Do HER2-Low Tumors Have a Distinct Clinicopathologic Phenotype?

BACKGROUND: Breast cancer subtypes, distinguished by hormone receptor (HR) and HER2 status, have different clinicopathologic features. With recognition of the clinical relevance of HER2-low, there is debate as to whether this is a distinct subtype. Our study aimed to determine whether HER2-low breast cancers have specific clinicopathologic features that differ from those of HER2-negative and HER2-positive cancers. PATIENTS AND METHODS: A total of 11,072 patients undergoing upfront surgery from 1998 to 2010 were identified from a single-institution prospectively maintained database. HER2 status was classified by immunohistochemistry (IHC)/fluorescence in situ hybridization (FISH) as HER2 negative (41.2%), HER2 low (45%; IHC 1+ or 2+ with negative FISH), and HER2 positive (13.7%), and stratified by HR status. Univariate (UVA) and multivariable multinomial logistic regression analysis (MVA) were performed to determine associations among variables and subtypes. RESULTS: Compared with HER2-negative tumors, HER2 low was associated with lymphovascular invasion [odds ratio (OR) 1.2, 95% confidence interval (CI) 1.06-1.36; p = 0.003], multifocality (OR 1.26, 95% CI 1.12-1.42; p < 0.001), nodal micrometastasis (OR 1.15, 95% CI 1.02-1.31; p = 0.024), and lower rates of ≥ 3 positive nodes (OR 0.77, 95% CI 0.66-0.90, p = 0.001). When stratified by HR expression, in both HR-positive and HR-negative tumors, age and multifocality were associated with HER2 low on UVA. On MVA, no variables were independently associated with both HR-negative and HR-positive/HER2-low tumors compared with HER2-negative tumors. In contrast, HER2-positive tumors, regardless of HR status, were associated with multifocality and an extensive intraductal component. CONCLUSION: Clinicopathologic features of HER2-low tumors appear to be primarily related to HR status. Our findings do not support the characterization of HER2 low as a separate subtype.

Impact of Neoadjuvant Chemoimmunotherapy on Surgical Outcomes and Time to Radiation in Triple-Negative Breast Cancer.

BACKGROUND: We examined the association between immunotherapy-containing and standard chemotherapy regimens with treatment delays and postoperative complications in stage II-III triple-negative breast cancer. The effect of immune-related adverse events (irAEs) was compared. PATIENTS AND METHODS: We compared 139 women treated with neoadjuvant pembrolizumab plus chemotherapy (KEYNOTE-522 regimen) from August 2021 to September 2022 with 287 consecutive patients who received neoadjuvant chemotherapy alone prior to July 2021 and underwent surgery. Baseline characteristics, time to treatments, and surgical complications were compared using two-sample non-parametric tests. Linear regression evaluated association of irAEs with time to surgery and radiation. Logistic regression identified factors associated with surgical complications. RESULTS: Age, body mass index, race, American Society of Anesthesiologists (ASA) class, and mastectomy rates were similar among cohorts. No clinically relevant difference in time from end of neoadjuvant treatment to surgery was observed [KEYNOTE-522: median 32 (IQR 27, 43) days; non-KEYNOTE-522: median 31 (IQR 26, 37) days; P = 0.048]. Time to radiation did not differ (P = 0.7). A total of 26 patients (9%; non-KEYNOTE-522) versus 11 (8%; KEYNOTE-522) experienced postoperative complications (P = 0.6). In the KEYNOTE-522 cohort, 59 (43%) of 137 patients experienced 82 irAEs; 40 (68%) required treatment. Older age (P = 0.018) and ASA class 4 (P = 0.007) were associated with delays to surgery after adjusting for clinical factors. Experiencing ≥ 1 irAE was associated with delay to radiation (P = 0.029). IrAEs were not associated with surgical complications (P = 0.4). CONCLUSIONS: We observed no clinically meaningful difference between times to surgery/adjuvant radiation or postoperative complications and type of preoperative chemotherapy. IrAEs were associated with delay to adjuvant radiation but not with postoperative complications or delay to surgery.

