Neoadjuvant treatment (NAT) has become an option in early stage (stage I-II) breast cancer (EBC). New advances in systemic and targeted therapies have increased rates of pathologic complete response ...increasing the number of patients undergoing NAT. Clear benefits of NAT are downstaging the tumor and the axillary nodes to de-escalate surgery and to evaluate response to treatment. Selection of patients for NAT in EBC rely in several factors that are related to patient characteristics (i.e, age and comorbidities), to tumor histology, to stage at diagnosis and to the potential changes in surgical or adjuvant treatments when NAT is administered.
Imaging and histologic confirmation is performed to assess extent of disease y to confirm diagnosis. Besides mammogram and ultrasound, functional breast imaging MRI has been incorporated to better predict treatment response and residual disease. Contrast enhanced mammogram (CEM), shear wave elastography (SWE), or Dynamic Optical Breast Imaging (DOBI) are emerging techniques under investigation for assessment of response to neoadjuvant therapy as well as for predicting response. Surgical plan should be delineated after NAT taking into account baseline characteristics, tumor response and patient desire.
In the COVID era, we have witnessed also the increasing use of NAT in patients who may be directed to surgery, unable to have it performed as surgery has been reserved for emergency cases only.
Background
The accuracy of sentinel lymph node biopsy (SLNB) after neoadjuvant therapy (NAT) has been improved with the placement of a clip in the positive node prior to treatment. Several methods ...have been described for clipped node excision during SLNB after NAT. We assessed the feasibility of intraoperative ultrasound (IOUS)-guided excision of the clipped node during SLNB and investigated whether the accuracy of SLNB is improved.
Methods
After approval by the Institutional Ethics Committee, all breast cancer patients undergoing NAT had an US-visible clip placed in the positive node. The ILINA trial consisted of IOUS-guided excision of the clipped node along with SLNB and axillary lymph node dissection (ALND).
Results
Forty-six patients had a clip placed in the positive node. In two (4.3%) cases, the clip could not be seen prior to surgery and the patient underwent ALND; however, the clipped node was successfully removed by IOUS-guided excision in 44 patients. Thirty-five patients (79.5%) underwent SLNB along with IOUS-guided excision of the clipped node and ALND, and were subsequently included in the ILINA trial. Nine patients were not included (five patients with SLNB only and four patients with ALND without SLNB). SLNB matched the clipped node in 27 (77%) patients. The false negative rate for the ILINA protocol was 4.1% (95% confidence interval 0.1–21.1%).
Conclusions
IOUS-guided excision of the axillary clipped node after NAT was feasible, safe, and successful in 100% of cases. The ILINA trial is accurate in predicting axillary nodal status after NAT.
PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We ...hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient-derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal-regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture.
Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs.
Practice indicators (PI) measure provided care making use of real-world data. This study describes trends and variations in adjuvant treatment of early breast cancer (EBC) using the European Society ...of Breast Cancer Specialists (EUSOMA) database.
The analysis was conducted on anonymous cumulative data registered by 56 certified breast centres, which all entered at least 500 new diagnoses in the database in the 10-year period 2010–2019. Practice trends of radiotherapy, endocrine treatment, chemotherapy, and anti-HER2 therapy were evaluated. The association with age group (<50, 50–69, ≥70) and geographical area of the centre (Northern, Central, Southern Europe; NE, CE, SE) was assessed with the Pearson Chi2 test for independence in contingency tables.
In total, 150,150 patients with EBC were selected. Overall, radiotherapy was administered more frequently in NE centres, and conversely, endocrine, chemo-, and anti-HER2 therapy were used more frequently in SE centres (p<0.001). 46.9% of the pN1 patients received postmastectomy radiotherapy, with significant differences by age and geographical region (p < 0.001). Adjuvant endocrine treatment for endocrine-sensitive carcinoma in situ was administered in 46.1%, with a decreasing trend during the study period (58.5–34.5%; p < 0.001). Anti-HER2 therapy was delivered in 75.6% of all patients with HER2BC T1a/bN0, patients older than 70 received anti-HER2 in 67.6% in SE compared to 31.3% in NE centres.
Important variations in EBC management between European certified breast centres have been demonstrated. PI using real-world data can help to monitor, evaluate, and eventually guide and align good clinical practice in the management of breast cancer.
•Real-world data on early breast cancer management in Europe are informative.•Postmastectomy radiotherapy for pN1 breast cancer varies noticeably across Europe.•Adjuvant endocrine therapy for in situ breast cancer varies noticeably across Europe.•HER2 therapy is used in 76% of patients with HER2+ breast cancer ≤1 cm and N0.
The past two decades have seen an unprecedented trend towards de-escalation of surgical therapy in the setting of early BC, the most prominent examples being the reduction of re-excision rates for ...close surgical margins after breast-conserving surgery and replacing axillary lymph node dissection by less radical procedures such as sentinel lymph node biopsy (SLNB). Numerous studies confirmed that reducing the extent of surgery in the upfront surgery setting does not impact locoregional recurrences and overall outcome. In the setting of primary systemic treatment, there is an increased use of less invasive staging strategies reaching from SLNB and targeted lymph node biopsy (TLNB) to targeted axillary dissection (TAD). Omission of any axillary surgery in the presence of pathological complete response in the breast is currently being investigated in clinical trials. On the other hand, concerns have been raised that surgical de-escalation might induce an escalation of other treatment modalities such as radiation therapy. Since most trials on surgical de-escalation did not include standardized protocols for adjuvant radiotherapy, it remains unclear, whether the effect of surgical de-escalation was valid in itself or if radiotherapy compensated for the decreased surgical extent. Uncertainties in scientific evidence may therefore lead to escalation of radiotherapy in some settings of surgical de-escalation. Further, the increasing rate of mastectomies including contralateral procedures in patients without genetic risk is alarming. Future studies of locoregional treatment strategies need to include an interdisciplinary approach to integrate de-escalation approaches combining surgery and radiotherapy in a way that promotes optimal quality of life and shared decision-making.
