Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer.

BACKGROUND: Limited level 1 evidence is available on the omission of radiotherapy after breast-conserving surgery in older women with hormone receptor-positive early breast cancer receiving adjuvant endocrine therapy. METHODS: We performed a phase 3 randomized trial of the omission of irradiation; the trial population included women 65 years of age or older who had hormone receptor-positive, node-negative, T1 or T2 primary breast cancer (with tumors ≤3 cm in the largest dimension) treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were randomly assigned to receive whole-breast irradiation (40 to 50 Gy) or no irradiation. The primary end point was local breast cancer recurrence. Regional recurrence, breast cancer-specific survival, distant recurrence as the first event, and overall survival were also assessed. RESULTS: A total of 1326 women were enrolled; 658 were randomly assigned to receive whole-breast irradiation and 668 to receive no irradiation. The median follow-up was 9.1 years. The cumulative incidence of local breast cancer recurrence within 10 years was 9.5% (95% confidence interval [CI], 6.8 to 12.3) in the no-radiotherapy group and 0.9% (95% CI, 0.1 to 1.7) in the radiotherapy group (hazard ratio, 10.4; 95% CI, 4.1 to 26.1; P<0.001). Although local recurrence was more common in the group that did not receive radiotherapy, the 10-year incidence of distant recurrence as the first event was not higher in the no-radiotherapy group than in the radiotherapy group, at 1.6% (95% CI, 0.4 to 2.8) and 3.0% (95% CI, 1.4 to 4.5), respectively. Overall survival at 10 years was almost identical in the two groups, at 80.8% (95% CI, 77.2 to 84.3) with no radiotherapy and 80.7% (95% CI, 76.9 to 84.3) with radiotherapy. The incidence of regional recurrence and breast cancer-specific survival also did not differ substantially between the two groups. CONCLUSIONS: Omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event or overall survival among women 65 years of age or older with low-risk, hormone receptor-positive early breast cancer. (Funded by the Chief Scientist Office of the Scottish Government and the Breast Cancer Institute, Western General Hospital, Edinburgh; ISRCTN number, ISRCTN95889329.).

Postoperative radiotherapy omission in selected patients with early breast cancer following preoperative breast MRI (PROSPECT): primary results of a prospective two-arm study.

BACKGROUND: Adjuvant breast radiotherapy as a standard component of breast-conserving treatment for early cancer can overtreat many women. Breast MRI is the most sensitive modality to assess local tumour burden. The aim of this study was to determine whether a combination of MRI and pathology findings can identify women with truly localised breast cancer who can safely avoid radiotherapy. METHODS: PROSPECT is a prospective, multicentre, two-arm, non-randomised trial of radiotherapy omission in patients selected using preoperative MRI and postoperative tumour pathology. It is being conducted at four academic hospitals in Australia. Women aged 50 years or older with cT1N0 non-triple-negative breast cancer were eligible. Those with apparently unifocal cancer had breast-conserving surgery (BCS) and, if pT1N0 or N1mi, had radiotherapy omitted (group 1). Standard treatment including excision of MRI-detected additional cancers was offered to the others (group 2). All were recommended systemic therapy. The primary outcome was ipsilateral invasive recurrence rate (IIRR) at 5 years in group 1. Primary analysis occurred after the 100th group 1 patient reached 5 years follow-up. Quality-adjusted life-years (QALYs) and cost-effectiveness of the PROSPECT pathway were analysed. This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12610000810011). FINDINGS: Between May 17, 2011, and May 6, 2019, 443 patients with breast cancer underwent MRI. Median age was 63·0 years. MRI detected 61 malignant occult lesions separate from the index cancer in 48 patients (11%). Of 201 group 1 patients who had BCS without radiotherapy, the IIRR at 5 years was 1·0% (upper 95% CI 5·4%). In group 1, one local recurrence occurred at 4·5 years and a second at 7·5 years. In group 2, nine patients had mastectomy (2% of total cohort), and the 5-year IIRR was 1·7% (upper 95% CI 6·1%). The only distant metastasis in the entire cohort was genetically distinct from the index cancer. The PROSPECT pathway increased QALYs by 0·019 (95% CI 0·008-0·029) and saved AU$1980 (95% CI 1396-2528) or £953 (672-1216) per patient. INTERPRETATION: PROSPECT suggests that women with unifocal breast cancer on MRI and favourable pathology can safely omit radiotherapy. FUNDING: Breast Cancer Trials, National Breast Cancer Foundation, Cancer Council Victoria, the Royal Melbourne Hospital Foundation, and the Breast Cancer Research Foundation.

Non-surgical ablation for breast cancer: an emerging therapeutic option.