Impact of Imaging-Guided Localization on Performance of Tailored Axillary Surgery in Patients with Clinically Node-Positive Breast Cancer: Prospective Cohort Study Within TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101).

BACKGROUND: Tailored axillary surgery (TAS) is a novel surgical concept for clinical node-positive breast cancer. It consists of the removal of the sentinel lymph nodes (LNs), as well as palpably suspicious nodes. The TAS technique can be utilized in both the upfront and neoadjuvant chemotherapy (NACT) setting. This study assessed whether/how imaging-guided localization (IGL) influenced TAS. PATIENTS AND METHODS: This was a prospective observational cohort study preplanned in the randomized phase-III OPBC-03/TAXIS trial. IGL was performed at the surgeon's discretion for targeted removal of LNs during TAS. Immediate back-up axillary lymph node dissection (ALND) followed TAS according to TAXIS randomization. RESULTS: Five-hundred patients were included from 44 breast centers in six countries, 151 (30.2%) of whom underwent NACT. IGL was performed in 84.4% of all patients, with significant variation by country (77.6-100%, p < 0.001). No difference in the median number of removed (5 vs. 4, p = 0.3) and positive (2 vs. 2, p = 0.6) LNs by use of IGL was noted. The number of LNs removed during TAS with IGL remained stable over time (p = 0.8), but decreased significantly without IGL, from six (IQR 4-6) in 2019 to four (IQR 3-4) in 2022 (p = 0.015). An ALND was performed in 249 patients, removing another 12 (IQR 9-17) LNs, in which a median number of 1 (IQR 0-4) was positive. There was no significant difference in residual nodal disease after TAS with or without IGL (68.0% vs. 57.6%, p = 0.2). CONCLUSIONS: IGL did not significantly change either the performance of TAS or the volume of residual nodal tumor burden. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03513614.

Trends in use of neoadjuvant systemic therapy in patients with clinically node-positive breast cancer in Europe: prospective TAXIS study (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101).

PURPOSE: The aim of this study was to evaluate clinical practice heterogeneity in use of neoadjuvant systemic therapy (NST) for patients with clinically node-positive breast cancer in Europe. METHODS: The study was preplanned in the international multicenter phase-III OPBC-03/TAXIS trial (ClinicalTrials.gov Identifier: NCT03513614) to include the first 500 randomized patients with confirmed nodal disease at the time of surgery. The TAXIS study's pragmatic design allowed both the neoadjuvant and adjuvant setting according to the preferences of the local investigators who were encouraged to register eligible patients consecutively. RESULTS: A total of 500 patients were included at 44 breast centers in six European countries from August 2018 to June 2022, 165 (33%) of whom underwent NST. Median age was 57 years (interquartile range [IQR], 48-69). Most patients were postmenopausal (68.4%) with grade 2 and 3 hormonal receptor-positive and human epidermal growth factor receptor 2-negative breast cancer with a median tumor size of 28 mm (IQR 20-40). The use of NST varied significantly across the countries (p < 0.001). Austria (55.2%) and Switzerland (35.8%) had the highest percentage of patients undergoing NST and Hungary (18.2%) the lowest. The administration of NST increased significantly over the years (OR 1.42; p < 0.001) and more than doubled from 20 to 46.7% between 2018 and 2022. CONCLUSION: Substantial heterogeneity in the use of NST with HR+/HER2-breast cancer exists in Europe. While stringent guidelines are available for its use in triple-negative and HER2+ breast cancer, there is a need for the development of and adherence to well-defined recommendations for HR+/HER2-breast cancer.

Axillary Staging Is Not Justified in Postmenopausal Clinically Node-Negative Women Based on Nodal Disease Burden.

