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Background: Immune checkpoint inhibitors have shown minimal clinical activity in hormone receptor-positive metastatic breast cancer (HR + mBC). Doxorubicin and low-dose cyclophosphamide are reported to induce immune responses and counter regulatory T cells (Tregs). Here, we report the efficacy and safety of combined programmed cell death protein-1/cytotoxic T-lymphocyte-associated protein 4 blockade concomitant with or after immunomodulatory chemotherapy for HR + mBC., Methods: Patients with HR + mBC starting first-/second- line chemotherapy (chemo) were randomized 2:3 to chemotherapy (pegylated liposomal doxorubicin 20 mg/m 2 every second week plus cyclophosphamide 50 mg by mouth/day in every other 2-week cycle) with or without concomitant ipilimumab (ipi; 1 mg/kg every sixth week) and nivolumab (nivo; 240 mg every second week). Patients in the chemo-only arm were offered cross-over to ipi/nivo without chemotherapy. Co-primary endpoints were safety in all patients starting therapy and progression-free survival (PFS) in the per-protocol (PP) population, defined as all patients evaluated for response and receiving at least two treatment cycles. Secondary endpoints included objective response rate, clinical benefit rate, Treg changes during therapy and assessment of programmed death-ligand 1 (PD-L1), mutational burden and immune gene signatures as biomarkers., Results: Eighty-two patients were randomized and received immune-chemo (N=49) or chemo-only (N=33), 16 patients continued to the ipi/nivo-only cross-over arm. Median follow-up was 41.4 months. Serious adverse events occurred in 63% in the immune-chemo arm, 39% in the chemo-only arm and 31% in the cross-over-arm. In the PP population (N=78) median PFS in the immune-chemo arm was 5.1 months, compared with 3.6 months in the chemo-only arm, with HR 0.94 (95% CI 0.59 to 1.51). Clinical benefit rates were 55% (26/47) and 48% (15/31) in the immune-chemo and chemo-only arms, respectively. In the cross-over-arm (ipi/nivo-only), objective responses were observed in 19% of patients (3/16) and clinical benefit in 25% (4/16). Treg levels in blood decreased after study chemotherapy. High-grade immune-related adverse events were associated with prolonged PFS. PD-L1 status and mutational burden were not associated with ipi/nivo benefit, whereas a numerical PFS advantage was observed for patients with a high Treg gene signature in tumor., Conclusion: The addition of ipi/nivo to chemotherapy increased toxicity without improving efficacy. Ipi/nivo administered sequentially to chemotherapy was tolerable and induced clinical responses., Trial Registration Number: ClinicalTrials.gov Identifier: NCT03409198., Competing Interests: Competing interests: JAK has in the last 5 years received research support from Bristol Myers Squibb, F. Hoffmann-La Roche, NanoString, and NEC OncoImmunity and has previously received advisory board/lecture honoraria from pharmaceutical companies, including Bristol Myers Squibb. CQ has received honoraria for advisory board from AstraZeneca. BG has received honoraria for advisory boards from Eli Lilly, Gilead, Daiichi Sankyo, Roche, and Pierre Fabre. LJ has received lecture honoraria from Pfizer, Novartis, and AstraZeneca. AG has received travel grants or honoraria for advisory boards from Lilly, Daiichi Sankyo, Seagen, Pfizer, and AstraZeneca. HGR has received research support from Illumina and NanoString. OCL has over the last 2 years received honoraria for work as statistical advisor for Novartis. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Fear of cancer recurrence (FCR) in breast cancer survivors (BCSs) is common, associated with reduced quality of life and effective interventions exist. There are knowledge gaps concerning FCR among long-term, early-stage BCSs and its associations with other late effects. Within a national cohort, we explored these knowledge gaps, with the ultimate aim of improved care for BCSs experiencing long-term FCR., Methods: In this cross-sectional study, all BCSs aged 20-65 years with early-stage breast cancer in 2011-2012 ( n  = 2803), were identified by the Cancer Registry of Norway in 2019 and mailed a survey including the Assessment of Survivor Concerns used to measure FCR. Factors associated with moderate/high FCR (defined as a sum score of ≥ 6 of a possible range 3-12, or a single score on one of the items of ≥ 3) were explored using a three-block regression analyses including relevant sociodemographic-, health- and cancer-related variables., Results: In total, 1311 BCSs were included (47%). Median age at survey was 60 years. Fifty-six % reported moderate-to-high FCR, associated with younger age (OR 0.96, 95% CI 0.95-0.97) and receiving chemo- and endocrine therapy (OR 1.59, 95% CI 1.15-2.20). After adding late effects into the model, FCR remained significantly associated with these variables, in addition to sleep disturbances (OR 1.58, 95% CI 1.18-2.10). In the final block, adding mental distress, FCR remained significantly associated with younger age (OR 0.97, 95% CI 0.96-0.99), receiving chemo- and endocrine therapy (OR 1.14, 95% CI 1.00-1.97), sleep disturbances (OR 1.44, 95% CI 1.08-1.94) and anxiety (OR 2.67, 95% CI 1.38-5.19)., Conclusions: FCR was prevalent eight years after early-stage breast cancer. Being younger, receiving intensive treatment, experiencing sleep disturbances and/or anxiety were associated with moderate/high FCR. Addressing FCR should be part of standard follow-up care of long-term BCSs.