Non-surgical ablation is emerging as an alternative local therapy option for patients with early-stage breast cancer and encompasses two main types of percutaneous therapeutic procedures: radiofrequency ablation and cryoablation. Both techniques involve obliteration of a spherical lesion and feasibility studies have shown that complete tumour ablation is achievable with good or excellent cosmetic results. Although few clinical studies have directly compared non-surgical ablation with conventional surgical resection, observational studies indicate that clinical outcomes are favourable with acceptable rates of local control and no detriment to long-term survival. There remain outstanding issues with these percutaneous ablative techniques that require resolution before they could be incorporated into routine clinical practice. Hence, a consensus meeting was convened to discuss the challenges of non-surgical ablation and clarify indications for its use alongside clinical management pathways. In this Policy Review we will address some of the broader biological aspects of non-surgical ablation, including immune-modulatory effects and potential novel applications for the future.

Selective omission of sentinel lymph node biopsy in mastectomy for ductal carcinoma in situ: identifying eligible candidates.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is recommended for patients with ductal carcinoma in situ (DCIS) undergoing mastectomy, given the concerns regarding upstaging and technical difficulties of post-mastectomy SLNB. However, this may lead to potential overtreatment, considering favorable prognosis and de-escalation trends in DCIS. Data regarding upstaging and axillary lymph node metastasis among these patients remain limited. METHODS: We retrospectively reviewed patients with DCIS who underwent mastectomy with SLNB or axillary lymph node dissection at Gangnam Severance Hospital between January 2010 and December 2021. To explore the feasibility of omitting SLNB, we assessed the rates of DCIS upgraded to invasive carcinoma and axillary lymph node metastasis. Binary Cox regression analysis was performed to identify clinicopathologic factors associated with upstaging and axillary lymph node metastasis. RESULTS: Among 385 patients, 164 (42.6%) experienced an invasive carcinoma upgrade: microinvasion, pT1, and pT2 were confirmed in 53 (13.8%), 97 (25.2%), and 14 (3.6%) patients, respectively. Seventeen (4.4%) patients had axillary lymph node metastasis. Multivariable analysis identified age ≤ 50 years (adjusted odds ratio [OR], 12.73; 95% confidence interval [CI], 1.18-137.51; p = 0.036) and suspicious axillary lymph nodes on radiologic evaluation (adjusted OR, 9.31; 95% CI, 2.06-41.99; p = 0.004) as independent factors associated with axillary lymph node metastasis. Among patients aged > 50 years and/or no suspicious axillary lymph nodes, only 1.7-2.3%) experienced axillary lymph node metastasis. CONCLUSIONS: Although underestimation of the invasive component was relatively high among patients with DCIS undergoing mastectomy, axillary lymph node metastasis was rare. Our findings suggest that omitting SLNB may be feasible for patients over 50 and/or without suspicious axillary lymph nodes on radiologic evaluation.

The role of surgical tissue injury and intraoperative sympathetic activation in postoperative immunosuppression after breast-conserving surgery versus mastectomy: a prospective observational study.

BACKGROUND: Breast cancer is the second most common cause of death from cancer in women worldwide. Counterintuitively, large population-based retrospective trials report better survival after breast-conserving surgery (BCS) compared to mastectomy, corrected for tumour- and patient variables. More extensive surgical tissue injury and activation of the sympathetic nervous system by nociceptive stimuli are associated with immune suppression. We hypothesized that mastectomy causes a higher expression of plasma damage associated molecular patterns (DAMPs) and more intraoperative sympathetic activation which induce postoperative immune dysregulation. Immune suppression can lead to postoperative complications and affect tumour-free survival. METHODS: In this prospective observational study, plasma DAMPs (HMGB1, HSP70, S100A8/A9 and S100A12), intraoperative sympathetic activation (Nociception Level (NOL) index from 0 to 100), and postoperative immune function (plasma cytokine concentrations and ex vivo cytokine production capacity) were compared in patients undergoing elective BCS (n = 20) versus mastectomy (n = 20). RESULTS: Ex vivo cytokine production capacity of TNF, IL-6 and IL-1ß was nearly absent in both groups one hour after surgery. Levels appeared recovered on postoperative day 3 (POD3), with significantly higher ex vivo production capacity of IL-1ß after BCS (p = .041) compared to mastectomy. Plasma concentration of IL-6 was higher one hour after mastectomy (p = .045). Concentrations of plasma alarmins S100A8/A9 and S100A12 were significantly higher on POD3 after mastectomy (p = .003 and p = .041, respectively). Regression analysis showed a significantly lower percentage of NOL measurements ≤ 8 (absence of nociception) during mastectomy when corrected for norepinephrine equivalents (36% versus 45% respectively, p = .038). Percentage of NOL measurements ≤ 8 of all patients correlated with ex vivo cytokine production capacity of IL-1ß and TNF on POD3 (r = .408; p = .011 and r = .500; p = .001, respectively). CONCLUSIONS: This pilot study revealed substantial early postoperative immune suppression after BCS and mastectomy that appears to recover in the following days. Differences between BCS and mastectomy in release of DAMPs and intraoperative sympathetic activation could affect postoperative immune homeostasis and thereby contribute to the better survival reported after BCS in previous large population-based retrospective trials. These results endorse further exploration of (1) S100 alarmins as potential therapeutic targets in breast cancer surgery and (2) suppression of intraoperative sympathetic activation to substantiate the observed association with postoperative immune dysregulation.