BACKGROUND: RxPONDER showed no benefit of adjuvant chemotherapy in postmenopausal women with estrogen receptor (ER) positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer and limited nodal burden (pN1) with a recurrence score ≤ 25, suggesting that axillary staging could be omitted in cN0 patients if significant numbers of such women do not have pN2-3 disease. Here we evaluate the pN2-3 disease rate in a large cohort of postmenopausal women presenting with cN0 breast cancer. PATIENTS AND METHODS: Consecutive postmenopausal patients presenting with T1-2N0 breast cancer who underwent axillary surgery from February 2006 to December 2011 were identified. Clinicopathologic characteristics associated with pN2-3 disease were examined using chi-square or Fisher's exact tests. RESULTS: Of 3363 postmenopausal women with cT1-2N0 breast cancer (median age 58 years, IQR 48-67 years), median tumor size was 1.3 cm (IQR 0.90-1.90cm). Post-axillary staging, 2600 (77.3%) were pN0, 643 (19.1%) were pN1, and 120 (3.6%) were pN2-3. The pN2-3 disease rate did not differ across subtypes (4.4% HER2+, 3.5% HR-/HER2-, 3.5% HR+/HER2-, p = 0.70). In the subset with HR+/HER2- tumors, on multivariable analysis, age < 65 years (odds ratio [OR] 2.38, 95% confidence interval [CI] 1.32-4.49), lymphovascular invasion (OR 5.29, 95% CI 2.72-11.2), multifocal/centric tumors (OR 3.08, 95% CI 1.79-5.32), and tumor size > 2 cm (OR 5.51, 95% CI 3.05-10.4) were significantly associated with pN2-3 nodal burden. Of 506 patients with tumors > 2 cm, 49 (9.7%) had pN2-3 disease; in the subset of 90 patients age < 65 years who had multifocal/centric tumors > 2 cm, 23 (25.6%) had pN2-3 disease. CONCLUSIONS: In postmenopausal women with cN0 disease, pN2-3 nodal burden is uncommon; omitting axillary staging would not miss a significant number of patients who might benefit from adjuvant chemotherapy. Information available preoperatively indicating a higher risk of nodal disease such as younger age and large, multifocal tumors should be considered in the multidisciplinary management of the axilla.

Estimating the Benefit of Preoperative Systemic Therapy to Reduce the Extent of Breast Cancer Surgery: Current Standard and Future Directions.

Once reserved for locally advanced tumors which were deemed inoperable at presentation, preoperative systemic therapy (PST) is nowadays increasingly used to treat early breast cancer. PST allows for in vivo assessment of tumor response, for tailoring of adjuvant systemic therapy and for de-escalation of breast and the axillary surgery. Increased rates of pathological complete response together with more accurate response assessment and surgical planning have led to a significant reduction in surgical morbidity. While surgical assessment remains the standard of care, ongoing studies are evaluating whether surgery can be omitted in patients who achieve a complete pathological response. In this chapter, I will review the impact of PST on surgical de-escalation and the data supporting the safety of this approach.

Is Nodal Clipping Beneficial for Node-Positive Breast Cancer Patients Receiving Neoadjuvant Chemotherapy?

BACKGROUND: In cN1 patients rendered cN0 with neoadjuvant chemotherapy, the false-negative rate of sentinel lymph node biopsy (SLNB) is < 10% when ≥ 3 sentinel lymph nodes (SLNs) are removed. The added value of nodal clipping in this scenario is unknown. Here we determine how often the clipped node is a sentinel node when ≥ 3 SLNs are retrieved. METHODS: We identified cT1-3N1 patients treated between 02/2018 and 10/2021 with a clipped lymph node at presentation. SLNB was performed with a standardized approach of dual-tracer mapping and retrieval of ≥ 3 SLNs. Clipped nodes were not localized; SLNs were X-rayed intraoperatively to determine clip location. Axillary lymph node dissection (ALND) was performed for any residual disease or retrieval of < 3 SLNs. RESULTS: Of 269 patients, 251 (93%) had ≥ 3 SLNs. Median age was 51 years; the majority (92%) had ductal histology; 46% were HR+/HER2-. The median number of SLNs removed was 4 (IQR 3,5). The clipped node was an SLN in 88% (220/251) of cases. Of the 31 where the clipped node was not, 13 had a positive SLN mandating ALND, and the clip was identified in the ALND specimen. In the remaining 18, where ≥ 3 negative SLNs were retrieved and an ALND was not performed, the clip was not retrieved, with no axillary failures in this group (median follow-up: 55 months). CONCLUSION: When the SLNB procedure is optimized with dual tracer and retrieval of ≥ 3 SLNs, the clipped node is an SLN in the majority of cases, suggesting that failure to retrieve the clipped node should not be an indication for ALND.

