1 disease who convert to ycN0.
Furthermore, surgical decision-making should not be limited to patients achieving nodal pCR. The management of residual low-volume nodal disease, particularly isolated tumour cells and micrometastases, represents an important area of ongoing de-escalation research.
In patients with residual macrometastatic nodal disease, axillary lymph node dissection generally remains the standard approach, although future strategies may increasingly integrate axillary surgery, regional nodal irradiation and systemic treatment.
The presence of a breast pCR does not necessarily establish an axillary pCR, and vice versa. These two compartments must be assessed independently.
Moreover, surgical de-escalation cannot be considered in isolation from radiotherapy. Decisions regarding the extent of axillary surgery must be integrated with the initial nodal burden, pathological response, regional nodal irradiation and the overall locoregional treatment strategy. Avoiding axillary lymph node dissection does not automatically mean that regional nodal irradiation can also be omitted.
In my opinion, the future of breast cancer surgery lies in response-adapted surgery: the extent of breast and axillary surgery should be determined by the initial disease burden, biological subtype, response to systemic treatment and the reliability of post-treatment assessment.
The objective is not simply to perform less surgery but to achieve the best possible balance between oncological safety, functional outcomes, cosmetic results and quality of life.
This approach makes preparation before systemic treatment particularly consequential. Accurate marking of the breast lesion and a biopsy-proven metastatic node preserves the anatomical information needed to interpret a subsequent response. The opportunity to de-escalate surgery may therefore depend partly on decisions made before the first treatment cycle.
When the Tumour Disappears on Imaging, What Remains?
The possibility of omitting surgery depends on answering a difficult diagnostic question: can residual disease be excluded reliably without examining the surgically removed tumour bed?
The NRG-BR005 trial, published in JAMA Surgery, tested tumour-bed biopsy in patients with a clinical complete response and complete or near-complete response on multimodality imaging after neoadjuvant chemotherapy. Its results did not support surgery omission using the study’s assessment criteria. Although not specific to chemoimmunotherapy, the study illustrates why apparent response and reliable exclusion of residual disease must be evaluated separately.
How accurately can imaging and image-guided biopsy predict pathological complete response after chemoimmunotherapy?
Accurately identifying patients who achieve a pathological complete response (pCR) after neoadjuvant systemic therapy remains one of the major challenges in contemporary breast cancer surgery. The possibility of omitting breast surgery increasingly depends not only on predicting treatment response, but also on reliably excluding clinically meaningful residual disease.
Multiparametric breast MRI is currently the most informative imaging modality for assessing response to neoadjuvant systemic therapy. Mammography and ultrasound provide complementary information, particularly regarding residual microcalcifications, tumour-bed abnormalities and axillary lymph nodes. However, radiological complete response does not necessarily correspond to pathological complete response. This discrepancy may be particularly relevant following immunotherapy, as treatment-related inflammation, fibrosis and immune-mediated changes may alter imaging appearances, while microscopic invasive disease or residual ductal carcinoma in situ (DCIS) may remain undetected.
Image-guided vacuum-assisted biopsy (VAB) has therefore emerged as a promising strategy to improve the identification of patients without residual breast disease who might eventually be considered for surgical de-escalation.
Nevertheless, prospective studies have demonstrated important limitations in the diagnostic performance of image-guided biopsy. False-negative results vary according to biopsy technique, sampling strategy, tumour characteristics and patient selection. Although combining imaging assessment with VAB appears to improve diagnostic accuracy, the available evidence remains insufficient to establish its reliability across different clinical and biological settings. Furthermore, prospective evaluation of multimodal imaging combined with tumour-bed biopsy has highlighted that a negative result may still leave a clinically relevant probability of residual disease.
These findings underline an essential distinction: a negative biopsy does not necessarily establish the absence of residual disease. Diagnostic reliability depends on accurate localisation of the original tumour bed, adequate tissue sampling, the extent and spatial distribution of residual disease, and radiological-pathological concordance. The negative predictive value (NPV) must also be interpreted in the context of residual disease prevalence and patient selection, rather than considered an intrinsic characteristic of the diagnostic technique.
An important development comes from a prospective phase II trial published in JAMA Oncology in 2025, evaluating the omission of breast surgery in highly selected patients with triple-negative or HER2-positive breast cancer following neoadjuvant systemic therapy. Among 50 patients undergoing image-guided VAB, 31 achieved biopsy-confirmed pCR and proceeded to whole-breast radiotherapy without breast surgery. At a median follow-up of 55.4 months, no ipsilateral breast tumour recurrences were observed, and both five-year disease-free survival and overall survival were 100% in the cohort managed without breast surgery.