Deep learning-based risk stratification of preoperative breast biopsies using digital whole slide images.

BACKGROUND: Nottingham histological grade (NHG) is a well established prognostic factor in breast cancer histopathology but has a high inter-assessor variability with many tumours being classified as intermediate grade, NHG2. Here, we evaluate if DeepGrade, a previously developed model for risk stratification of resected tumour specimens, could be applied to risk-stratify tumour biopsy specimens. METHODS: A total of 11,955,755 tiles from 1169 whole slide images of preoperative biopsies from 896 patients diagnosed with breast cancer in Stockholm, Sweden, were included. DeepGrade, a deep convolutional neural network model, was applied for the prediction of low- and high-risk tumours. It was evaluated against clinically assigned grades NHG1 and NHG3 on the biopsy specimen but also against the grades assigned to the corresponding resection specimen using area under the operating curve (AUC). The prognostic value of the DeepGrade model in the biopsy setting was evaluated using time-to-event analysis. RESULTS: Based on preoperative biopsy images, the DeepGrade model predicted resected tumour cases of clinical grades NHG1 and NHG3 with an AUC of 0.908 (95% CI: 0.88; 0.93). Furthermore, out of the 432 resected clinically-assigned NHG2 tumours, 281 (65%) were classified as DeepGrade-low and 151 (35%) as DeepGrade-high. Using a multivariable Cox proportional hazards model the hazard ratio between DeepGrade low- and high-risk groups was estimated as 2.01 (95% CI: 1.06; 3.79). CONCLUSIONS: DeepGrade provided prediction of tumour grades NHG1 and NHG3 on the resection specimen using only the biopsy specimen. The results demonstrate that the DeepGrade model can provide decision support to identify high-risk tumours based on preoperative biopsies, thus improving early treatment decisions.

Contrast-enhanced ultrasound to predict malignant upgrading of atypical ductal hyperplasia.

BACKGROUND: A malignancy might be found at surgery in cases of atypical ductal hyperplasia (ADH) diagnosed via US-guided core needle biopsy (CNB). The objective of this study was to investigate the diagnostic performance of contrast-enhanced ultrasound (CEUS) in predicting ADH diagnosed by US-guided CNB that was upgraded to malignancy after surgery. METHODS: In this retrospective study, 110 CNB-diagnosed ADH lesions in 109 consecutive women who underwent US, CEUS, and surgery between June 2018 and June 2023 were included. CEUS was incorporated into US BI-RADS and yielded a CEUS-adjusted BI-RADS. The diagnostic performance of US BI-RADS and CEUS-adjusted BI-RADS for ADH were analyzed and compared. RESULTS: The mean age of the 109 women was 49.7 years ± 11.6 (SD). The upgrade rate of ADH at CNB was 48.2% (53 of 110). The sensitivity, specificity, positive predictive value, and negative predictive value of CEUS for identification of malignant upgrading were 96.2%, 66.7%,72.9%, and 95.0%, respectively, based on BI-RADS category 4B threshold. The two false-negative cases were low-grade ductal carcinoma in situ. Compared with the US, CEUS-adjusted BI-RADS had better specificity for lesions smaller than 2 cm (76.7% vs. 96.7%, P = 0.031). After CEUS, 16 (10 malignant and 6 nonmalignant) of the 45 original US BI-RADS category 4A lesions were up-classified to BI-RADS 4B, and 3 (1 malignant and 2 nonmalignant) of the 41 original US BI-RADS category 4B lesions were down-classified to BI-RADS 4A. CONCLUSIONS: CEUS is helpful in predicting malignant upgrading of ADH, especially for lesions smaller than 2 cm and those classified as BI-RADS 4A and 4B on ultrasound.

Breast density knowledge and willingness to delay treatment for pre-operative breast cancer imaging among women with a personal history of breast cancer.

