The effect of omitting axillary dissection and the impact of radiotherapy on patients with breast cancer sentinel node macrometastases: a cohort study following the ACOSOG Z0011 and AMAROS trials.

PURPOSE: To report the outcomes of implementing the ACOSOG Z0011 and AMAROS trials relevant to clinical practice, and to define target groups in whom to avoid or recommend axillary radiotherapy (ART). We also aimed to analyse the reduction in morbidity when axillary lymph node dissection (ALND) was omitted. METHODS: A retrospective cohort study of T1-T2 patients with macrometastases at sentinel lymph node (SLN) who were treated between 2011 and 2020. Breast surgery included either lumpectomy or mastectomy. Patients with ≤ 2 positive SLN were divided into two cohorts by whether they received ART or not. Survival outcomes and morbidity were analysed by Kaplan-Meyer curves and Cox-regression, respectively. RESULTS: 260 pN1a patients were included and ALND was avoided in 167 (64.2%). According the Z0011 results, 72 (43.1%) received no further ART; and based on AMAROS criteria 95 (56.9%) received ART. Median follow-up was 54 months. The 5-year overall survival was 96.8% in the non-RT cohort and 93.4% in the RT cohort (p = 0.19), while the respective 5-year disease-free survivals were 100% and 92.3% (p = 1.06). Lymphedema developed in 3.6% of patients after SLNB versus 43% after ALND (OR 20.25; 95%CI 8.13-50.43). Decreased upper-extremity range of motion appeared in 8.4% of patients after SLNB versus 31.2% after ALND (OR 4.95; 95%CI 2.45-9.98%). CONCLUSIONS: Our study confirms that omitting ALND is safe and has high survival rates in patients with T1-T2 tumours and ≤ 2 positive SLNs. Adding ART could be a treatment option for patients who present other risk factors. Avoiding ALND with or without ART was associated with significantly less arm morbidity.

Can we avoid axillary lymph node dissection in N2 breast cancer patients with chemo-sensitive tumours such as HER2 and TNBC?

PURPOSE: To find a group of cN2 patients or patients with high axillary burden who become ypN0 after neoadjuvant chemotherapy (NACT) and who may benefit from avoiding a lymphadenectomy. METHODS: A retrospective observational cohort study was conducted with 221 clinically staged N2 patients or patients with at least 3 suspicious lymph nodes found by ultrasound at diagnosis. The predictive factors for ypN0 analysed were age, MRI-determined tumour size, histological subtype, the Nottingham histologic grade, surrogate molecular subtype, ki-67 and vascular invasion when present. Clinical and radiological responses after NACT were also evaluated. Univariate and multivariate analyses by logistic regression were performed. Distant disease-free survival (DDFS) was calculated in relation to the status of the axillary lymph nodes after NACT. RESULTS: After NACT, 89 patients (40.3%) had axillary pathologic complete response (pCR) (ypN0) and 132 (59.7%) had residual axillary disease (ypN+). Molecular surrogate subtype, Ki-67 expression, and the clinical and radiological responses to NACT were the only independent factors associated with ypN0. Axillary pCR was observed more often in HER2-positive and triple-negative tumours than in luminal ones (OR 7.5 and 3.6, respectively). DDFS was 88.7% (95% CI 80.7-96.7%) for ypN0 and 56.2% (95% CI 32.1-80.3%) for ypN+ (p = 0.09). CONCLUSIONS: In HER2-positive and triple-negative breast cancer patients staged as cN2 or with high axillary burden before NACT, a sentinel lymph node biopsy after NACT could be recommended if there is a clinical and radiological response.

Predictive factors for omitting lymphadenectomy in patients with node-positive breast cancer treated with neo-adjuvant systemic therapy.

A pathologic complete response (pCR) in the axilla occurs in 30%-40% of patients with initially node-positive breast cancer after neo-adjuvant chemotherapy (NACT). Debate persists about whether to perform systematic axillary lymphadenectomy (ALND) in patients with initial node-positive disease and clinical complete response after NACT. We aimed to identify predictive factors of axillary pCR (ypN0) after NACT. This retrospective study analyzed data for all patients with initial biopsy-proven node-positive disease who underwent ALND after NACT between June 2008 and December 2016 at our institution. Clinical and pathologic features, recurrence and specific mortality rates were compared between patients who achieved an axillary pCR and those who did not (ypN0 vs ypN+, respectively). A total of 331 patients were included, of whom 128 (38.7%) became ypN0 after NACT. Among patients with >2 suspicious axillary lymph nodes before treatment, 54 (38%) achieved ypN0 status. The independent predictors of ypN0 were Ki-67 > 30 (OR 1.98; 95% CI, 1.146-3.381), HER2 positivity (OR 2.6; 95% CI, 1.354-5.108), nonluminal molecular-like subtype (OR 4.15; 95% CI, 2.068-5.108), and clinical complete response, defined as negative clinical and ultrasonographic findings (OR 2.8; 95% CI, 1.110-7.081). After a mean follow-up of 61 months, distant disease-free and overall survival rates were higher in patients with ypN0 disease (HR 4.14; 95% CI, 2.03-8.43) than ypN+ patients. Complete clinical response and the presence of nonluminal molecular-like subtypes independently predicted ypN0. Patients meeting these criteria might be suitable form omitting ALND and just performing targeted axillary procedures to patients meeting these criteria.