Background: Automatically calculated breast density is a promising alternative to subjective BI-RADS density assessment. However, such software needs a cutoff value for density classification., Purpose: To determine the volumetric density threshold which classifies fatty and dense breasts with highest accuracy compared to average BI-RADS density assessment, and to analyze radiologists' inter-observer variation., Material and Methods: A total of 537 full field digital mammography examinations were randomly selected from a population based screening program. Five radiologists assessed density using the BI-RADS density scale, where BI-RADS I-II were classified as fatty and III-IV as dense. A commercially available software (Quantra) calculated volumetric breast density. We calculated the cutoff (threshold) values in volumetric density that yielded highest accuracy compared to median and individual radiologists' classification. Inter-observer variation was analyzed using the kappa statistic., Results: The threshold that best matched the median radiologists' classification was 10%, which resulted in 87% accuracy. Thresholds that best matched individual radiologist's classification had a range of 8-15%. A total of 191 (35.6 %) cases were scored both dense and fatty by at least one radiologist. Fourteen (2.6 %) cases were unanimously scored by the radiologists, yet differently using automatic assessment. The agreement (kappa) between reader's median classification and individual radiologists was 0.624 to 0.902, and agreement between median classification and Quantra was 0.731., Conclusion: The optimal volumetric threshold of 10% using automatic assessment would classify breast parenchyma as fatty or dense with substantial accuracy and consistency compared to radiologists' BI-RADS categorization, which suffers from high inter-observer variation., (© The Foundation Acta Radiologica 2016.)

Purpose: The presence of disseminated tumor cells (DTCs) in bone marrow (BM) predicts survival in early breast cancer. This study explores the use of DTCs for identification of patients insufficiently treated with adjuvant therapy so they can be offered secondary adjuvant treatment and the subsequent surrogate marker potential of DTCs for outcome determination., Patients and Methods: Patients with early breast cancer who had completed six cycles of adjuvant fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapy underwent BM aspiration 2 to 3 months (BM1) and 8 to 9 months (BM2) after FEC. Presence of DTCs in BM was determined by immunocytochemistry using pan-cytokeratin monoclonal antibodies. If one or more DTCs were present at BM2, six cycles of docetaxel (100 mg/m(2), once every 3 weeks) were administered, followed by DTC analysis 1 and 13 months after the last docetaxel infusion (after treatment). Cox regression analysis was used to evaluate disease-free interval (DFI)., Results: Of 1,066 patients with a DTC result at BM2 and available follow-up information (median follow-up, 71.9 months from the time of BM2), 7.2% were DTC positive. Of 72 docetaxel-treated patients analyzed for DTCs after treatment, 15 (20.8%) had persistent DTCs. Patients with remaining DTCs had markedly reduced DFI (46.7% experienced relapse) compared with patients with no DTCs after treatment (adjusted hazard ratio, 7.58; 95% CI, 2.3 to 24.7). The docetaxel-treated patients with no DTCs after treatment had comparable DFI (8.8% experienced relapse) compared with those with no DTCs both at BM1 and BM2 (12.7% experienced relapse; P = .377, log-rank test)., Conclusion: DTC status identifies high-risk patients after FEC chemotherapy, and DTC monitoring status after secondary treatment with docetaxel correlated strongly with survival. This emphasizes the potential for DTC analysis as a surrogate marker for adjuvant treatment effect in breast cancer., (© 2014 by American Society of Clinical Oncology.)

Increased incidence of ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC) after introduction of organized screening has prompted debate about overdiagnosis. The aim was to examine the excess in incidence of DCIS and IBC during the screening period and the deficit after women left the program, and thereby to estimate the proportion of overdiagnosis. Women invited to the Norwegian Breast Cancer Screening Program were analyzed for DCIS or IBC during the period 1995-2009. Incidence rate ratios (IRRs) were calculated for attended vs. never attended women. The IRRs were adjusted by Mantel-Haenszel (MH) method and applied to a set of reference rates and a reference population to estimate the proportion of overdiagnosis during the women's lifespan after the age of 50 years. A total of 702,131 women were invited to the program. An excess of DCIS and IBC was observed among women who attended screening during the screening period; prevalently invited women aged 50-51 years had a MH IRR of 1.86 (95% CI 1.65-2.09) and subsequently invited women aged 52-69 years had a MH IRR of 1.56 (95% CI 1.45-1.68). In women aged 70-79 years, a deficit of 30% (MH IRR 0.70, 95% CI 0.62-0.80) was observed 1-10 years after they left the screening program. The estimated proportion of overdiagnosis varied from 10 to 20% depending on outcome and whether the women were invited or actually screened. The results highlight the need for individual data with longitudinal screening history and long-term follow-up as a basis for estimating overdiagnosis., (Copyright © 2013 UICC.)

The incidence of ductal carcinoma in situ (DCIS) of the breast has increased in recent decades, particularly, in counties offering mammography screening. The aims of the present study are to examine factors that may predict subsequent breast malignancy amongst patients with DCIS, and to compare the incidence of the subsequent malignancy and mortality with that of the general population. This population-based study includes all primary cases of pure DCIS diagnosed in Norway in the period 1993 to 2007 (N = 3167). The patients were followed to subsequent malignancy (DCIS or invasive cancer) or death. Risk estimates within 10 years of follow-up were calculated using Kaplan-Meier methods adjusting for competing risks, Cox regression models and Standard Incidence and Mortality Ratios. Patients with DCIS had a 11.2% risk of being diagnosed with a subsequent breast malignancy within 10 years (9.4% for invasive cancer), implying that they were five times as likely to be diagnosed with breast malignancy as the general female population in Norway. The risk was dependent on the treatment of the DCIS; patients treated with mastectomy and breast-conserving treatment had a 3.8 and 9.8% risk of ipsilateral invasive cancer within 10 years, respectively. Breast cancer mortality was 2.5% within 10 years of follow-up, a fourfold risk compared with the general population. Patients with DCIS have an increased risk of both subsequent breast malignancy and breast cancer death compared with women in the general population. Our results support previous knowledge of DCIS as a heterogeneous disease.