BACKGROUND: Following a breast cancer diagnosis, it is uncertain whether women's breast density knowledge influences their willingness to undergo pre-operative imaging to detect additional cancer in their breasts. We evaluated women's breast density knowledge and their willingness to delay treatment for pre-operative testing. METHODS: We surveyed women identified in the Breast Cancer Surveillance Consortium aged ≥ 18 years, with first breast cancer diagnosed within the prior 6-18 months, who had at least one breast density measurement within the 5 years prior to their diagnosis. We assessed women's breast density knowledge and correlates of willingness to delay treatment for 6 or more weeks for pre-operative imaging via logistic regression. RESULTS: Survey participation was 28.3% (969/3,430). Seventy-two percent (469/647) of women with dense and 11% (34/322) with non-dense breasts correctly knew their density (p < 0.001); 69% (665/969) of all women knew dense breasts make it harder to detect cancers on a mammogram; and 29% (285/969) were willing to delay treatment ≥ 6 weeks to undergo pre-operative imaging. Willingness to delay treatment did not differ by self-reported density (OR:0.99 for non-dense vs. dense; 95%CI: 0.50-1.96). Treatment with chemotherapy was associated with less willingness to delay treatment (OR:0.67; 95%CI: 0.46-0.96). Having previously delayed breast cancer treatment more than 3 months was associated with an increased willingness to delay treatment for pre-operative imaging (OR:2.18; 95%CI: 1.26-3.77). CONCLUSIONS: Understanding of personal breast density was not associated with willingness to delay treatment 6 or more weeks for pre-operative imaging, but aspects of a woman's treatment experience were. CLINICALTRIALS: GOV : NCT02980848 registered December 2, 2016.

Nomogram predicts survival and surgical benefits for patients with breast cancer with initial bone metastasis: A population-based study.

BACKGROUND: Primary stage IV breast cancer is associated with a poor prognosis. At present, the value of local surgical treatment for patients with stage IV breast cancer remains uncertain; therefore, treatment principles remain controversial. Because of the high heterogeneity of these patients, it is often difficult to evaluate their prognoses. As a result, this study aimed to establish a prognostic nomogram to evaluate the prognosis of patients with breast cancer experiencing primary bone metastasis. METHODS: The clinical characteristics and follow-up data of patients with primary breast cancer and bone metastasis from 2010 to 2018 were collected from the Surveillance, Epidemiology, and End Results database and from 2013 to 2021 at the Peking Union Medical College Hospital. Patients were divided into training and validation groups. Multivariate Cox regression analysis was used to identify the independent prognostic variables for predicting cancer-specific survival (CSS). On the basis of these independent risk factors, a nomogram was developed and used calibration curves to evaluate its accuracy. Patients were divided into three risk groups according to their scores and surgery-related survival curves plotted using the log-rank test. RESULTS: Overall, 6372 patients were included, with 6319 from the Surveillance, Epidemiology, and End Results database and 53 from the Peking Union Medical College Hospital Breast Surgery Department. Multivariate analysis showed that age, race, marital status, grade, tumor stage, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status, and burden of other metastatic lesions were all associated with CSS. Based on these results, a nomogram that predicted the 1-, 3-, and 5-year CSS rates in patients with primary breast cancer and bone metastasis (concordance index > 0.69) was developed. After dividing patients into low-risk, high-risk, or super-high-risk groups based on nomogram scoring criteria, survival analysis revealed that patients in the low- and high-risk groups had significant survival benefits from primary focal surgery. CONCLUSION: Independent risk factors for primary breast cancer in patients with bone metastasis were analyzed and a nomogram established to predict CSS. The prognostic tool derived in this study can assist clinicians in predicting the survival and surgical benefits of these patients through scoring, thereby providing further guidance for treatment strategies.

Association of travel time, patient characteristics, and hospital quality with patient mobility for breast cancer surgery: A national population-based study.

BACKGROUND: This national study investigated hospital quality and patient factors associated with treatment location for breast cancer surgery. METHODS: By using linked administrative data sets from the English National Health Service, the authors identified all women diagnosed between January 2, 2016, and December 31, 2018, who underwent breast-conserving surgery (BCS) or a mastectomy with or without immediate breast reconstruction. The extent to which patients bypassed their nearest hospital was investigated using a geographic information system (ArcGIS). Conditional logistic regressions were used to estimate the impact of travel time, hospital quality, and patient characteristics. RESULTS: 22,622 Of 69,153 patients undergoing BCS, 22,622 (32.7%) bypassed their nearest hospital; and, of 23,536 patients undergoing mastectomy, 7179 (30.5%) bypassed their nearest hospital. Women who were younger, without comorbidities, or from rural areas were more likely to travel to more distant hospitals (p < .05). Patients undergoing BCS (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.36-2.50) or mastectomy (OR, 1.52; 95% CI, 1.14-2.02) were more likely to be treated at specialist breast reconstruction centers despite not undergoing the procedure. Patients receiving mastectomy and immediate breast reconstruction were more likely to travel to hospitals employing surgeons who had a media reputation (OR, 2.41; 95% CI, 1.28-4.52). Patients undergoing BCS were less likely to travel to hospitals with shorter surgical waiting times (OR, 0.65; 95% CI, 0.46-0.92). The authors did not observe a significant impact for research activity, hospital quality rating, breast re-excision rates, or the status as a multidisciplinary cancer center. CONCLUSIONS: Patient choice policies may drive inequalities in the health care system without improving patient outcomes.

Should patients with hormone receptor-positive, HER2-negative breast cancer and one or two positive sentinel nodes undergo axillary dissection to determine candidacy for adjuvant abemaciclib?