Radiofrequency Ablation Followed by Surgical Excision versus Lumpectomy for Early Stage Breast Cancer: A Randomized Phase II Clinical Trial.

Purpose To compare the safety and efficacy of US-guided percutaneous radiofrequency ablation (RFA) as a local treatment for breast cancer with that of lumpectomy. Materials and Methods A prospective, randomized open-label phase II clinical trial (clinicaltrials.gov identification number NCT02281812) was conducted in a single institution from 2013 to 2017. Women with invasive ductal carcinoma of the breast measuring 2 cm or smaller were randomly assigned to receive RFA or lumpectomy alone (control group). Margin status at surgery, tumor cell viability after RFA (with nicotinamide adenine dinucleotide [NADH] and cytokeratin 18 [CK18] staining), cosmetic results, adverse events, and local recurrences were evaluated with univariable and multivariable analyses. Results Forty subjects (20 in the RFA group and 20 in the lumpectomy group) were evaluated. The mean participant age was 64 years (range, 46-86 years). NADH and CK18 staining demonstrated absence of tumor cell viability after RFA with at least one of the two techniques. The surgical margins were positive in 11 of the 20 participants in the lumpectomy group (55%) and four of the 20 in the RFA group (20%) (P = .02). Median follow-up was 25 months (range, 1-83 months). Local breast inflammation after surgery was higher in the RFA group than in the lumpectomy group (40% [eight of 20 participants] vs 5% [one of 20 participants], respectively; P = .01). Local infection occurred in three participants who underwent RFA (two of whom had undergone partial irradiation of the breast). None of the participants in the control group developed local infection. No participants had recurrence or the need for a second surgery during the study period. Conclusion This preliminary study showed that radiofrequency ablation was effective for local tumor control and that tumor-free margins were obtained more often with radiofrequency ablation than with lumpectomy. Surgical excision after radiofrequency ablation was infrequently associated with local infection. © RSNA, 2018 Online supplemental material is available for this article.

Study of breast cancer incidence in patients of lymphangioleiomyomatosis.

Molecular evidence has linked the pathophysiology of lymphangioleiomyomatosis (LAM) to that of metastatic breast cancer. Following on this observation, we assessed the association between LAM and subsequent breast cancer. An epidemiological study was carried out using three LAM country cohorts, from Japan, Spain, and the United Kingdom. The number of incident breast cancer cases observed in these cohorts was compared with the number expected on the basis of the country-specific incidence rates for the period 2000-2014. Immunohistochemical studies and exome sequence analysis were performed in two and one tumors, respectively. All cohorts revealed breast cancer standardized incidence ratios (SIRs) ≥ 2.25. The combined analysis of all cases or restricted to pre-menopausal age groups revealed significantly higher incidence of breast cancer: SIR = 2.81, 95 % confidence interval (CI) = 1.32-5.57, P = 0.009; and SIR = 4.88, 95 % CI = 2.29-9.99, P = 0.0007, respectively. Immunohistochemical analyses showed positivity for known markers of lung metastatic potential. This study suggests the existence of increased breast cancer risk among LAM patients. Prospective studies may be warranted to corroborate this result, which may be particularly relevant for pre-menopausal women with LAM.

Pigmented paget disease of the breast nipple with underlying infiltrating carcinoma: a case report and review of the literature.

Paget disease of the breast represents a cutaneous manifestation of an underlying breast malignancy. The rare finding of a pigmented Paget disease mimicking melanoma represents a diagnostic problem. We report a case of a pigmented lesion involving the breast nipple with an underlying infiltrating breast carcinoma, and we describe the clinical presentation, histological findings, and immunohistochemical features with a review of reported cases.

Adenoid cystic carcinoma and basaloid carcinoma of the breast: A clinicopathological study.

