Surgical Management of the Axilla in Clinically Node-Positive Breast Cancer Patients Converting to Clinical Node Negativity through Neoadjuvant Chemotherapy: Current Status, Knowledge Gaps, and Rationale for the EUBREAST-03 AXSANA Study.

In the last two decades, surgical methods for axillary staging in breast cancer patients have become less extensive, and full axillary lymph node dissection (ALND) is confined to selected patients. In initially node-positive patients undergoing neoadjuvant chemotherapy, however, the optimal management remains unclear. Current guidelines vary widely, endorsing different strategies. We performed a literature review on axillary staging strategies and their place in international recommendations. This overview defines knowledge gaps associated with specific procedures, summarizes currently ongoing clinical trials that address these unsolved issues, and provides the rationale for further research. While some guidelines have already implemented surgical de-escalation, replacing ALND with, e.g., sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD) in cN+ patients converting to clinical node negativity, others recommend ALND. Numerous techniques are in use for tagging lymph node metastasis, but many questions regarding the marking technique, i.e., the optimal time for marker placement and the number of marked nodes, remain unanswered. The optimal number of SLNs to be excised also remains a matter of debate. Data on oncological safety and quality of life following different staging procedures are lacking. These results provide the rationale for the multinational prospective cohort study AXSANA initiated by EUBREAST, which started enrollment in June 2020 and aims at recruiting 3000 patients in 20 countries (NCT04373655; Funded by AGO-B, Claudia von Schilling Foundation for Breast Cancer Research, AWOgyn, EndoMag, Mammotome, and MeritMedical).

Prepectoral direct-to-implant breast reconstruction with complete ADM or synthetic mesh coverage - 36-Months follow-up in 200 reconstructed breasts.

BACKGROUND: Prepectoral implant placement is an innovative option for breast reconstruction, due to multiple advantages over subpectoral implant placement. The adoption of various ADMs and meshes supports the utilization of the prepectoral technique. METHODS: 200 breasts were reconstructed with prepectoral implant placement after nipple-sparing mastectomy in a one-stage direct-to-implant procedure. The implants were completely covered and fixed with porcine ADMs (Strattice™ or Artia™), or with synthetic meshes (TIGR®). The pectoralis major muscle was not detached at all and kept intact entirely. RESULTS: Minor complications included minimal nipple necrosis without further intervention and complete healing in 14 breasts (7.0%). Major complications comprised implant loss due to skin necrosis and wound infection in 7 breasts (3.5%), and hematoma with revision surgery in 8 breasts (4.0%). At a mean follow-up of 36 months cosmetic results were excellent and good in 180 breasts (90.0%), sufficient in 13 breasts (6.5%) and insufficient in 7 breasts (3.5%). Breast animation deformity and implant displacement could not be observed, while implant rotation was documented in 5 breasts (2.5%). Capsular contractures grade III or IV could not be observed neither in patients with previous radiotherapy nor in patients with radiotherapy to the reconstructed breast. CONCLUSIONS: The single-stage direct-to-implant prepectoral implant placement after NSM with complete coverage of the implant with ADM or synthetic mesh represents a novel and feasible technique for breast reconstruction. This technique provides an alternative to the subpectoral implant placement with excellent cosmetic results avoiding the disadvantages of the subpectoral implant placement.

National Breast Screening Programs across Europe.

BACKGROUND: Mammography screening programs in Europe revealed a 25-30% breast cancer mortality reduction in women between 50 and 74 years. Early cancer detection and less radical treatment in dedicated multidisciplinary breast centers have improved breast cancer care. Breast population-based screening (persons are individually identified and personally invited to attend screening) is intended to detect breast cancer at an early stage to enable lower mortality rates. METHODS: The status of implementation of cancer screening programs among European countries, quality parameters and possible differences will be reviewed. RESULTS: Implementation of the recommended maximum age range was adopted in most programs. Almost all the European countries established digital mammography as the method of screening instead of screen-film mammography. Inequalities in implementation of cancer screening in the European Union have been observed. CONCLUSION: Improvement of data quality and mortality registries linked to the screening programs are needed.