Longitudinal Prospective Evaluation of Quality of Life After Axillary Lymph Node Dissection.

BACKGROUND: Patients often fear axillary lymph node dissection (ALND) because of its associated complications; however, its effect on quality of life (QOL) is not well described. We aimed to evaluate the effect of ALND on QOL over time and to identify predictors of worse QOL. PATIENTS AND METHODS: Breast cancer patients undergoing ALND were enrolled in a prospective lymphedema screening study. Arm volumes were measured and QOL questionnaires completed at baseline, postoperatively, and at 6-month intervals. The upper limb lymphedema-27 questionnaire was used to assess the effect of upper extremity symptoms on QOL in three domains (physical, psychological, and social). Predictors of QOL were identified by univariate and multivariable regression analyses. RESULTS: From November 2016 through March 2020, 304 ALND patients were enrolled; 242 patients with at least two measurements and 6 months of follow-up were included. Median age was 48 years, and median follow-up was 1.2 years. The 18-month lymphedema rate was 18%. Overall, QOL scores in all three domains decreased postoperatively and improved over time. On multivariable analysis, after adjusting for baseline scores, symptoms necessitating lymphedema therapy referral (p = 0.006) were associated with worse physical QOL. Younger age (p = 0.005) and lymphedema therapy referral (p = 0.006) were associated with worse psychological QOL. Arm volume was not correlated with QOL. CONCLUSIONS: QOL scores initially decreased after ALND but improved by 6 months post-surgery. Decreases in QOL were independent of arm volume. Patients with worse QOL more often sought lymphedema therapy, although the effect of therapy on QOL remains unknown.

Retrospective, Multicenter Analysis Comparing Conventional with Oncoplastic Breast Conserving Surgery: Oncological and Surgical Outcomes in Women with High-Risk Breast Cancer from the OPBC-01/iTOP2 Study.

INTRODUCTION: Recent data suggest that margins ≥2 mm after breast-conserving surgery may improve local control in invasive breast cancer (BC). By allowing large resection volumes, oncoplastic breast-conserving surgery (OBCII; Clough level II/Tübingen 5-6) may achieve better local control than conventional breast conserving surgery (BCS; Tübingen 1-2) or oncoplastic breast conservation with low resection volumes (OBCI; Clough level I/Tübingen 3-4). METHODS: Data from consecutive high-risk BC patients treated in 15 centers from the Oncoplastic Breast Consortium (OPBC) network, between January 2010 and December 2013, were retrospectively reviewed. RESULTS: A total of 3,177 women were included, 30% of whom were treated with OBC (OBCI n = 663; OBCII n = 297). The BCS/OBCI group had significantly smaller tumors and smaller resection margins compared with OBCII (pT1: 50% vs. 37%, p = 0.002; proportion with margin <1 mm: 17% vs. 6%, p < 0.001). There were significantly more re-excisions due to R1 ("ink on tumor") in the BCS/OBCI compared with the OBCII group (11% vs. 7%, p = 0.049). Univariate and multivariable regression analysis adjusted for tumor biology, tumor size, radiotherapy, and systemic treatment demonstrated no differences in local, regional, or distant recurrence-free or overall survival between the two groups. CONCLUSIONS: Large resection volumes in oncoplastic surgery increases the distance from cancer cells to the margin of the specimen and reduces reexcision rates significantly. With OBCII larger tumors are resected with similar local, regional and distant recurrence-free as well as overall survival rates as BCS/OBCI.

Breast conservation and axillary management after primary systemic therapy in patients with early-stage breast cancer: the Lucerne toolbox.

