Local treatment of the axilla in clinically node-negative (cN0) early breast cancer patients with routine sentinel lymph node biopsy (SLNB) is debated after publication of ACOSOG Z0011 data in 2010. ...Currently, prospective randomized surgical trials investigating the omission of SLNB in upfront breast-conserving surgery (BCS) and in the neoadjuvant setting, respectively. Several prospective randomized trials (SOUND, INSEMA, BOOG 2013–08, and NAUTILUS) with axillary observation alone versus SLNB in cN0 patients and primary BCS have primary objectives to evaluate oncologic safety when omitting SLNB. The Italian SOUND trial was the earliest to open in 2012 and has completed accrual in 2017. First oncologic outcome data are expected soon for SOUND and at the end of 2024 for INSEMA. Improvements in systemic treatments for breast cancer have increased the rates of pathologic complete response (pCR) in patients receiving neoadjuvant systemic therapy (NAST), offering the opportunity to de-escalate surgery in patients who have a pCR. Two prospective single-arm trials (EUBREAST-01, ASICS) include only patients with the highest likelihood of having a pCR after NAST (triple-negative or HER2-positive breast cancer) and type of surgery will be defined according to the response to NAST rather than on the classical T and N status. The ongoing trials will hopefully help us to understand whether we might take the best therapeutic decisions without the pathologic evaluation of nodal status.
•Discussion of background for de-escalation strategies in axillary surgery.•Available current guidelines in early-stage invasive breast cancer.•Overview of randomized clinical trials with upfront breast-conserving surgery.•Overview of ongoing single-arm trials in the neoadjuvant setting.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Currently, axillary surgery for breast cancer is considered only as staging procedure, since the risk of developing metastasis depends on the biological behavior of the primary. The postsurgical ...therapy should be considered on the basis of biologic tumor characteristics rather than nodal involvement. Improvements in systemic treatments for breast cancer have increased the rates of pathologic complete response (pCR) in patients receiving neoadjuvant systemic therapy (NAST), offering the opportunity to de-escalate surgery in patients who have a pCR. European Breast Cancer Research Association of Surgical Trialists (EUBREAST)-01 is a clinical trial in which only patients with the highest likelihood of having a pCR after NAST (triple-negative or HER2-positive breast cancer) will be included and type of surgery will be defined according to the response to NAST rather than on the classical T (for tumor size in the breast) and N (for axillary lymph node involvement) status. In the discussed trial, axillary surgery will be eliminated completely (no axillary sentinel lymph node biopsy) for initially clinical node-negative (cN0) patients with radiologic complete remission and a breast pCR in the lumpectomy specimen. The trial design is a multicenter single-arm study with a limited number of patients (
= 267), which might give practice-changing results in a short period of time, sparing the time and the costs of a randomized comparison.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Observational studies suggested that luteinizing hormone-releasing hormone agonists (LHRHa) might prevent premature ovarian failure resulting from adjuvant chemotherapy in premenopausal patients. We ...aimed to test the efficacy of ovarian function preservation with the LHRHa goserelin in patients with breast cancer.
In a prospective, randomized, open-label, controlled multicenter study, 60 patients younger than age 46 years with hormone-insensitive breast cancer were allocated to receive anthracycline/cyclophosphamide (with or without taxane) -based neoadjuvant chemotherapy with or without goserelin. The first goserelin injection was administered at least 2 weeks before the first chemotherapy cycle, continuing at 3.6 mg subcutaneously every 4 weeks until the end of the last cycle. The primary objective was the reappearance of normal ovarian function, defined as two consecutive menstrual periods within 21 to 35 days at 6 months after end of chemotherapy.
Fifty-three patients (88.3%) experienced temporary amenorrhea (93.3% with v 83.3% without goserelin). No significant difference was observed regarding the reappearance of menstruation at 6 months after chemotherapy (70.0% with v 56.7% without goserelin; difference of 13.3%; 95% CI, -10.85 to 37.45; P = .284). All but one evaluable patient reported regular menses at 2 years after chemotherapy. Time to restoration of menstruation was 6.8 months (95% CI, 5.2 to 8.4) with goserelin and 6.1 months (95% CI, 5.3 to 6.8) without goserelin (P = .304). Chemotherapy resulted in a decreased ovarian reserve measured by inhibin B and anti-Müllerian hormone during follow-up, supporting the other findings.