Current Status and Future Perspectives of Axillary Management in the Neoadjuvant Setting.

Axillary surgery has undergone considerable changes in recent years, especially in relation to patients who undergo neoadjuvant chemotherapy (NACT). Due to constantly decreasing rates of recurrence and death from breast cancer, modern surgical strategies aim at de-escalating the extent of local treatment and avoiding unnecessary procedures. This relates especially to lymph node surgery which is associated with considerable morbidity. In patients who initially present with clinically node-negative disease, sentinel lymph node biopsy (SLNB) is increasingly performed after NACT. The determination of the post-NACT nodal status does not only spare patients from additional surgery but also allows the assessment of pathologic complete response which is increasingly becoming an important tool for treatment planning. Since more than 70% of these patients have a ypN0 status after NACT, future trials will aim to identify patients who might be spared any axillary surgery after NACT. In patients who initially present with positive lymph nodes, the success rates of SLNB in terms of detection and accuracy are less favorable compared to those in patients who undergo primary surgery. The clinical significance of this is unclear. To reduce unnecessary axillary dissection in patients with cN1ycN0 status, prospective outcome data after SLNB without further lymph node removal are urgently needed. Improvements in surgical technique by localizing positive nodes at the time of diagnosis and removing them in a targeted surgical procedure (targeted axillary dissection) are under evaluation. Risk assessment and patient selection (including gene expression profiles) might be other ways of safely omitting axillary dissection.

Lymph Nodes in Breast Cancer - What Can We Learn from Translational Research?

Clinical observations about lack of survival benefit after extensive axillary surgery and biological discordance between primary breast tumors and axillary lymph nodes raise the question of the actual metastatic potential of axillary nodal disease. The exploration of intratumoral heterogeneity and detection of genomic differences between the primary and lymph nodes indicate some similarity between the number of mutations in synchronous axillary node metastases and those in the primary lesion, suggesting a favorable prognosis. The hematogenous route of metastasis needs to be considered in findings of different subclones between nodal and distant metastases. Modern tools such as whole-genome sequencing applied in multiple tumor areas may guide more precisely the extent of axillary surgery.

KCNJ3 is a new independent prognostic marker for estrogen receptor positive breast cancer patients.

Numerous studies showed abnormal expression of ion channels in different cancer types. Amongst these, the potassium channel gene KCNJ3 (encoding for GIRK1 proteins) has been reported to be upregulated in tumors of patients with breast cancer and to correlate with positive lymph node status. We aimed to study KCNJ3 levels in different breast cancer subtypes using gene expression data from the TCGA, to validate our findings using RNA in situ hybridization in a validation cohort (GEO ID GSE17705), and to study the prognostic value of KCNJ3using survival analysis. In a total of > 1000 breast cancer patients of two independent data sets we showed a) that KCNJ3 expression is upregulated in tumor tissue compared to corresponding normal tissue (p < 0.001), b) that KCNJ3 expression is associated with estrogen receptor (ER) positive tumors (p < 0.001), but that KCNJ3 expression is variable within this group, and c) that ER positive patients with high KCNJ3 levels have worse overall (p < 0.05) and disease free survival probabilities (p < 0.01), whereby KCNJ3 is an independent prognostic factor (p <0.05). In conclusion, our data suggest that patients with ER positive breast cancer might be stratified into high risk and low risk groups based on the KCNJ3 levels in the tumor.

Standardization of pathologic evaluation and reporting of postneoadjuvant specimens in clinical trials of breast cancer: recommendations from an international working group.