Primary systemic therapy is increasingly used in the treatment of patients with early-stage breast cancer, but few guidelines specifically address optimal locoregional therapies. Therefore, we established an international consortium to discuss clinical evidence and to provide expert advice on technical management of patients with early-stage breast cancer. The steering committee prepared six working packages to address all major clinical questions from diagnosis to surgery. During a consensus meeting that included members from European scientific oncology societies, clinical trial groups, and patient advocates, statements were discussed and voted on. A consensus was reached in 42% of statements, a majority in 38%, and no decision in 21%. Based on these findings, the panel developed clinical guidance recommendations and a toolbox to overcome many clinical and technical requirements associated with the diagnosis, response assessment, surgical planning, and surgery of patients with early-stage breast cancer. This guidance could convince clinicians and patients of the major clinical advancements purported by primary systemic therapy, the use of less extensive and more targeted surgery to improve the lives of patients with breast cancer.

The Impact of the COVID-19 Pandemic on Surgical Management of Breast Cancer: Global Trends and Future Perspectives.

INTRODUCTION: The rapid spread of COVID-19 across the globe is forcing surgical oncologists to change their daily practice. We sought to evaluate how breast surgeons are adapting their surgical activity to limit viral spread and spare hospital resources. METHODS: A panel of 12 breast surgeons from the most affected regions of the world convened a virtual meeting on April 7, 2020, to discuss the changes in their local surgical practice during the COVID-19 pandemic. Similarly, a Web-based poll based was created to evaluate changes in surgical practice among breast surgeons from several countries. RESULTS: The virtual meeting showed that distinct countries and regions were experiencing different phases of the pandemic. Surgical priority was given to patients with aggressive disease not candidate for primary systemic therapy, those with progressive disease under neoadjuvant systemic therapy, and patients who have finished neoadjuvant therapy. One hundred breast surgeons filled out the poll. The trend showed reductions in operating room schedules, indications for surgery, and consultations, with an increasingly restrictive approach to elective surgery with worsening of the pandemic. CONCLUSION: The COVID-19 emergency should not compromise treatment of a potentially lethal disease such as breast cancer. Our results reveal that physicians are instinctively reluctant to abandon conventional standards of care when possible. However, as the situation deteriorates, alternative strategies of de-escalation are being adopted. IMPLICATIONS FOR PRACTICE: This study aimed to characterize how the COVID-19 pandemic is affecting breast cancer surgery and which strategies are being adopted to cope with the situation.

How Often Does Modern Neoadjuvant Chemotherapy Downstage Patients to Breast-Conserving Surgery?

BACKGROUND: Neoadjuvant chemotherapy (NAC) has been proven to increase breast-conserving surgery (BCS) rates, but data are limited on conversion rates from BCS-ineligible (BCSi) to BCS-eligible (BCSe), specifically, in patients with large tumors. METHODS: Consecutive patients with stage I-III breast cancer treated with NAC from November 2013 to March 2019 were identified. BCS eligibility before and after NAC was prospectively determined. Patients deemed BCSi before NAC due to large tumor size were studied. Statistical analyses were conducted using Student's t-test, Wilcoxon rank sum test, Chi-square test, Fisher's test, and logistic regression. RESULTS: In this study, 600 of 1353 cancers were BCSi with large tumors; 69% were non-BCS candidates, 31% were borderline-BCS (bBCS) candidates. Of non-BCS candidates, 69% became BCSe after NAC; 66% chose BCS, and 90% were successful. Among bBCS candidates, 87% were BCSe after NAC, 73% chose BCS, and 96% were successful. On univariate analysis, bBCS candidacy, lower cT stage, cN0 status, absence of calcifications, human epidermal growth factor receptor 2 positive (HER2+)/triple negative (TN) receptor status, poor differentiation, ductal histology, and breast pCR were associated with conversion to BCS eligibility. On multivariable analysis, receptor status (hormone receptor positive [HR+]/HER2- ref; odds ratio [OR] HER2+ 1.63, P = 0.047; HR-/HER2- OR, 2.26, P = 0.003) and breast pCR (OR 2.62, P < 0.001) predicted successful downstaging, while larger clinical tumor size (OR 0.86, P = 0.003), non-BCS candidacy (OR 0.46, P = 0.003), cN+ status (OR 0.54, P = 0.008), and calcifications (OR 0.56, P = 0.007) predicted lower downstaging rates. CONCLUSION: In patients with large tumors precluding BCS, conversion to BCS eligibility was high with NAC, particularly in bBCS candidates. HER2+/TN receptor status predicted successful downstaging, while lower downstaging rates were observed with larger tumors, cN+ status, and calcifications. These factors should be considered when selecting patients for NAC.

