In this review, we evaluate the potential and recent advancements in using artificial intelligence techniques to de-escalate loco-regional breast cancer therapy, with a special focus on surgical ...treatment after neoadjuvant systemic treatment (NAST). The increasing use and efficacy of NAST make the optimal loco-regional management of patients with pathologic complete response (pCR) a clinically relevant knowledge gap. It is hypothesized that patients with pCR do not benefit from therapeutic surgery because all tumor has already been eradicated by NAST. It is unclear, however, how residual cancer after NAST can be reliably excluded prior to surgery to identify patients eligible for omitting breast cancer surgery. Evidence from clinical trials evaluating the potential of imaging and minimally-invasive biopsies to exclude residual cancer suggests that there is a high risk of missing residual cancer. More recently, AI-based algorithms have shown promising results to reliably exclude residual cancer after NAST. This example illustrates the great potential of AI-based algorithms to further de-escalate and individualize loco-regional breast cancer treatment.
•AI shows promising potential to de-escalate loco-regional breast cancer treatment.•AI may help to exclude residual cancer after neoadjuvant treatment to omit surgery.•Future challenges include prospective performance validation and AI-fairness.
Breast and axillary surgery after neoadjuvant systemic treatment for women with breast cancer has undergone multiple paradigm changes within the past years. In this review, we provide a ...state-of-the-art overview of breast and axillary surgery after neoadjuvant systemic treatment from both, a clinical routine perspective and a clinical research perspective. For axillary disease, axillary lymph node dissection, sentinel lymph node biopsy, or targeted axillary dissection are nowadays recommended depending on the lymph node status before and after neoadjuvant systemic treatment. For the primary tumor in the breast, breast conserving surgery remains the standard of care. The clinical management of exceptional responders to neoadjuvant systemic treatment is a pressing knowledge gap due to the increasing number of patients who achieve a pathologic complete response to neoadjuvant systemic treatment and for whom surgery may have no therapeutic benefit. Current clinical research evaluates whether less invasive procedures can exclude residual cancer after neoadjuvant systemic treatment as reliably as surgery to possibly omit surgery for those patients in the future.
•Breast and axillary surgery after neoadjuvant systemic treatment has evolved.•Choice of axillary surgery depends on lymph node status before and after treatment.•Optimal management of exceptional responders to neoadjuvant treatment is unclear.•Clinical research aims to reliably exclude residual cancer without surgery.•For exceptional responders, breast cancer surgery may be omitted in the future.
Background
About 40 % of women with breast cancer achieve a pathologic complete response in the breast after neoadjuvant systemic treatment (NST). To identify these women, vacuum-assisted biopsy ...(VAB) was evaluated to facilitate risk-adaptive surgery. In confirmatory trials, the rates of missed residual cancer false-negative rates (FNRs) were unacceptably high (> 10%). This analysis aimed to improve the ability of VAB to exclude residual cancer in the breast reliably by identifying key characteristics of false-negative cases.
Methods
Uni- and multivariable logistic regressions were performed using data of a prospective multicenter trial (
n
= 398) to identify patient and VAB characteristics associated with false-negative cases (no residual cancer in the VAB but in the surgical specimen). Based on these findings FNR was exploratively re-calculated.
Results
In the multivariable analysis, a false-negative VAB result was significantly associated with accompanying ductal carcinoma in situ (DCIS) in the initial diagnostic biopsy odds ratio (OR), 3.94;
p
< 0.001, multicentric disease on imaging before NST (OR, 2.74;
p
= 0.066), and age (OR, 1.03;
p
= 0.034). Exclusion of women with DCIS or multicentric disease (
n
= 114) and classication of VABs that did not remove the clip marker as uncertain representative VABs decreased the FNR to 2.9% (3/104).
Conclusion
For patients without accompanying DCIS or multicentric disease, performing a distinct representative VAB (i.e., removing a well-placed clip marker) after NST suggests that VAB might reliably exclude residual cancer in the breast without surgery. This evidence will inform the design of future trials evaluating risk-adaptive surgery for exceptional responders to NST.
Neoadjuvant chemotherapy (NACT) is widely used as an efficient breast cancer treatment. Ideally, a pathological complete response (pCR) can be achieved. Up to date, there is no reliable way of ...predicting a pCR. For the first time, we explore the ability of minimal invasive biopsy (MIB) techniques to diagnose pCR in patients with clinical complete response (cCR) to NACT in this study. This question is of high clinical relevance because a reliable pCR prediction could have direct implications for clinical practice.