Neoadjuvant systemic therapy is being used increasingly in the treatment of early-stage breast cancer. Response, in the form of pathological complete response, is a validated and evaluable surrogate end point of survival after neoadjuvant therapy. Thus, pathological complete response has become a primary end point for clinical trials. However, there is a current lack of uniformity in the definition of pathological complete response. A review of standard operating procedures used by 28 major neoadjuvant breast cancer trials and/or 25 sites involved in such trials identified marked variability in specimen handling and histologic reporting. An international working group was convened to develop practical recommendations for the pathologic assessment of residual disease in neoadjuvant clinical trials of breast cancer and information expected from pathology reports. Systematic sampling of areas identified by informed mapping of the specimen and close correlation with radiological findings is preferable to overly exhaustive sampling, and permits taking tissue samples for translational research. Controversial areas are discussed, including measurement of lesion size, reporting of lymphovascular space invasion and the presence of isolated tumor cells in lymph nodes after neoadjuvant therapy, and retesting of markers after treatment. If there has been a pathological complete response, this must be clearly stated, and the presence/absence of residual ductal carcinoma in situ must be described. When there is residual invasive carcinoma, a comment must be made as to the presence/absence of chemotherapy effect in the breast and lymph nodes. The Residual Cancer Burden is the preferred method for quantifying residual disease in neoadjuvant clinical trials in breast cancer; other methods can be included per trial protocols and regional preference. Posttreatment tumor staging using the Tumor-Node-Metastasis system should be included. These recommendations for standardized pathological evaluation and reporting of neoadjuvant breast cancer specimens should improve prognostication for individual patients and allow comparison of treatment outcomes within and across clinical trials.

Reproducibility of residual cancer burden for prognostic assessment of breast cancer after neoadjuvant chemotherapy.

The residual cancer burden index was developed as a method to quantify residual disease ranging from pathological complete response to extensive residual disease. The aim of this study was to evaluate the inter-Pathologist reproducibility in the residual cancer burden index score and category, and in their long-term prognostic utility. Pathology slides and pathology reports of 100 cases from patients treated in a randomized neoadjuvant trial were reviewed independently by five pathologists. The size of tumor bed, average percent overall tumor cellularity, average percent of the in situ cancer within the tumor bed, size of largest axillary metastasis, and number of involved nodes were assessed separately by each pathologist and residual cancer burden categories were assigned to each case following calculation of the numerical residual cancer burden index score. Inter-Pathologist agreement in the assessment of the continuous residual cancer burden score and its components and agreement in the residual cancer burden category assignments were analyzed. The overall concordance correlation coefficient for the agreement in residual cancer burden score among pathologists was 0.931 (95% confidence interval (CI) 0.908-0.949). Overall accuracy of the residual cancer burden score determination was 0.989. The kappa coefficient for overall agreement in the residual cancer burden category assignments was 0.583 (95% CI 0.539-0.626). The metastatic component of the residual cancer burden index showed stronger concordance between pathologists (overall concordance correlation coefficient=0.980; 95% CI 0.954-0.992), than the primary component (overall concordance correlation coefficient=0.795; 95% CI 0.716-0.853). At a median follow-up of 12 years residual cancer burden determined by each of the pathologists had the same prognostic accuracy for distant recurrence-free and survival (overall concordance correlation coefficient=0.995; 95% CI 0.989-0.998). Residual cancer burden assessment is highly reproducible, with reproducible long-term prognostic significance.

IOERT as anticipated tumor bed boost during breast-conserving surgery after neoadjuvant chemotherapy in locally advanced breast cancer--results of a case series after 5-year follow-up.