BACKGROUND: The monarchE trial demonstrated improved outcomes with the use of adjuvant abemaciclib in patients with high-risk hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer defined as ≥4 positive lymph nodes (+LNs) or one to three +LNs with one or more additional high-risk features (HRFs). The proportion of patients with one or two positive sentinel lymph nodes (+SLNs) without HRFs who had ≥4 +LNs at the time of completion axillary lymph node dissection (cALND), and who therefore qualified for receipt of abemaciclib, was investigated. METHODS: Females with pathologically node-positive nonmetastatic HR+/HER2- breast cancer stratified by the number of +SLNs and +LNs and the presence of one or more HRFs were identified from the National Cancer Database (2018-2019). The proportion of patients meeting the criteria for abemaciclib both before and after ALND was assessed. RESULTS: Of the 22,048 patients identified, 1578 patients underwent upfront surgery, had one or two +SLNs without HRFs, and went on to cALND. Only 213 (13%) of these patients had ≥4 +LNs; thus, cALND performed solely to determine abemaciclib candidacy would have constituted surgical overtreatment in 1365 patients (87%). When stratified by the number of +SLNs, only 10% of those with one +SLN and 24% of those with two +SLNs had ≥4 +LNs after cALND, which meets the criteria for abemaciclib. CONCLUSIONS: Patients with one +SLN without HRFs are unlikely to have ≥4 +LNs and should not be subjected to the morbidity of ALND in order to inform candidacy for abemaciclib. An individualized multidisciplinary discussion should be undertaken about the risk:benefit ratio of ALND and abemaciclib for those with two +SLNs.

Nonclinical factors associated with the treatment of older women with newly diagnosed low-grade ductal carcinoma in situ.

BACKGROUND: Ductal carcinoma in situ (DCIS) is the most common form of noninvasive breast cancer and is associated with an excellent prognosis. As a result, there is concern about overdiagnosis and overtreatment of DCIS because most patients with DCIS are treated as though they have invasive breast cancer and undergo either breast-conserving surgery (BCS)-most commonly followed by radiation therapy (RT)-or mastectomy. Little research to date has focused on nonclinical factors influencing treatments for DCIS. METHODS: Population-based data were analyzed from five state cancer registries (California, Florida, New Jersey, New York, and Texas) on women aged 65 years and older newly diagnosed with DCIS during the years 2003 to 2014 using a retrospective cohort design and multinominal logistic modeling. The registry records with Medicare enrollment data and fee-for-service claims to obtain treatments (BCS alone, BCS with RT, or mastectomy) were merged. Surgeon practice structure was identified through physician surveys and internet searches. RESULTS: Patients of surgeons employed by cancer centers or health systems were less likely to receive BCS with RT or mastectomy than patients of surgeons in single specialty or multispecialty practices. There also was substantial geographic variation in treatments, with patients in New York, New Jersey, and California being less likely to receive BCS with RT or mastectomy than patients in Texas or Florida. CONCLUSIONS: These findings suggest nonclinical factors including the culture of the practice and/or financial incentives are significantly associated with the types of treatment received for DCIS. Increasing awareness and targeted efforts to educate physicians about DCIS management among older women with low-grade DCIS could reduce patient harm and yield substantial cost savings.

Risk-reducing mastectomy and breast cancer mortality in women with a BRCA1 or BRCA2 pathogenic variant: an international analysis.

BACKGROUND: Risk-reducing mastectomy (RRM) is offered to women with a BRCA1 or BRCA2 pathogenic variant, however, there are limited data on the impact on breast cancer mortality. METHODS: Participants were identified from a registry of women with BRCA1/2 pathogenic variants. We used a pseudo-randomised trial design and matched one woman with a RRM to one woman without a RRM on year of birth, gene, and country. We estimated the hazard ratio (HR) and 95% confidence intervals (CI) for dying of breast cancer in the follow-up period. RESULTS: There were 1654 women included; 827 assigned to the RRM arm and 827 assigned to the control arm. After a mean follow-up of 6.3 years, there were 20 incident breast cancers (including 15 occult cancers) and two breast cancer deaths in the RRM arm, and 100 incident breast cancers and 7 breast cancer deaths in the control arm (HR = 0.26; 95% CI 0.05-1.35; p = 0.11). The probability of dying of breast cancer within 15 years after RRM was 0.95%. CONCLUSIONS: In women with a BRCA1 or BRCA2 pathogenic variant, RRM reduces the risk of breast cancer, and the probability of dying of breast cancer is low.

A nationwide study of breast reconstruction after mastectomy in patients with breast cancer receiving postmastectomy radiotherapy: comparison of complications according to radiotherapy fractionation and reconstruction procedures.