Adenoid cystic carcinoma of the breast (ACCB) is a rare triple negative tumor (TNT) with an excellent prognosis in most cases. Three different histologic types are recognized: classic ACCB, solid basaloid ACCB (SB-ACCB), and ACCB with high-grade transformation. A majority of these tumors show characteristic molecular and immunohistochemical (IHC) features, with fusion of MYB and NFIB genes and overexpression of MYB, respectively. Basaloid carcinomas of the breast (BCB) are infrequently described. They resemble SB-ACCB and TNT of no special type (TNT-NST). We have studied the clinicopathological features of 17 ACCB and 9 BCB, investigating the expression of MYB by IHC and the rearrangements of MYB by fluorescence in situ hybridization (FISH). MYB was expressed by IHC in 15 ACCB and in 3 BCB. MYB FISH detected rearrangements in 11 ACCB and in 2 BCB. After a mean follow-up of 90 months, with a range of 12-204 months, 2 patients with ACCB with high-grade transformation and 1 patient with BCB developed metastases and died of disease. In summary, most ACCB have a good prognosis, but tumors with adverse histopathological features may metastasize. BCB may overlap with ACCB and TNT-NST, and their prognosis should be further studied.

The Shift From Sentinel Lymph Node Biopsy Performed Either Before or After Neoadjuvant Systemic Therapy in the Clinical Negative Nodes of Breast Cancer Patients. Results, and the Advantages and Disadvantages of Both Procedures.

BACKGROUND: In patients with breast cancer who are candidates for neoadjuvant therapy (NAT), the timing of when to perform sentinel lymph node biopsy (SLNB) remains under discussion. The aim of this study was to compare the advantages and disadvantages of SLNB performed before and after NAT. PATIENTS AND METHODS: One hundred seventy-two patients, T1c to T3 and N0 (clinically and according to ultrasound) candidates for NAT were included. We compared the outcomes of 2 groups: (1) 122 patients of whom SLNB was performed before NAT (pre-NAT) from December 2006 to April 2014; and (2) 50 patients with SLNB performed after NAT (post-NAT) from May 2014 to July 2016. RESULTS: Both groups were homogeneous in baseline patient characteristics. The SLNB was positive in 50 patients [41.7%] (33 macrometastases [66%] and 17 micrometastases [34%]) versus 6 patients [12%] (5 macrometastases [83.3%] and 1 micrometastases [16.7%]) in pre- and post-NAT groups, respectively. The lymphadenectomy was performed in 34 patients [28.3%] versus 4 patients [8%], with an odds ratio of 3.48 (95% confidence interval, 1.3-9.3). The recurrences in the pre-NAT group after a median follow-up of 62 months were 12 systemic, 2 local and systemic, and none axillary. In the post-NAT group were no recurrences after a median follow-up of 16 months. Finally, SLNB after NAT reduces the delay in starting NAT from 24 to 14 days (medians; P < .001) and the identification of the SLNB was in 122 patients [100%] versus 49 patients [98%]. CONCLUSION: SLNB performed after NAT significantly reduces the rate of lymphadenectomies without any increase in recurrences at early follow-up. Furthermore, it allows systemic treatment to be started earlier without interfering in the SLNB identification rate.

Tumor xenograft modeling identifies an association between TCF4 loss and breast cancer chemoresistance.

Understanding the mechanisms of cancer therapeutic resistance is fundamental to improving cancer care. There is clear benefit from chemotherapy in different breast cancer settings; however, knowledge of the mutations and genes that mediate resistance is incomplete. In this study, by modeling chemoresistance in patient-derived xenografts (PDXs), we show that adaptation to therapy is genetically complex and identify that loss of transcription factor 4 (TCF4; also known as ITF2) is associated with this process. A triple-negative BRCA1-mutated PDX was used to study the genetics of chemoresistance. The PDX was treated in parallel with four chemotherapies for five iterative cycles. Exome sequencing identified few genes with de novo or enriched mutations in common among the different therapies, whereas many common depleted mutations/genes were observed. Analysis of somatic mutations from The Cancer Genome Atlas (TCGA) supported the prognostic relevance of the identified genes. A mutation in TCF4 was found de novo in all treatments, and analysis of drug sensitivity profiles across cancer cell lines supported the link to chemoresistance. Loss of TCF4 conferred chemoresistance in breast cancer cell models, possibly by altering cell cycle regulation. Targeted sequencing in chemoresistant tumors identified an intronic variant of TCF4 that may represent an expression quantitative trait locus associated with relapse outcome in TCGA. Immunohistochemical studies suggest a common loss of nuclear TCF4 expression post-chemotherapy. Together, these results from tumor xenograft modeling depict a link between altered TCF4 expression and breast cancer chemoresistance.