Predictors of Nodal Pathological Complete Response in Asian Women with Stage II-III Node-Positive Breast Cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is increasingly used to treat node-positive (N+) breast cancer. Predictors of nodal pathological complete response (pCR) in Asian women are poorly described and there is variety in the management of the axilla after NAC. We evaluated predictors of nodal pCR and axillary management in a cohort of Asian N+ patients. METHODS: Consecutive biopsy-proven N+ breast cancer patients treated with NAC were identified from the Shanghai Ruijin Hospital in China. Axillary lymph node dissection was performed on all patients, irrespective of the nodal response to NAC. RESULTS: A total of 323 patients were included. Nodal pCR was achieved in 105 patients (33%), 15% of HR+/HER2- tumors, 38% of HR+/HER2+ tumors, 49% of HR-/HER2+ tumors, and 42% of HR-/HER2-tumors (p < 0.001). Factors associated with nodal pCR were (1) receptor status (HR+/HER2- [referent]: OR 3.42, 95% CI 1.43-8.16, p = 0.006 for HR+/HER2+; OR 4.19, 95% CI 1.85-9.50, p = 0.001 for HR-/HER2+; and OR 2.94, 95% CI 1.11-7.74, p = 0.029 for HR-/HER2-), (2) breast pCR (no pCR [referent]: OR 15.22, 95% CI 6.29-36.79, p < 0.001), and (3) absence of lymphovascular invasion (LVI [referent]: OR 9.04, 95% CI 2.09-39.18, p = 0.003). CONCLUSION: This study confirmed expected predictors of nodal pCR in Asian women and the benefit of NAC in downstaging the axilla independently of ethnicity.

Intraoperative opioids are associated with improved recurrence-free survival in triple-negative breast cancer.

BACKGROUND: Opioid-induced immunomodulation may be of particular importance in triple-negative breast cancer (TNBC) where an immune response is associated with improved outcome and response to immunotherapy. We evaluated the association between intraoperative opioids and oncological outcomes and explored patterns of opioid receptor expression in TNBC. METHODS: Consecutive patients with stage I-III primary TNBC were identified from a prospectively maintained database. Opioid receptor expression patterns in the tumour microenvironment were analysed using publicly available bulk and single-cell RNA-seq data. RESULTS: A total of 1143 TNBC cases were retrospectively analysed. In multivariable analysis, higher intraoperative opioid dose was associated with favourable recurrence-free survival, hazard ratio 0.93 (95% confidence interval 0.88-0.99) per 10 oral morphine milligram equivalents increase (P=0.028), but was not significantly associated with overall survival, hazard ratio 0.96 (95% confidence interval 0.89-1.02) per 10 morphine milligram equivalents increase (P=0.2). Bulk RNA-seq analysis of opioid receptors showed that OPRM1 was nearly non-expressed. Compared with normal breast tissue OGFR, OPRK1, and OPRD1 were upregulated, while TLR4 was downregulated. At a single-cell level, OPRM1 and OPRD1 were not detectable; OPRK1 was expressed mainly on tumour cells, whereas OGFR and TLR4 were more highly expressed on immune cells. CONCLUSIONS: We found a protective effect of intraoperative opioids on recurrence-free survival in TNBC. Opioid receptor expression was consistent with a net protective effect of opioid agonism, with protumour receptors either not expressed or downregulated, and antitumour receptors upregulated. In this era of personalised medicine, efforts to differentiate the effects of opioids across breast cancer subtypes (and ultimately individual patients) should continue.

De-escalating Treatment for Ductal Carcinoma In Situ.