Premenopausal patients with breast cancer receiving goserelin simultaneously with modern neoadjuvant chemotherapy did not experience statistically significantly less amenorrhea 6 months after end of chemotherapy compared with those receiving chemotherapy alone.
The presence of tumor-infiltrating lymphocytes has been associated with prognosis and chemotherapy response, particularly in high-risk breast cancer subtypes. There is limited data so far as to (i) ...how tumor-infiltrating lymphocyte (TIL) measurements correlate with genomic measurements such as the Oncotype DX Recurrence Score® and (ii) whether the survival impact of TIL measurements varies according to different adjuvant systemic therapies.
The WSG PlanB trial compared an anthracycline-free chemotherapy regimen (6x docetaxel/cyclophosphamide, TC) to an anthracycline-taxane sequence (4xEC followed by 4x docetaxel) in patients with intermediate-risk, HER2-negative early breast cancer (EBC). Patients with HR-positive HER2-negative EBC were further stratified to receive endocrine therapy alone vs. chemotherapy followed by endocrine therapy based on Recurrence Score results and nodal status. In this analysis, three independent observers quantified and categorized the presence of TILs among tumor samples from patients in PlanB. TIL measurements were correlated with clinical/pathological parameters and treatment outcome overall and according to the treatment arm.
Disease-free survival (DFS) rates were significantly better (p = .04) in HR-negative patients with high vs. intermediate TIL levels and were higher in low vs. intermediate TIL patients, however with borderline significance only (p = .06). There were no significant differences among TIL categories in HR+ patients. High RS categories, HR-negative status, and high KI67 were independently and significantly associated with high TIL categories. There was no significant impact of TIL category on DFS in patients treated by endocrine therapy only; however, in patients receiving chemotherapy, DFS in the intermediate TIL category was lower than that in the other categories.
Although the presence of high TILs is associated with negative prognostic parameters such as high KI67 and HR-negative status among patients with HR-positive HER2-negative EBC, patients with high TILs show a favorable 5-year DFS in both HR-positive/HER2-negative and triple-negative breast cancer.
Purpose
In clinically node-positive breast cancer patients receiving neoadjuvant systemic therapy (NST), nodal metastases can be initially marked and then removed during surgical axillary staging. ...Marking methods vary significantly in terms of feasibility and cost. The purpose of the extended TATTOO trial was to report on the false-negative rate (FNR) of the low-cost method carbon tattooing.
Methods
The international prospective single-arm TATTOO trial included clinically node-positive breast cancer patients planned for NST from November 2017 to January 2021. For the present analysis, patients who received both the targeted procedure with or without an additional sentinel lymph node (SLN) biopsy
and
a completion axillary lymph node dissection (ALND) were selected. Primary endpoint was the FNR.
Results
Out of 172 included patients, 149 had undergone a completion ALND. The detection rate for the tattooed node was 94.6% (141 out of 149). SLN biopsy was attempted in 132 out of 149 patients with a detection rate of 91.7% (121 out of 132). SLN and tattooed node were identical in 58 out of 121 individuals (47.9%). The combined procedure, i.e. targeted axillary dissection (TAD) was successful in 147 of 149 cases (98.7%). Four out of 65 patients with a clinically node-negative status after NST had a negative TAD but metastases on ALND, corresponding to a FNR of 6.2%. All false-negative TAD procedures were performed in the first 2 years of the trial (2018–2019,
p
= 0.022).
Conclusion
Carbon tattooing is a feasible marking method for TAD with a high detection rate and an acceptably low FNR.
The TATTOO trial was preregistered as prospective trial before initiation at the University of Rostock, Germany (DRKS00013169).