BACKGROUND: We examined the patterns of breast reconstruction postmastectomy in breast cancer patients undergoing postmastectomy radiotherapy (PMRT) and compared complications based on radiotherapy fractionation and reconstruction procedures. METHODS: Using National Health Insurance Service (NHIS) data (2015-2020), we analysed 4669 breast cancer patients with PMRT and reconstruction. Using propensity matching, cohorts for hypofractionated fractionation (HF) and conventional fractionation (CF) were created, adjusting for relevant factors and identifying grade ≥3 complications. RESULT: Of 4,669 patients, 30.6% underwent HF and 69.4% CF. The use of HF has increased from 19.4% in 2015 to 41.0% in 2020. Immediate autologous (32.9%) and delayed two-stage implant reconstruction (33.9%) were common. Complication rates for immediate (N = 1286) and delayed two-stage (N = 784) reconstruction were similar between HF and CF groups (5.1% vs. 5.4%, P = 0.803, and 10.5% vs. 10.7%, P = 0.856, respectively) with median follow-ups of 2.5 and 2.6 years. HF showed no increased risk of complications across reconstruction methods. CONCLUSION: A nationwide cohort study revealed no significant difference in complication rates between the HF and CF groups, indicating HF for reconstructed breasts is comparable to CF. However, consultation regarding the fractionation for reconstructed breast cancer patients may still be necessary.

Rethinking surgical revisions: impact of the MonarchE trial on axillary dissection in hormone-positive HER2-negative early breast cancer patients potentially eligible for abemaciclib.

INTRODUCTION: The MonarchE trial explored the use of abemaciclib, a CDK4/6 inhibitor, as an adjuvant treatment in high-risk early-stage luminal-like breast cancer. The study's inclusion criteria, especially the N2 status, may require revisiting surgical interventions, including invasive axillary lymph node dissection (ALND)-a procedure that current guidelines generally do not recommend. METHODS: We conducted a single-centre, retrospective, observational cohort study on non-metastatic breast cancer patients managed from 2002 to 2011, at the Institut Curie. Data collection involved clinical and histological characteristics plus treatment follow-up. RESULTS: Out of 8715 treated patients, 721 met the inclusion criteria. Overall, 12% (87) were classified as N2 ( ≥ 4 positive lymph nodes), thus eligible for abemaciclib per "node criterion." Tumour size, positive sentinel lymph nodes, and lobular histology showed a significant correlation with N2 status. Approximately 1000 ALNDs would be required to identify 120 N2 cases and prevent four recurrences. CONCLUSION: The MonarchE trial may significantly affect surgical practices due to the need for invasive procedures to identify high-risk patients for adjuvant abemaciclib treatment. The prospect of unnecessary morbidity demands less invasive N2 status determination methods. Surgical decisions must consider patient health and potential treatment benefits.

Tumor microenvironment and immune system preservation in early-stage breast cancer: routes for early recurrence after mastectomy and treatment for lobular and ductal forms of disease.

BACKGROUND: Intra-ductal cancer (IDC) is the most common type of breast cancer, with intra-lobular cancer (ILC) coming in second. Surgery is the primary treatment for early stage breast cancer. There are now irrefutable data demonstrating that the immune context of breast tumors can influence growth and metastasis. Adjuvant chemotherapy may be administered in patients who are at a high risk of recurrence. Our goal was to identify the processes underlying both types of early local recurrences. METHODS: This was a case-control observational study. Within 2 years of receiving adjuvant taxan and anthracycline-based chemotherapy, as well as modified radical mastectomy (MRM), early stage IDC and ILC recurred. Vimentin, α-smooth muscle actin (SMA), platelet-derived growth factor (PDGF), matrix metalloproteinase (MMP1), and clustered differentiation (CD95) were investigated. RESULTS: Of the samples in the ductal type group, 25 showed local recurrence, and 25 did not. Six individuals in the lobular-type group did not experience recurrence, whereas seven did. Vimentin (p = 0.000 and 0.021), PDGF (p = 0.000 and 0.002), and CD95 (p = 0.000 and 0.045) expressions were significantly different in ductal and lobular carcinoma types, respectively. Measurement of ductal type was the sole significant difference found in MMP1 (p = 0.000) and α-SMA (p = 0.000). α-SMA and CD95 were two variables that helped the recurrence mechanism in the ductal type according to the pathway analysis. In contrast, the CD95 route is a recurrent mechanism for the lobular form. CONCLUSIONS: While the immune system plays a larger role in ILC, the tumor microenvironment and immune system both influence the recurrence of IDC. According to this study, improving the immune system may be a viable cancer treatment option.

Robotic Versus Conventional or Endoscopic-assisted Nipple-sparing Mastectomy and Immediate Prosthesis Breast Reconstruction in the Management of Breast Cancer: A Prospectively Designed Multicenter Trial Comparing Clinical Outcomes, Medical Cost, and Patient-reported Outcomes (RCENSM-P).