Ductal carcinoma in situ (DCIS) is a heterogenous disease. The mainstay of its management is surgery, and lumpectomy with or without radiation therapy (RT) or mastectomy are standard options. Endocrine therapy may be given to maximize risk reduction. With standard treatment, the longterm breast cancer-specific survival is excellent and exceeds 95%. Currently, management strategies are based on standard clinicopathological features. Genomic tools to predict local recurrence have been developed, and prospective studies to evaluate their impact on RT recommendations and outcomes are ongoing. Because of concerns regarding overtreatment of DCIS, there has been much enthusiasm for de-escalating locoregional therapy. RT halves the risk of local recurrence but does not affect survival, and its omission can be considered in low-risk groups. Active surveillance for lowrisk DCIS is being evaluated in 4 prospective trials. The concern regarding these trials is whether the selected "low-risk" cases are truly at low risk, and what threshold of recurrence is considered acceptable. Additionally, it is unclear whether patients will be willing to trade short outpatient procedures for more biopsies, more imaging, and possibly increased concern about recurrence. The clinical relevance and the safety of this approach are yet to be determined.

Knowledge gaps in oncoplastic breast surgery.

The aims of the Oncoplastic Breast Consortium initiative were to identify important knowledge gaps in the field of oncoplastic breast-conserving surgery and nipple-sparing or skin-sparing mastectomy with immediate breast reconstruction, and to recommend appropriate research strategies to address these gaps. A total of 212 surgeons and 26 patient advocates from 55 countries prioritised the 15 most important knowledge gaps from a list of 38 in two electronic Delphi rounds. An interdisciplinary panel of the Oncoplastic Breast Consortium consisting of 63 stakeholders from 20 countries obtained consensus during an in-person meeting to select seven of these 15 knowledge gaps as research priorities. Three key recommendations emerged from the meeting. First, the effect of oncoplastic breast-conserving surgery on quality of life and the optimal type and timing of reconstruction after nipple-sparing or skin-sparing mastectomy with planned radiotherapy should be addressed by prospective cohort studies at an international level. Second, the role of adjunctive mesh and the positioning of implants during implant-based breast reconstruction should ideally be investigated by randomised controlled trials of pragmatic design. Finally, the BREAST-Q questionnaire is a suitable tool to assess primary outcomes in these studies, but other metrics to measure patient-reported outcomes should be systematically evaluated and quality indicators of surgical morbidity should be further assessed.

E-cadherin deregulation in breast cancer.

E-cadherin protein (CDH1 gene) integrity is fundamental to the process of epithelial polarization and differentiation. Deregulation of the E-cadherin function plays a crucial role in breast cancer metastases, with worse prognosis and shorter overall survival. In this narrative review, we describe the inactivating mechanisms underlying CDH1 gene activity and its possible translation to clinical practice as a prognostic biomarker and as a potential targeted therapy.

How Effective is Neoadjuvant Endocrine Therapy (NET) in Downstaging the Axilla and Achieving Breast-Conserving Surgery?

BACKGROUND: Neoadjuvant endocrine therapy (NET) is effective in downstaging large hormone receptor-positive (HR+) breast cancers and increasing rates of breast-conserving surgery (BCS), but data regarding nodal pathologic complete response (pCR) are sparse. We reported nodal and breast downstaging rates with NET, and compared axillary response rates following NET and neoadjuvant chemotherapy (NAC). METHODS: Consecutive stage I-III breast cancer patients treated with NET and surgery from January 2009 to December 2019 were identified from a prospectively maintained database. Nodal pCR rates were compared between biopsy-proven node-positive patients treated with NET, and HR+/HER2- patients treated with NAC from November 2013 to July 2019. RESULTS: 127 cancers treated with NET and 338 with NAC were included. NET recipients were older, more likely to have lobular and lower-grade tumors, and higher HR expression. With NET, the nodal pCR rate was 11% (4/38) of biopsy-proven cases, and the breast pCR rate was 1.6% (2/126). Nodal-dowstaging rates with NET and NAC were not significantly different (11% vs 18%; P = 0.37). Patients achieving nodal pCR with NET versus NAC were older (median age 70 vs 50, P = 0.004) and had greater progesterone receptor (PR) expression (85% vs 13%, P = 0.031), respectively. Of patients not candidates for BCS due to a large tumor relative to breast size, 36/47 (77%) became BCS-eligible with NET (median PR expression 55% vs 5% in those remaining ineligible, P < 0.05). CONCLUSION: Although nodal pCR is more frequent than breast pCR, NET is more likely to de-escalate breast surgery than axillary surgery. However, with a nodal pCR rate of 11%, NET remains an option for downstaging node-positive patients without clear indications for NAC.