Author Correction: Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

This corrects the article DOI: 10.1038/ncomms15908.

Feasibility, accuracy and prognosis of sentinel lymph node biopsy before neoadjuvant therapy in breast cancer. A prospective study.

BACKGROUND AND OBJECTIVE: It remains controversial whether sentinel lymph node biopsy (SLNB) should be performed before or after neoadjuvant therapy (NAT). We aimed to evaluate the feasibility and accuracy of SLNB before NAT at a single institution, and to determine its relation to patient prognosis. METHODS: A prospective study of T1c-T2-T3 N0 breast cancer patients, after ultrasound examination, who underwent SLNB prior to NAT. Overall, disease-specific and disease-free survival were calculated by Kaplan-Meier curves. RESULTS: SLNB before NAT was performed in 123 patients from December 2006 to May 2014. The identification rate was 100%. SLNB was positive in 42.3% of cases (27.6% macrometastases). NAT was chemotherapy in 88.6% of cases and endocrine-therapy in 11.4%. Lymphadenectomy was avoided in 72.4% of cases. Median follow-up was 40 months (range 8-100). Overall and disease-free survival was 90.2% and 88.6% respectively.SLN involvement was not related to patient outcome (p 0.72); however there were significant differences in survival according to molecular-like subtypes (p < 0.025) and NAT response (p < 0.0001). CONCLUSIONS: SLNB prior to NAT is an accurate method of axillary staging associated with a high identification rate. It avoided lymphadenectomy in more than 70% of patients. SLN involvement did not worsen the prognosis in our cohort.

Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development.

p53 and p21 Expression levels predict organ preservation and survival in invasive bladder carcinoma treated with a combined-modality approach.

BACKGROUND: The purpose of the current study was to evaluate the expression levels of p53, p21 and pRB as predictors of for long-term organ preservation and survival in patients with bladder carcinoma who were treated with bladder-sparing intent using a combined-modality approach. METHODS: Tumor samples from 82 consecutive patients with localized invasive bladder carcinoma treated on 3 different bladder-sparing studies were examined for p53, p21, and pRB expression by immunohistochemical methods. Treatment consisted of transurethral resection, platinum-based neoadjuvant chemotherapy, and, according to response, either radiotherapy or radical cystectomy. The median follow-up duration was 55 months. RESULTS: Positive immunoreactivity for p53, p21, and pRB was observed in 47%, 52%, and 67% of patients, respectively. Positive p53 immunoreactivity and positive p21 immunoreactivity were independent predictors of decreased survival with bladder preservation (P = 0.02 and P = 0.02, respectively) and disease-free survival (DFS; P = 0.005 and P = 0.009, respectively) in a multivariate analysis adjusting for clinical stage, ureteral obstruction, and age. Regarding overall survival (OS), p53 overexpression was associated with poor outcome (P = 0.03), whereas the association of poor outcome with p21 expression did not reach statistical significance (P = 0.07). No association between pRB immunoreactivity and outcome was found. When the combined expression of p53 and p21 was assessed, the positive expression of both markers was a strong and unfavorable prognostic factor for survival with bladder preservation (P = 0.006), DFS (P = 0.003), and OS (P = 0.02). CONCLUSIONS: Expression levels of p53 and p21, especially when simultaneously assessed, exhibit independent predictive value for long-term bladder preservation and survival in patients with bladder carcinoma treated with combined-modality therapy. These determinations could be useful in the selection of candidates for bladder-preserving treatment.

Analgesic use for postoperative pain: differences arise when comparing departments of surgery.

PURPOSE: The goal of the study is to analyse whether the analgesic therapy of postoperative pain during the first 2 days after surgery differs among the different surgical departments. METHODS: Patients were randomly chosen from among all those who underwent elective surgery. Characteristics of analgesic treatment (drug, dosage, schedule) and pain intensity were determined at the postoperative anaesthetic care unit and in the first and second postoperative days on the ward. All comparisons were carried out by surgical departments. RESULTS: Six hundred and twenty-three patients from six surgical departments were studied. Analgesic treatment orders varied greatly among the different departments, and these differences were statistically significant regarding number of drugs, type of drugs, analgesic schedule, and completeness of medical orders. Some differences were also observed regarding drug dosage. Patients from gynaecology and obstetrics, traumatology and orthopaedics and general surgery reported the most severe pain. CONCLUSIONS: The treatment of postoperative pain differs among the surgical departments, especially regarding analgesic schedules and completeness of analgesic orders. Analgesic therapy may often be based more on customary habits than on the patients' pain intensity.