OBJECTIVE: To compare the clinical and patient-reported outcomes of minimal access and conventional nipple-sparing mastectomy (C-NSM). The secondary outcomes investigated included medical costs and oncological safety. BACKGROUND: Minimal-access NSM has been increasingly applied in the treatment of patients with breast cancer. However, prospective multicenter trials comparing robotic-assisted NSM (R-NSM) versus C-NSM or endoscopic-assisted NSM (E-NSM) are lacking. METHODS: A prospectively designed 3-arm multicenter, nonrandomized trial (NCT04037852) was conducted from October 1, 2019 to December 31, 2021, to compare R-NSM with C-NSM or E-NSM. RESULTS: A total of 73 R-NSM, 74 C-NSM, and 84 E-NSM procedures were enrolled. The median wound length and operation time of C-NSM was (9 cm, 175 minutes), (4 cm, and 195 minutes) in R-NSM, and (4 cm and 222 minutes) in E-NSM. Complications were comparable among the groups. Better wound healing was observed in the minimal-access NSM group. The R-NSM procedure was 4000 and 2600 United States Dollars more expensive than C-NSM and E-NSM, respectively. Wound/scar and postoperative acute pain evaluation favored the use of minimal access NSM over C-NSM. Quality of life in terms of chronic breast/chest pain, mobility, and range of motion of the upper extremity showed no significant differences. The preliminary oncologic results showed no differences among the 3 groups. CONCLUSIONS: R-NSM or E-NSM is a safe alternative if compared with C-NSM in terms of perioperative morbidities, especially with better wound healing. The advantage of minimal access groups was higher wound-related satisfaction. Higher costs remain one of the major limiting factors in the widespread adoption of R-NSM.

Association of Medicaid Expansion with Reduction in Racial Disparities in the Timely Delivery of Upfront Surgical Care for Patients With Early-Stage Breast Cancer.

OBJECTIVE: We evaluated the association between Medicaid expansion and time to surgery among patients with early-stage breast cancer (BC). BACKGROUND: Delays in surgery are associated with adverse outcomes. It is known that underrepresented minorities are more likely to experience treatment delays. Understanding the impact of Medicaid expansion on reducing racial and ethnic disparities in health care delivery is critical. METHODS: This was a population-based study including women ages 40 to 64 with stage I-II BC who underwent upfront surgery identified in the National Cancer Database (2010-2017) residing in states that expanded Medicaid on January 1, 2014. Difference-in-difference analysis compared rates of delayed surgery (>90 d from pathological diagnosis) according to time period (preexpansion [2010-2013] and postexpansion [2014-2017]) and race/ethnicity (White vs. racial and ethnic minority), stratified by insurance type (private vs. Medicaid/uninsured). Secondary analyses included logistic and Cox proportional hazards (PH) regression. All analyses were conducted among a cohort of patients in the nonexpansion states as a falsification analysis. Finally, a triple-differences approach compared preexpansion with the postexpansion trend between expansion and nonexpansion states. RESULTS: Among Medicaid expansion states, 104,569 patients were included (50,048 preexpansion and 54,521 postexpansion). In the Medicaid/uninsured subgroup, Medicaid expansion was associated with a -1.8% point (95% CI: -3.5% to -0.1, P =0.04) reduction of racial disparity in delayed surgery. Cox regression models demonstrated similar findings (adjusted difference-in-difference hazard ratio 1.12 [95% CI: 1.05 to 1.21]). The falsification analysis showed a significant racial disparity reduction among expansion states but not among nonexpansion states, resulting in a triple-difference estimate of -2.5% points (95% CI: -4.9% to -0.1%, P =0.04) in this subgroup. CONCLUSIONS: As continued efforts are being made to increase access to health care, our study demonstrates a positive association between Medicaid expansion and a reduction in the delivery of upfront surgical care, reducing racial disparities among patients with early-stage BC.

Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trial.