In all, 164 patients were included in this review-board approved, multicenter pooled analysis of prospectively assembled data. Core-cut (CC)-MIB or vacuum-assisted (VAB)-MIB were performed after NACT and before surgery. Negative predictive values (NPV) and false-negative rates (FNR) to predict a pCR in surgical specimen (diagnose pCR through MIB) were the main outcome measures.
Pathological complete response in surgical specimen was diagnosed in 93 (56.7%) cases of the whole cohort. The NPV of the MIB diagnosis of pCR was 71.3% (95% CI: (63.3%; 79.3%)). The FNR was 49.3% (95% CI: (40.4%; 58.2%)). Existence of a clip marker tended to improve the NPV (odds ratio 1.98; 95% CI: (0.81; 4.85)). None of the mammographically guided VABs (n=16) was false-negative (FNR 0%, NPV 100%).
Overall accuracy of MIB diagnosis of pCR was insufficient to suggest changing clinical practice. However, subgroup analyses (mammographically guided VABs) suggest a potential capacity of MIB techniques to precisely diagnose pCR after NACT. Representativity of MIB could be a crucial factor to be focused on in further analyses.
Severe immune suppression is frequent in late-stage tumor patients and promotes tumor immune evasion and subsequent tumor progression. Regulatory T cells (Treg) are major suppressors of anti-tumor ...immune responses. Therefore, targeting of Treg has become a key goal of anti-tumor therapy. Several preclinical and clinical observations suggest that Treg can be depleted by cyclophosphamide. Over a period of 3 months, we investigated the effect of metronomic low-dose cyclophosphamide on Treg numbers, suppressive capacity and proliferation on endogenous anti-tumor T-cell responses and on their correlation to clinical outcome in 12 patients with treatment-refractory metastasized breast cancer who received single-agent 50 mg cyclophosphamide p.o. daily. Cyclophosphamide treatment initially caused a significant reduction in circulating Treg by more than 40% (
P
= 0.002). However, Treg numbers completely recovered during the treatment due to increased proliferative activity and maintained their suppressive capacity. Treg depletion coincided with a strong increase in breast tumor–reactive T cells (
P
= 0.03) that remained at high levels during the whole period. Numbers of tumor-reactive T cells but not of Treg correlated with disease stabilization (
P
= 0.03) and overall survival (
P
= 0.027). We conclude that metronomic low-dose cyclophosphamide only transiently reduces Treg but induces stable tumor-specific T-cell responses, which correlate with improved clinical outcome in advanced-stage breast cancer patients.
Background
This study evaluated breast imaging procedures for predicting pathologic complete response (pCR = ypT0) after neoadjuvant chemotherapy (NACT) for breast cancer to challenge surgery as a ...diagnostic procedure after NACT.
Methods
This retrospective, exploratory, monocenter study included 150 invasive breast cancers treated by NACT. The patients received magnetic resonance imaging (MRI), mammography (MGR), and ultrasound (US). The results were classified in three response subgroups according to response evaluation criteria in solid tumors. To incorporate specific features of MRI and MGR, an additional category clinical near complete response (near-cCR) was defined. Residual cancer in imaging and pathology was defined as a positive result. Negative predictive values (NPVs), false-negative rates (FNRs), and false-positive rates (FPRs) of all imaging procedures were analyzed for the whole cohort and for triple-negative (TN), HER2-positive (HER2+), and HER2-negative/hormone-receptor-positive (HER2−/HR+) cancers, respectively.
Results
In 46 cases (31 %), pCR (ypT0) was achieved. Clinical complete response (cCR) and near-cCR showed nearly the same NPVs and FNRs. The NPV was highest with 61 % for near-cCR in MRI and lowest with 44 % for near-cCR in MGR for the whole cohort. The FNRs ranged from 4 to 25 % according to different imaging methods. The MRI performance seemed to be superior, especially in TN cancers (NPV 94 %; FNR 5 %). The lowest FPR was 10 % in MRI, and the highest FPR was 44 % in US.
Conclusion
Neither MRI nor MGR or US can diagnose a pCR (ypT0) with sufficient accuracy to replace pathologic diagnosis of the surgical excision specimen.