These findings are particularly encouraging and provide prospective evidence supporting the feasibility of breast surgery omission in carefully selected patients. However, their interpretation requires caution. The study was small, non-randomised and conducted in a highly selected population under stringent imaging and biopsy protocols. Importantly, patients with initially documented nodal disease underwent targeted axillary dissection when breast pCR was identified by VAB. Furthermore, the neoadjuvant regimens did not include immunotherapy. Consequently, these results cannot be directly extrapolated to patients receiving contemporary pembrolizumab-containing regimens.
This distinction is particularly important in triple-negative breast cancer, where chemoimmunotherapy has become an established neoadjuvant treatment approach. Although immunotherapy may influence tumour regression patterns and treatment-related tissue changes, its specific impact on the diagnostic performance of MRI and image-guided biopsy remains insufficiently characterised. It would therefore be inappropriate to assume that diagnostic accuracy established after conventional chemotherapy is equivalent to that achieved after chemoimmunotherapy.
In this setting, a reliable multimodal assessment is essential. This should incorporate high-quality breast MRI, mammography and ultrasound when indicated, accurate localisation of the original tumour bed using previously placed markers, and adequately performed VAB with representative sampling of the tumour bed. Radiological-pathological concordance is crucial, as residual tumour cells may be scattered, fragmented or distributed in small microscopic foci that can be missed by percutaneous sampling. Residual calcifications also deserve particular attention: radiological abnormalities do not necessarily indicate viable malignancy, while the absence of suspicious calcifications does not exclude residual DCIS.
Another important consideration is the definition of pathological complete response. The commonly used definition ypT0/is ypN0 allows residual in situ carcinoma in the breast but requires the absence of invasive disease in both the breast and regional lymph nodes. By contrast, ypT0 ypN0 requires the absence of both invasive and in situ carcinoma. This distinction is particularly relevant when evaluating biopsy-based strategies, as excluding residual invasive disease is not necessarily equivalent to excluding all residual in situ disease. The pathological endpoint must therefore be clearly defined when assessing the diagnostic performance of imaging and VAB.
The axilla must also be evaluated independently. Radiological normalisation of previously abnormal lymph nodes cannot establish pathological nodal response. In patients presenting with biopsy-proven node-positive disease before neoadjuvant treatment, targeted axillary dissection, incorporating retrieval of the previously marked positive lymph node and sentinel lymph node assessment, represents an important strategy for evaluating residual nodal disease. Breast and axillary responses should therefore be considered distinct diagnostic endpoints when assessing the feasibility of locoregional treatment de-escalation.
Ultimately, the most relevant diagnostic parameters are the false-negative rate and NPV, rather than overall imaging-pathology agreement. Nevertheless, even excellent diagnostic performance does not automatically establish the oncological safety of omitting surgery. Three distinct objectives must be recognised: predicting pCR through imaging, confirming the absence of residual disease through representative tissue sampling, and demonstrating that omission of surgery does not compromise long-term oncological outcomes. These objectives require progressively stronger levels of clinical evidence.
In conclusion, MRI and image-guided VAB represent promising tools for identifying exceptional responders after neoadjuvant treatment but they cannot currently replace surgical pathology in routine clinical practice, particularly following chemoimmunotherapy. Prospective studies specifically designed for patients receiving immunotherapy are needed to establish diagnostic accuracy, reproducibility and long-term oncological safety. The ultimate challenge is not simply to predict pathological complete response but to reliably establish the absence of residual disease and demonstrate that this information can safely guide the omission of breast surgery.
His assessment identifies three separate research tasks: predicting response, excluding residual disease and demonstrating that a treatment decision based on those findings preserves long-term outcomes. Each requires evidence beyond the preceding step.
Reconstruction After Pembrolizumab: How Should Risk Be Assessed?
Reconstructive planning brings the discussion from tumour response to tissue recovery, patient selection and treatment sequencing.
In a retrospective study of 254 patients published in the European Journal of Surgical Oncology, Barjot and colleagues found that pembrolizumab was not independently associated with increased overall postoperative complication risk. Delayed wound healing, however, was more frequent with chemoimmunotherapy—10% versus 3.8%. The findings illustrate why overall complication rates may not capture every consideration relevant to reconstructive practice. pubmed.ncbi.nlm.nih.gov
How should perioperative pembrolizumab exposure influence reconstructive strategy and timing?