To evaluate retrospectively rates of local (LCR) and locoregional tumor control (LRCR) in patients with locally advanced breast cancer (LABC) who were treated with preoperative chemotherapy (primary systemic treatment, PST) followed by breast-conserving surgery (BCS) and either intraoperative radiotherapy with electrons (IOERT) preceding whole-breast irradiation (WBI) (Group 1) or with WBI followed by an external tumor bed boost (electrons or photons) instead of IOERT (Group 2). From 2002 to 2007, 83 patients with clinical Stage II or III breast cancer were enrolled in Group 1 and 26 in Group 2. All patients received PST followed by BCS and axillary lymph node dissection. IOERT boosts were applied by single doses of 9 Gy (90% reference isodose) versus external boosts of 12 Gy (median dose range, 6-16) in 2 Gy/fraction (ICRU). WBI in both groups was performed up to total doses of 51-57 Gy (1.7-1.8 Gy/fraction). The respective median follow-up times for Groups 1 and 2 amount 59 months (range, 3-115) and 67.5 months (range, 13-120). Corresponding 6-year rates for LCR, LRCR, metastasis-free survival, disease-specific survival and overall survival were 98.5, 97.2, 84.7, 89.2 and 86.4% for Group 1 and 88.1, 88.1, 74, 92 and 92% for Group 2, respectively, without any statistical significances. IOERT as boost modality during BCS in LABC after PST shows a trend to be superior in terms of LCR and LRCR in comparison with conventional boosts.

Prepectoral implant placement and complete coverage with porcine acellular dermal matrix: a new technique for direct-to-implant breast reconstruction after nipple-sparing mastectomy.

BACKGROUND: Nipple-sparing mastectomy (NSM) and implant-based breast reconstruction are increasingly replacing conventional mastectomy for risk-reducing purposes in high-risk patients as well as for therapeutic purposes in breast cancer patients. For implant-based breast reconstruction, generally, subpectoral implant placement with partial detachment of the pectoralis major muscle (PMM) is recommended. The advantage of a potentially better cosmetic result has to be balanced with the disadvantages, such as partial injury of the PMM with subsequent muscular deficit, breast animation, and postoperative pain. We hypothesize that prepectoral implant placement and complete coverage with a porcine acellular dermal matrix (ADM) may provide an alternative to subpectoral implant placement with an excellent cosmetic result, avoiding the disadvantages of subpectoral implant placement. METHODS: In a total of 22 breasts in 13 patients (nine bilateral and four unilateral), NSM and immediate direct-to-implant breast reconstruction were performed with prepectoral implant placement. The implant was completely covered by a porcine ADM, which was sutured to the fascia of the PMM and the inframammary fold to keep the implant in place. RESULTS: The cosmetic results were excellent and patients were fully satisfied at a median follow-up of 6 months. Breast animation and implant dislocation could not be observed. Implant rims were not visible, and capsular contractures grade III and IV could not be observed. The complications comprised minimal nipple necrosis in two patients and hemorrhage with evacuation in one patient. CONCLUSION: Prepectoral implant placement and complete coverage with porcine ADM represents a novel approach and a feasible alternative to subpectoral implant placement after NSM and implant-based breast reconstruction for patients who prefer their PMM to be left intact.

Bone health in breast cancer patients: a comprehensive statement by CECOG/SAKK Intergroup.

Bone is the most common site of distant metastases in breast cancer that can cause severe and debilitating skeletal related events (SRE) including hypercalcemia of malignancy, pathologic fracture, spinal cord compression and the need for palliative radiation therapy or surgery to the bone. SRE are associated with substantial pain and morbidity leading to frequent hospitalization, impaired quality of life and poor prognosis. The past 25 years of research on the pathophysiology of bone metastases led to the development of highly effective treatment options to delay or prevent osseous metastases and SRE. Management of bone metastases has become an integral part of cancer treatment requiring expertise of multidisciplinary teams of medical and radiation oncologists, surgeons and radiologists in order to find an optimal treatment for each individual patient. A group of international breast cancer experts attended a Skeletal Care Academy Meeting in November 2012 in Istanbul and discussed current preventive measures and treatment options of SRE, which are summarized in this evidence-based consensus for qualified decision- making in clinical practice.

First experience using contrast-enhanced ultrasound to evaluate vascularisation of acellular dermal matrices after implant-based breast reconstruction.