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose: To assess the impact of the removal of the target lymph node (TLN) on therapy after the completion of primary systemic therapy (PST) in initially node-positive breast cancer patients. ...Methods: Pooled data analysis of participants of the prospective CLIP- and TATTOO-study at the University of Rostock was performed. Results: A total of 75 patients were included; 63 of them (84.0%) converted to clinically node-negative after PST. Both TLN and sentinel lymph node (SLN) were identified in 41 patients (51.2%). In five out of 63 patients (7.9%), the TLN was metastatic after PST and the SLN was either tumor-free or not detected. Axillary lymph node dissection (ALND) was conducted in all five patients. In one patient, systemic therapy recommendation was influenced by the TLN; adjuvant radiotherapy was influenced by the TLN in zero patients. For patients with fewer than three removed SLNs, the FNR was 28.6% for the SLN biopsy alone and 7.1% for targeted axillary dissection (TAD). Conclusions: Removal of the TLN in addition to the SLN after PST has only minimal impact on the type of adjuvant systemic therapy and radiotherapy. However, the extent of axillary surgery was relevantly affected and FNR was improved by TAD.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Neoadjuvant chemotherapy (NACT) is a standard approach of the multidisciplinary treatment of breast cancer. Depending on the biological subtype a pathological complete response in the breast (bpCR) ...can be achieved in up to 60% of the patients. However, only limited accuracy can be reached when using imaging for prediction of bpCR prior to surgery. Due to this diagnostic uncertainty, surgery after NACT is considered to be obligatory for all patients in order to either completely remove residual disease or to diagnose a bpCR histologically. The purpose of this trial is to evaluate the accuracy of a vacuum-assisted biopsy (VAB) to diagnose a bpCR after NACT prior to surgery.
This study is a multicenter, confirmative, one-armed, intra-individually-controlled, open, diagnostic trial. The study will take place at 21 trial sites in Germany. Six hundred female patients with breast cancer after completed NACT showing at least a partial response to NACT treatment will be enrolled. A vacuum-assisted biopsy (VAB) guided either by ultrasound or mammography will be performed followed by histopathological evaluation of the VAB specimen before standard, guideline-adherent breast surgery. The study is designed to prove that the false negative rate of the VAB is below 10%.
As a bpCR is becoming a more frequent result after NACT, the question arises whether breast surgery is therapeutically necessary in such cases. To study this subject further, it will be crucial to develop a reliable test to diagnose a bpCR without surgery. During the study we anticipate possible problems in patient recruitment as the VAB intervention does not provide participating patients with any personal benefit. Hence, a proficient informed consent discussion with the patient and a detailed explanation of the study aim will be crucial for patient recruitment. Another critical issue is the histopathological VAB evaluation of a non-tumorous specimen as this may have been taken either from the former tumor region (bpCR) or outside of the (former) tumor region (non-representative VAB, sampling error).
The trial has been registered at clinicaltrials.gov with the identifier NCT02948764 on October 28, 2016 and at the German Clinical Trials Register ( DRKS00011761 ) on February 20, 2017. The date of enrolment of the first participant to the trial was on March 8, 2017.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial.
450 pre-therapeutic, formalin-fixed, paraffin-embedded core ...biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup.
Of 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers of tumor-infiltrating lymphocytes (TILs, P = 0.028). p53 protein overexpression was also linked with imporved survival (P = 0.019).
Our study confirms high TP53 mutation rates in TNBC and HER2-positive breast cancer. Mutations did not predict the response to an intense neoadjuvant chemotherapy in these two molecular breast cancer subtypes.
Purpose
None of the key randomised trials on the omission of axillary lymph node dissection (ALND) in sentinel lymph-positive breast cancer have reported external validity, even though results ...indicate selection bias. Our aim was to assess the external validity of the ongoing randomised SENOMAC trial by comparing characteristics of Swedish SENOMAC trial participants with non-included eligible patients registered in the Swedish National Breast Cancer Register (NKBC).
Methods
In the ongoing non-inferiority European SENOMAC trial, clinically node-negative cT1–T3 breast cancer patients with up to two sentinel lymph node macrometastases are randomised to undergo completion ALND or not. Both breast-conserving surgery and mastectomy are eligible interventions. Data from NKBC were extracted for the years 2016 and 2017, and patient and tumour characteristics compared with Swedish trial participants from the same years.
Results
Overall, 306 NKBC cases from non-participating and 847 NKBC cases from participating sites (excluding SENOMAC participants) were compared with 463 SENOMAC trial participants. Patients belonging to the middle age groups (
p
= 0.015), with smaller tumours (
p
= 0.013) treated by breast-conserving therapy (50.3 versus 47.1 versus 65.2%,
p
< 0.001) and less nodal tumour burden (only 1 macrometastasis in 78.8 versus 79.9 versus 87.3%,
p
= 0.001) were over-represented in the trial population. Time trends indicated, however, that differences may be mitigated over time.
Conclusions
This interim external validity analysis specifically addresses selection mechanisms during an ongoing trial, potentially increasing generalisability by the time full accrual is reached. Similar validity checks should be an integral part of prospective clinical trials.
Trial registration: NCT 02240472, retrospective registration date September 14, 2015 after trial initiation on January 31, 2015
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
PDF