Selecting Node-Positive Patients for Axillary Downstaging with Neoadjuvant Chemotherapy.

BACKGROUND: Axillary lymph node dissection (ALND) can be avoided in node-positive patients who receive neoadjuvant chemotherapy (NAC) if three or more negative sentinel lymph nodes (SLNs) are retrieved. We evaluate how often node-positive patients avoid ALND with NAC, and identify predictors of identification of three or more SLNs and of nodal pathological complete response (pCR). METHODS: From November 2013 to July 2019, all patients with cT1-3, biopsy-proven N1 tumors who converted to cN0 after NAC received SLN biopsy (SLNB) with dual mapping and were identified from a prospectively maintained database. RESULTS: 630 consecutive N1 patients were eligible for axillary downstaging with NAC; 573 (91%) converted to cN0 and had SLNB, and 531 patients (93%) had three or more SLNs identified. Lymphovascular invasion (LVI; odds ratio [OR] 0.46, 95% confidence interval [CI] 0.24-0.87; p = 0.02) and increasing body mass index (BMI; OR 0.77, 95% CI 0.62-0.96 per 5-unit increase; p = 0.02) were significantly associated with failure to identify three or more SLNs. 255/573 (46%) patients achieved nodal pCR; 237 (41%) had adequate mapping. Factors associated with ALND avoidance included high grade (OR 2.51, 95% CI 1.6-3.94, p = 0.001) and receptor status (HR+/HER2- [referent]: OR 1.99, 95% CI 1.15-3.46 [p = 0.01] for HR-/HER2-, OR 3.93, 95% CI 2.40-6.44 [p < 0.001] for HR+/HER2+, and OR 8.24, 95% CI 4.16-16.3 [p < 0.001] for HR-/HER2+). LVI was associated with a lower likelihood of avoiding ALND (OR 0.28, 95% CI 0.18-0.43; p < 0.001). CONCLUSIONS: ALND was avoided in 41% of cN1 patients after NAC. Increased BMI and LVI were associated with lower retrieval rates of three or more SLNs. ALND avoidance rates varied with receptor status, grade, and LVI. These factors help select patients most likely to avoid ALND.

How Useful Are Tumor Markers in Detecting Metastases with FDG-PET/CT during Breast Cancer Surveillance?

BACKGROUND: To assess the clinical usefulness of serum tumor markers for early detection of distant breast cancer recurrence using FDG-PET/CT. METHODS: We retrospectively analyzed 561 consecutive patients who underwent surgery for invasive primary breast cancer and had increased tumor markers (CA 15-3 and CEA) after completion of locoregional therapy. FDG-PET/CT data were reviewed for all cases. CA 15-3 and CEA were evaluated both in a continuous and in a quartile (Q) distribution. The Wilcoxon rank-sum test and logistic regression models were used to evaluate the association between increased tumor marker values and the presence (and type) of distant metastases. RESULTS: The median value of CA 15-3 was 35.0 U/mL (IQR, 29.5-43.0) in cases where no distant metastases were detected, and it was 58.9 U/mL (IQR, 40.0-108.0) in cases where metastases were detected (p < 0.001). The median value of CEA was 6.6 U/mL (IQR, 4.4-10.0) in cases of no metastases and 12.4 U/mL (IQR, 6.9-30.0) in cases of metastases (p < 0.001). Increased levels of both tumor markers (Q3 and Q4) were strongly associated with the presence of distant metastases. The association between CA 15-3 and bone/liver metastases was stronger compared with other types of metastases (p heterogeneity between odds ratios [ORs] = 0.03 for Q3 and <0.001 for Q4), while no relevant heterogeneity between ORs emerged for CEA. CONCLUSION: Increased tumor marker levels detected in asymptomatic breast cancer patients during adjuvant therapies and follow-up are significantly predictive of distant metastases identified on FDG-PET/CT.