The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5–96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive ...chemotherapy. We present long-term follow-up results together with an exploratory analysis by age.
MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18–70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0–1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical–pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005–002625–31. Recruitment is complete and further long-term follow-up is ongoing.
Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8·7 years (IQR 7·8–9·7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95·1% (95% CI 93·1–96·6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92·0% (95% CI 89·6–93·8) for chemotherapy versus 89·4% (86·8–91·5) for no chemotherapy (hazard ratio 0·66; 95% CI 0·48–0·92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 90.7% of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93·6% (95% CI 89·3–96·3) with chemotherapy versus 88·6% (83·5–92·3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5·0 percentage points SE 2·8, 95% CI −0·5 to 10·4) and 90·2% (86·8–92·7) versus 90·0% (86·6–92·6) in 894 women older than 50 years (absolute difference 0·2 percentage points 2·1, −4·0 to 4·4). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91·7% (95% CI 88·1–94·3) with chemotherapy and 89·2% (85·2–92·2) without chemotherapy in 699 node-negative patients (absolute difference 2·5 percentage points SE 2·3, 95% CI −2·1 to 7·2) and 91·2% (87·2–94·0) versus 89·9% (85·8–92·8) for 658 patients with one to three positive nodes (absolute difference 1·3 percentage points 2·4, −3·5 to 6·1).
With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2·6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy.
European Commission Sixth Framework Programme.
The non-radioactive method that uses the magnetic tracer (SPIO/Sienna) has shown to be a feasible technique for the SLN detection in breast cancer patients. The aim of this study is to assess the ...efficacy of different doses of a new magnetic tracer Sienna XP (Magtrace) compared to Tc-99 m and to evaluate its non-inferiority.
Patients diagnosed with early-stage breast cancer cT1-3 N0, from October 2016 to August 2018 were eligible and consecutively randomized to three different doses of new SPIO used: group 1 (1 mL), group 2 (1.5 mL) and group 3 (2 mL).
A total of 135 patients were included in the study, 45 in each group. Detection of SLNs with the three doses of Sienna XP (1 mL, 1.5 mL and 2 mL) showed non-inferior rates compared to the conventional technique with radiotracer (p = 0.654). Concordance by patients with SLN positive was 100% for all groups.
83 (70.3%) patients reported skin staining at one month postoperatively, significantly lower in group 1 (p = 0.042). At 6 months follow up, group 1 remains with significantly lower skin discoloration (p = 0,01). In multivariate analysis, dose of 2 mL showed statistically significant for the skin staining. The majority of patients (70%) felt that skin discoloration does not represent a problem.
The use of the Sienna XP magnetic tracer at 1 mL is not inferior to higher doses of magnetic tracer neither is inferior to radiotracer. 1 mL of magnetic tracer resulted in significantly less skin discoloration compared to higher doses.
Abstract
Background
Superparamagnetic iron oxide nanoparticles (SPIO) have been used as a tracer for sentinel lymph node (SLN) localization in breast cancer, demonstrating comparable performance to ...the combination of radioisotope (RI) and blue dye (BD).
Methods
A systematic literature search and meta-analysis with subgroup and meta-regression analysis were undertaken to update the available evidence, assess technique evolution, and define knowledge gaps. Recommendations were made using the GRADE approach.
Results
In 20 comparative studies, the detection rate was 97.5 per cent for SPIO and 96.5 per cent for RI ± BD (risk ratio 1.006, 95 per cent c.i. 0.992 to 1.019; P = 0.376, high-certainty evidence). Neoadjuvant therapy, injection site, injection volume or nodal metastasis burden did not affect the detection rate, but injection over 24 h before surgery increased the detection rate on meta-regression. Concordance was 99.0 per cent and reverse concordance 97.1 per cent (rate difference 0.003, 95 per cent c.i. −0.009 to 0.015; P = 0.656, high-certainty evidence). Use of SPIO led to retrieval of slightly more SLNs (pooled mean 1.96 versus 1.89) with a higher nodal detection rate (94.1 versus 83.5 per cent; RR 1.098, 1.058 to 1.140; P < 0.001; low-certainty evidence). In meta-regression, injection over 24 h before surgery increased the SPIO nodal yield over that of RI ± BD. The skin-staining rate was 30.8 per cent (very low-certainty evidence), and possibly prevented with use of smaller doses and peritumoral injection.
Conclusion
The performance of SPIO is comparable to that of RI ± BD. Preoperative injection increases the detection rate and nodal yield, without affecting concordance. Whether skin staining and MRI artefacts are reduced by lower dose and peritumoral injection needs to be investigated.
The magnetic technique for sentinel lymph node (SLN) biopsy has gained interest and popularity in recent years. In this comprehensive systematic review and meta-analysis, the performance of the magnetic technique was comparable to that of the isotope and blue dye combination for SLN detection (97.5 versus 96.5 per cent; risk ratio 1.006, 95 per cent c.i. 0.992 to 1.019; P = 0.376). The magnetic technique provides flexibility and facilitates logistics. Further research should focus on the existing knowledge gaps, namely expansion of novel techniques such as delayed SLN biopsy and reduction of the risk of skin staining and artefacts on postoperative MRI.
PDF