UNLABELLED: Acellular dermal matrices (ADM) have been used frequently in therapeutic and prophylactic breast procedures. To date there have been no reports on vascularisation of ADMs and formation of tissue around them as seen with modern non-invasive imaging techniques such as contrast-enhanced ultrasound (CEUS). In this case series, we used CEUS to investigate the features of ADM in relation to vascular ingrowth and scaffold for "new" tissue formation. This is a retrospective evaluation of patients who underwent successful skin- and nipple-sparing mastectomy (SSM, NSM) with immediate IBBR using ADM from May 31, 2010, through December 28, 2012. Over a 24-month period, 16 patients, with an average age of 44 years (range 27-70 years), were evaluated with CEUS. No contrast agent allergies or side effects were reported for the ultrasound examination. After contrast agent injection (1-18 months postoperatively), homogeneous normal enhancement in the ADM and peripheral region with physiological tissue formation was seen in all patients. In this small study, the most obvious contribution of CEUS is the in vivo evaluation of vascular ingrowth and tissue formation after IBBR with ADM after follow-up of 1-18 months postoperatively. LEVEL OF EVIDENCE III: Retrospective cohort or comparative study; case-control study; or systematic review of these studies.

Using molecular profiles to tailor treatment in breast cancer: are they ready for prime time?

PURPOSE OF REVIEW: In this article, recent developments with molecular profiling in breast cancer and future directions will be highlighted. RECENT FINDINGS: Gene-expression profiling revealed four major biologic subtypes that reflect intertumoral heterogeneity of breast cancer and have led to the development of prognostic tools to facilitate adequate treatment in early breast cancer. A number of commercially available prognostic tests have been introduced for implementation in clinical routine. Also, predictive tools and approaches to characterize molecular portraits of metastatic breast cancer in order to overcome treatment resistance have been investigated. Efforts to identify the quantity and quality of clonal selection and genomic variability through modern genomic profiling led successfully to new insights into targeted treatment with more effective drugs and the promise to overcome resistance. SUMMARY: Multigene approaches and novel microarray platforms such as the next-generation sequencing technology are feasible in clinical practice in order to assess the prognosis more precisely and to identify new molecular targets for developing more effective drugs in the near future.

German, Austrian and Swiss consensus conference on the diagnosis and local treatment of the axilla in breast cancer.

The German, Austrian and Swiss (D.A.CH) Societies of Senology gathered together in 2012 to address dwelling questions regarding axillary clearance in breast cancer patients. The Consensus Panel consisted of 14 members of these societies and included surgical oncologists, gynaecologists, pathologists and radiotherapists. With regard to omitting axillary lymph node dissection in sentinel lymph node macrometastases, the Panel consensually accepted this option for low-risk patients only. A simple majority voted against extending radiotherapy to the axilla after omitting axillary dissection in N1 disease. Consensus was yielded for the use of axillary ultrasound and prospective registers for such patients in the course of follow-up. The questions regarding neoadjuvant therapy and the timing of sentinel lymph node biopsy failed to yield consensus, yet both options (before or after) are possible in clinically node-negative disease.

The positive non-sentinel status is not the main decisional factor for chemotherapy assignment in breast cancer with micrometastatic disease in the sentinel lymph node.

BACKGROUND: Surgical and systemic treatment modalities for breast cancer (BC) patients with micrometastatic disease in the sentinel lymph node biopsy (SNB) are controversial. The aim of this study was to evaluate decisional factors associated with assignment of adjuvant chemotherapy (CT). PATIENTS AND METHODS: In a retrospective multicentric European study we evaluated cases of primary BC patients who underwent SNB. Logistic regression (LR) and recursive partitioning analyses (RPA) were performed to determine factors associated with CT. RESULTS: Of the 172 patients with micrometastatic disease, 39.5% received adjuvant CT. In the group treated with CT, patients tended to be younger (P = 0.001), with higher grade (P = 0.001) and HER2 positive tumors (P = 0.006) compared to patients without CT. In multivariate LR, age (P = 0.0027), high grading (P = 0.01) HER2 positivity (P = 0.03), and positive non-SN status (P = 0.03) were significantly associated with CT. RPA demonstrated that tumor grade, and not the non-SN status, was the first split in the partition tree followed by HER2 status, and non-SN status influencing the probability for CT administration. CONCLUSION: High tumor grade is the main decisional factor followed by HER2 positivity and then by the positive non-SN status for CT in micrometastatic disease in the SN.