BACKGROUND: A tumour-bed boost delivered after whole-breast radiotherapy increases local cancer-control rates but requires more patient visits and can increase breast hardness. IMPORT HIGH tested simultaneous integrated boost against sequential boost with the aim of reducing treatment duration while maintaining excellent local control and similar or reduced toxicity. METHODS: IMPORT HIGH is a phase 3, non-inferiority, open-label, randomised controlled trial that recruited women after breast-conserving surgery for pT1-3pN0-3aM0 invasive carcinoma from radiotherapy and referral centres in the UK. Patients were randomly allocated to receive one of three treatments in a 1:1:1 ratio, with computer-generated random permuted blocks used to stratify patients by centre. The control group received 40 Gy in 15 fractions to the whole breast and 16 Gy in 8 fractions sequential photon tumour-bed boost. Test group 1 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 48 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. Test group 2 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 53 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. The boost clinical target volume was the clip-defined tumour bed. Patients and clinicians were not masked to treatment allocation. The primary endpoint was ipsilateral breast tumour relapse (IBTR) analysed by intention to treat; assuming 5% 5-year incidence with the control group, non-inferiority was predefined as 3% or less absolute excess in the test groups (upper limit of two-sided 95% CI). Adverse events were assessed by clinicians, patients, and photographs. This trial is registered with the ISRCTN registry, ISRCTN47437448, and is closed to new participants. FINDINGS: Between March 4, 2009, and Sept 16, 2015, 2617 patients were recruited. 871 individuals were assigned to the control group, 874 to test group 1, and 872 to test group 2. Median boost clinical target volume was 13 cm3 (IQR 7 to 22). At a median follow-up of 74 months there were 76 IBTR events (20 for the control group, 21 for test group 1, and 35 for test group 2). 5-year IBTR incidence was 1·9% (95% CI 1·2 to 3·1) for the control group, 2·0% (1·2 to 3·2) for test group 1, and 3·2% (2·2 to 4·7) for test group 2. The estimated absolute differences versus the control group were 0·1% (-0·8 to 1·7) for test group 1 and 1·4% (0·03 to 3·8) for test group 2. The upper confidence limit for test group 1 versus the control group indicated non-inferiority for 48 Gy. Cumulative 5-year incidence of clinician-reported moderate or marked breast induration was 11·5% for the control group, 10·6% for test group 1 (p=0·40 vs control group), and 15·5% for test group 2 (p=0·015 vs control group). INTERPRETATION: In all groups 5-year IBTR incidence was lower than the 5% originally expected regardless of boost sequencing. Dose-escalation is not advantageous. 5-year moderate or marked adverse event rates were low using small boost volumes. Simultaneous integrated boost in IMPORT HIGH was safe and reduced patient visits. FUNDING: Cancer Research UK.

Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials.

BACKGROUND: Anthracycline-taxane chemotherapy for early-stage breast cancer substantially improves survival compared with no chemotherapy. However, concerns about short-term and long-term side-effects of anthracyclines have led to increased use of taxane chemotherapy without anthracycline, which could compromise efficacy. We aimed to better characterise the benefits and risks of including anthracycline, and the comparative benefits of different anthracycline-taxane regimens. METHODS: We did an individual patient-level meta-analysis of randomised trials comparing taxane regimens with versus without anthracycline, and updated our previous meta-analysis of anthracycline regimens with versus without taxane, as well as analysing 44 trials in six related comparisons. We searched databases, including MEDLINE, Embase, the Cochrane Library, and meeting abstracts to identify trials assessing anthracycline and taxane chemotherapy. Adjuvant or neoadjuvant trials were eligible if they began before Jan 1, 2012. Primary outcomes were breast cancer recurrence and cause-specific mortality. Log-rank analyses yielded first-event rate ratios (RRs) and CIs. FINDINGS: 28 trials of taxane regimens with or without anthracycline were identified, of which 23 were deemed eligible, and 15 provided data on 18 103 women. Across all 15 trials that provided individual data, recurrence rates were 14% lower on average (RR 0·86, 95% CI 0·79-0·93; p=0·0004) with taxane regimens including anthracycline than those without. Non-breast cancer deaths were not increased but there was one additional acute myeloid leukaemia case per 700 women treated. The clearest reductions in recurrence were found when anthracycline was added concurrently to docetaxel plus cyclophosphamide versus the same dose of docetaxel plus cyclophosphamide (10-year recurrence risk 12·3% vs 21·0%; risk difference 8·7%, 95% CI 4·5-12·9; RR 0·58, 0·47-0·73; p<0·0001). 10-year breast cancer mortality in this group was reduced by 4·2% (0·4-8·1; p=0·0034). No significant reduction in recurrence risk was found for sequential schedules of taxane plus anthracycline when compared with docetaxel plus cyclophosphamide (RR 0·94, 0·83-1·06; p=0·30). For the analysis of anthracycline regimens with versus without taxane, 35 trials (n=52 976) provided individual patient data. Larger recurrence reductions were seen from adding taxane to anthracycline regimens when the cumulative dose of anthracycline was the same in each group (RR 0·87, 0·82-0·93; p<0·0001; n=11 167) than in trials with two-fold higher cumulative doses of non-taxane (mostly anthracycline) in the control group than in the taxane group (RR 0·96, 0·90-1·03; p=0·27; n=14 620). Direct comparisons between anthracycline and taxane regimens showed that a higher cumulative dose and more dose-intense schedules were more efficacious. The proportional reductions in recurrence for taxane plus anthracycline were similar in oestrogen receptor-positive and oestrogen receptor-negative disease, and did not differ by age, nodal status, or tumour size or grade. INTERPRETATION: Anthracycline plus taxane regimens are most efficacious at reducing breast cancer recurrence and death. Regimens with higher cumulative doses of anthracycline plus taxane provide the greatest benefits, challenging the current trend in clinical practice and guidelines towards non-anthracycline chemotherapy, particularly shorter regimens, such as four cycles of docetaxel-cyclophosphamide. By bringing together data from almost all relevant trials, this meta-analysis provides a reliable evidence base to inform individual treatment decisions, clinical guidelines, and the design of future clinical trials. FUNDING: Cancer Research UK, UK Medical Research Council.