With current advances in neoadjuvant systemic therapy (NST) and improved breast imaging, the potential of nonoperative therapy for invasive breast cancer has emerged as a viable option when utilizing ...meticulous image-guided percutaneous biopsy to document pathologic complete response. Feasibility clinical trials utilizing this approach are being performed by teams of investigators from single and multicenter/cooperative groups around the world. Imaging alone after NST lacks sufficient sensitivity and specificity in predicting pCR and therefore cannot be utilized for clinical selection of patients for omission of surgery. Imaging with adequate sampling after NST of the residual lesions (or around the remaining clip if a complete radiologic response occurs) appears to be essential in selecting patients with pCR to lower the false-negative rates based on initial reported feasibility studies to identify pCR without surgery that range from 5 to 49%. In this manuscript, recently completed, ongoing, and planned clinical feasibility trials and a new omission of surgery trial are described. Drastic rethinking of all diagnostic and therapeutic management strategies that are ordinarily utilized for patients who receive standard breast cancer surgery is required. A roadmap of essential questions and issues that will have to be resolved as the field of nonoperative breast cancer management advances is described in detail.
Purpose
In the ACOSOG Z0011 trial, completing axillary lymph node dissection (cALND) did not benefit patients with T1–T2 cN0 early breast cancer and 1–2 positive sentinel lymph nodes (SLN) undergoing ...breast-conserving surgery (BCT). This paper reports cALND rates in the clinical routine for patients who had higher (T3–T4) tumor stages and/or underwent mastectomy but otherwise met the ACOSOG Z0011 eligibility criteria. Aim of this study is to determine cALND time trends and non-sentinel axillary metastases (NSAM) rates to estimate occult axillary tumor burden.
Methods
Data were included from patients treated in 179 German breast cancer centers between 2008 and 2015. Time-trend rates were analyzed for cALND of patients with T3–T4 tumors separated for BCT and mastectomy and regarding presence of axillary macrometastases or micrometastases.
Results
Data were available for 188,909 patients, of whom 19,009 were identified with 1–2 positive SLN. Those 19,009 patients were separated into 4 cohorts: (1) Patients with T1–T2 tumors receiving BCT (ACOSOG Z0011 eligible;
n
= 13,741), (2) T1–T2 with mastectomy (
n
= 4093), (3) T3–T4 with BCT (
n
= 269), (4) T3–T4 with mastectomy (
n
= 906). Among patients with T3–T4 tumors, cALND rates declined from 2008 to 2015: from 88.2 to 62.6% for patients receiving mastectomy and from 96.6 to 58.1% in patients receiving BCT. Overall rates for any NSAM after cALND for cohorts 1–4 were 33.4%, 42.3%, 46.9%, 58.8%, respectively.
Conclusions
The cALND rates have decreased substantially in routine care in patients with ‘extended’ ACOSOG Z0011 eligibility criteria. Axillary tumor burden is higher in these patients than in the ACOSOG Z0011 trial.
Purpose
The transverse musculocutaneous gracilis (TMG) flap is as a valuable alternative in autologous breast reconstruction. The purpose of this study was to evaluate the donor site morbidity and ...secondary refinement procedures after TMG flap breast reconstruction.
Methods
A retrospective study was conducted, including all patients who received TMG flap breast reconstructions, from January 2012 to August 2019. Primary outcomes were surgical site complications of the donor site and secondary refinement procedures carried out for aesthetic or reconstructive purposes for the medial thigh. Secondary outcomes of interest were lipofilling procedures for optimization of the reconstructed breasts.
Results
Ninety-nine patients received 159 TMG flaps for breast reconstruction. Patients’ mean BMI was 23.5 (15.6–32.5) kg/m
2
. Bilateral breast reconstructions were performed in 60.6%. The mean flap volume was 330 (231–440) g. Surgical site complications occurred in 14.5% of the TMG donor sites and wound dehiscence was the most common complication (9.4%). Lymphedema occurred in 1.8% of the donor thighs. Aesthetic refinement procedures were performed in 25.2% on the donor thigh or contralateral thigh. Secondary lipofilling was performed in 54.1% of the reconstructed breasts and fat was harvested in only 11.9% from the legs.
Conclusion
The TMG flap breast reconstruction combines low donor site morbidity with adequate volume for appealing breast results, particularly in slim-to-normal weight patients. However, patients should be informed about the likelihood of secondary refinement procedures on the donor site and the need of lipofilling to optimize the breast shape and volume.
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