Genomic index of sensitivity to endocrine therapy for breast cancer.

PURPOSE: We hypothesize that measurement of gene expression related to estrogen receptor α (ER; gene name ESR1) within a breast cancer sample represents intrinsic tumoral sensitivity to adjuvant endocrine therapy. METHODS: A genomic index for sensitivity to endocrine therapy (SET) index was defined from genes coexpressed with ESR1 in 437 microarray profiles from newly diagnosed breast cancer, unrelated to treatment or outcome. The association of SET index and ESR1 levels with distant relapse risk was evaluated from microarrays of ER-positive breast cancer in two cohorts who received 5 years of tamoxifen alone as adjuvant endocrine therapy (n = 225 and 298, respectively), a cohort who received neoadjuvant chemotherapy followed by tamoxifen and/or aromatase inhibition (n = 122), and two cohorts who received no adjuvant systemic therapy (n = 208 and 133, respectively). RESULTS: The SET index (165 genes) was significantly associated with distant relapse or death risk in both tamoxifen-treated cohorts (hazard ratio [HR] = 0.70, 95% CI, 0.56 to 0.88, P = .002; and HR = 0.76, 95% CI, 0.63 to 0.93, P = .007) and in the chemo-endocrine-treated cohort (HR = 0.19; 95% CI, 0.05 to 0.69, P = .011) independently from pathologic response to chemotherapy, but was not prognostic in two untreated cohorts. No distant relapse or death was observed after tamoxifen alone if node-negative and high SET or after chemo-endocrine therapy if intermediate or high SET. CONCLUSION: The SET index of ER-related transcription predicted survival benefit from adjuvant endocrine therapy, not inherent prognosis. Prior chemotherapy seemed to enhance the efficacy of adjuvant endocrine therapy related to SET index.

Higher parity and shorter breastfeeding duration: association with triple-negative phenotype of breast cancer.

BACKGROUND: The combination of increased parity and shorter breastfeeding duration might increase the odds of the least differentiated triple-negative breast cancer (BC) phenotype, theoretically because an expanded progenitor cell population from each pregnancy would incompletely differentiate postpartum. METHODS: Subjects consisted of a consecutive case series of 2473 women treated for invasive breast cancer between 2001 and 2006. Breast cancer phenotype (triple-negative BC, vs non-triple-negative BC) was compared with reproductive and demographic information. Odds ratios (OR) with 95% confidence intervals (CIs) for the association of breastfeeding duration (months per child) and parity with triple-negative BC were calculated after adjusting for ethnicity, age at menarche, family history, and age at diagnosis. RESULTS: Compared with non-triple-negative BC, triple-negative BC was associated with shorter duration of breastfeeding per child (OR, 0.93; 95% CI, 0.90-0.97) and with higher parity (OR, 1.12; 95% CI, 1.06-1.20). By using multivariate logistic regression, triple-negative BC was independently associated with higher parity (OR, 2.76 [95% CI, 1.86-4.08] if ≥3 live births; OR, 1.89 [95% CI, 1.30-2.74] if ≤2 live births vs nulliparae), breastfeeding duration (OR, 0.55 [95% CI, 0.41-0.74] if >2 mo/child and OR, 0.58 [95% CI, 0.42-0.82] if ≤2 mo/child vs none), African American ethnicity (OR, 2.10; 95% CI, 1.52-2.92), and younger age at diagnosis (OR, 3.02 [95% CI, 2.03-4.47] if ≤40 years vs >60 years). CONCLUSIONS: Among women with invasive breast cancer, higher parity and the absence or short duration of breastfeeding were independently associated with triple-negative BC. Any duration of breastfeeding was found to be associated with lower probability of triple-negative BC, and the odds of this phenotype decreased with increasing duration of breastfeeding.