Pembrolizumab introduces an additional dimension to perioperative planning, but its administration should not automatically preclude breast reconstruction or lead to unnecessary surgical delays.
The some studies established the role of pembrolizumab in combination with neoadjuvant chemotherapy, followed by surgery and adjuvant pembrolizumab, in patients with high-risk early-stage triple-negative breast cancer (TNBC).
From a surgical perspective, the main considerations include the patient’s general condition, immune-related adverse events, nutritional status, haematological recovery, tissue quality and the potential need for postmastectomy radiotherapy.
There is currently no established mandatory pembrolizumab washout period before breast surgery. Unlike cytotoxic chemotherapy, immune checkpoint inhibitors do not produce the same pattern of direct cumulative myelosuppression. Therefore, surgical timing should be individualised according to treatment-related toxicity and the patient’s overall clinical condition, rather than determined exclusively by the date of the last pembrolizumab administration.
For appropriately selected patients, immediate reconstruction remains a reasonable option. However, reconstructive planning requires particular attention when postmastectomy radiotherapy is anticipated or when clinically significant immune-related adverse events have occurred.
Both autologous and implant-based reconstruction, including tissue-expander placement, may be considered according to patient characteristics, tissue quality, comorbidities and the anticipated radiotherapy strategy. Pembrolizumab exposure alone should not determine the choice of reconstructive technique.
Three practical principles should guide management:
Multidisciplinary planning: Breast surgeons, plastic surgeons, medical oncologists, anaesthesiologists and radiation oncologists should agree on the treatment sequence and reconstructive strategy before surgery.
Individualised reconstructive selection: The choice between immediate and delayed reconstruction, and between implant-based and autologous techniques, should reflect oncological indications, anticipated radiotherapy, comorbidities, tissue quality and patient preferences.
Appropriate management of immunotherapy: Pembrolizumab should be managed in close coordination with the medical oncologist. Active or clinically significant immune-related toxicity may require treatment interruption, additional evaluation or postponement of surgery. Exposure alone, however, does not justify automatic discontinuation.
Breast-specific evidence regarding the effects of pembrolizumab on wound healing and reconstructive complications remains limited, particularly for implant-based and autologous reconstruction. Prospective studies with well-defined surgical and reconstructive endpoints are therefore needed.
In my opinion, pembrolizumab exposure alone should not be considered a contraindication to immediate breast reconstruction. Rather, reconstructive decisions should be guided by individual patient factors, immune-related toxicity, anticipated radiotherapy and the overall oncological treatment strategy.
For Professor Franceschini, reconstructive timing belongs within the full oncological plan. The relevant assessment includes anticipated radiotherapy, the consequences of any active toxicity, tissue condition and the patient’s preferences.
When Should Immune-Related Toxicity Postpone Surgery?
Immunotherapy introduces perioperative considerations that may persist beyond the final preoperative dose. The American Society of Breast Surgeons’ preoperative resource guide permits checkpoint inhibitors to continue during the perioperative period while recommending assessment for treatment-related toxicity, including thyroid and adrenal dysfunction.
The practical question is how to recognize toxicity that makes proceeding with surgery unsafe—and how to establish readiness once it has been treated.
Which immune-related adverse events warrant postponement of breast surgery?
The presence and severity of immune-related adverse events (irAEs), rather than pembrolizumab exposure itself, should determine whether breast surgery needs to be postponed.
Preoperative assessment should focus on identifying active toxicities that may compromise organ function, anaesthetic safety or postoperative recovery.
In general, mild, stable grade 1 toxicities do not necessarily require postponement. Grade 2 toxicities should be assessed individually, whereas severe grade 3–4 toxicities generally warrant deferring elective surgery until adequate clinical stabilisation.
Particular attention should be paid to the following complications:
Cardiovascular: Suspected or confirmed immune-mediated myocarditis requires postponement of elective surgery until appropriate investigation, treatment and cardiac stabilisation.
Pulmonary: Symptomatic pneumonitis, particularly when requiring corticosteroids or oxygen supplementation, warrants postponement until respiratory recovery.
Endocrine: Adrenal insufficiency, hypophysitis and severe thyroid dysfunction must be adequately treated and stabilised. Patients with adrenal insufficiency may require perioperative corticosteroid coverage.
Hepatic and renal: Significant immune-mediated hepatitis or nephritis should be controlled before elective surgery, with particular attention to organ function and metabolic stability.
Gastrointestinal: Severe colitis, especially when associated with dehydration, bleeding or electrolyte disturbances, requires postponement until adequately controlled.
Neurological and haematological: Severe neurological toxicity, including myasthenia gravis, and clinically significant immune-mediated cytopenias require specialist assessment before anaesthesia and surgery.
Another important consideration is the use of corticosteroids or other immunosuppressive agents to manage irAEs. Prolonged high-dose corticosteroid treatment may increase infection risk, impair wound healing and complicate postoperative recovery.
I would therefore recommend an individualised preoperative assessment based on clinical symptoms, toxicity grading, laboratory investigations and organ-specific evaluation when indicated.
The key principle is that elective breast surgery should proceed only when clinically significant immune-related toxicities are adequately controlled, organ function is stable and anaesthetic risk is acceptable. There is no universal waiting interval that can replace this individualised assessment.
This makes the handover between medical oncology, surgery and anaesthesia especially important. Readiness for surgery depends on the course of toxicity and recovery, including the treatment required to achieve clinical stability.
What Would It Take to Safely Omit Breast Surgery?
The most ambitious form of de-escalation is omission of breast surgery altogether.
The prospective phase II study “Selective Elimination of Breast Surgery for Invasive Breast Cancer,” published in JAMA Oncology, offers an early clinical foundation for that possibility. Its small, highly selected population and non-immunotherapy treatment regimens remain central to interpreting its relevance to contemporary TNBC care.
For the immuno-oncology community, the next question is whether comparable approaches can be validated specifically after chemoimmunotherapy, with reproducible response assessment and durable locoregional control.
What evidence is required to support omission of breast surgery following an exceptional response to chemoimmunotherapy?
Omitting breast surgery after an exceptional response to neoadjuvant chemoimmunotherapy is a promising strategy, but its oncological safety must be demonstrated before it can become standard practice.
The key challenge is to reliably identify patients with no residual disease without requiring surgical excision of the tumour bed and to demonstrate that avoiding surgery does not compromise long-term oncological outcomes.
The prospective phase II study by Kuerer and colleagues, published in JAMA Oncology in 2025, provides encouraging preliminary evidence. Among 50 patients with HER2-positive or triple-negative breast cancer, 31 had no residual disease identified by vacuum-assisted biopsy (VAB) and underwent whole-breast radiotherapy without breast surgery. At a median follow-up of 55.4 months, no ipsilateral breast recurrences were observed. However, the study was relatively small, non-randomised and did not include pembrolizumab-based regimens. These results therefore cannot be directly extrapolated to patients treated with contemporary chemoimmunotherapy.
In my view, five requirements must be addressed before omission of breast surgery can be considered an acceptable therapeutic strategy:
Appropriate patient selection: Initial candidates should be carefully selected patients with HER2-positive or triple-negative disease, favourable post-treatment imaging and a well-localised original tumour bed.
Reliable confirmation of response: High-quality MRI, mammography and ultrasound, when indicated, should be combined with image-guided VAB. Adequate sampling, accurate tumour-bed localisation and radiological-pathological concordance are essential. A sufficiently low false-negative rate must be demonstrated.
Prospective clinical evidence: Multicentre studies must establish long-term safety, including ipsilateral breast recurrence, regional recurrence, disease-free survival, overall survival, quality of life and patient-reported outcomes.
A clearly defined radiotherapy strategy: Omitting breast surgery does not necessarily mean omitting radiotherapy. Whole-breast irradiation has been an integral component of the available prospective evidence, and its optimal role requires further investigation.
Independent assessment of the axilla: Breast pCR does not establish nodal pCR. Axillary response must be evaluated separately, particularly in patients who were initially clinically node-positive. Omission of breast surgery and omission of axillary surgery should therefore be considered distinct clinical decisions.
Importantly, evidence must also be generated specifically in patients receiving chemoimmunotherapy. Pembrolizumab may influence tumour regression patterns and treatment-related changes in the tumour bed. Whether these changes affect the diagnostic accuracy of imaging and VAB remains to be established. Diagnostic protocols validated after conventional chemotherapy therefore require specific prospective validation after immunotherapy.
My final position is that omission of breast surgery should be considered only when rigorous diagnostic criteria and prospective clinical evidence demonstrate that it does not compromise oncological safety. The goal is to reduce surgical morbidity without increasing the risk of local recurrence or compromising long-term survival.
We should await robust prospective evidence before abandoning breast surgery. The future is promising but we are not ready to hang up the scalpel just yet!
