Survival and prognostic factors in oligometastatic breast cancer.

BACKGROUND: Guidelines for oligometastatic breast cancer (OMBC) propagate multimodality treatment including polychemotherapy and local ablative treatment (LAT) of all lesions. The aim of this approach is prolonged disease remission, or even cure. Long-term outcomes in OMBC and factors associated with prognosis are largely unknown, due to the rarity of this condition. We report overall survival (OS), event-free survival (EFS), and prognostic factors in a large real-world cohort of patients with OMBC. METHODS: Patients with breast cancer and 1-3 distant metastatic lesions, treated in the Netherlands Cancer Institute between 1997 and 2020, were identified via text mining of medical files. We collected patient, tumor and treatment characteristics. The Kaplan-Meier method was used to calculate OS and EFS estimates, and Cox regression analyses to assess prognostic factors. RESULTS: The cohort included 239 patients, of whom 54% had ERpos/HER2neg, 20% HER2pos and 20% triple negative disease. Median follow-up was 88.0 months (95% confidence interval (CI) 82.9-93.1) during which 107 patients died and 139 developed disease progression/recurrence; median OS was 93.0 months (95%CI 66.2-119.8). Factors associated with OS in multivariable analysis were subtype, disease-free interval and radiologic response to first-line systemic therapy; LAT was associated with EFS, but not OS. CONCLUSIONS: In this large real-world cohort of patients with OMBC, OS and EFS compare favorably to survival in the general MBC population. Radiologic complete response to first-line systemic therapy was associated with favorable OS and EFS, indicating the importance of early optimal systemic therapy. The value of LAT in OMBC requires further study.

Publisher Correction: Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.

In the version of this article originally published, there was an error in Fig. 3j. A label on the heatmap read "TGF-α signaling via NF-κB". It should have read "TNF-α signaling via NF-κB". The error has been corrected in the HTML and PDF versions of this article.

Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.

The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low1-5, highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation6-13. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST14) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1-PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNF-α signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.

A robust volumetric arc therapy planning approach for breast cancer involving the axillary nodes.

We quantify the robustness of a proposed volumetric-modulated arc therapy (VMAT) planning and treatment technique for radiotherapy of breast cancer involving the axillary nodes. The proposed VMAT technique is expected to be more robust to breast shape changes and setup errors, yet maintain the improved conformity of VMAT compared to our current standard technique that uses tangential intensity-modulated radiation therapy (IMRT) fields. Treatment plans were created for 10 patients. To account for anatomical variation, planning was carried out on a computed tomography (CT) with an expanded breast, followed by segment weight optimization (SWO) on the original planning CT (VMAT + SWO). For comparison purposes, tangential field IMRT plans and conventional VMAT (cVMAT) plans were also created. Anatomical changes (expansion and contraction of the breast) and setup errors were simulated to quantify changes in target coverage, target maximum, and organ-at-risk (OAR) doses. Finally, robustness was assessed by calculating the actual delivered dose for each fraction using cone-beam CT images acquired during treatment. Target coverage of VMAT + SWO was shown to be significantly more robust compared to cVMAT technique, against anatomical variations and setup errors. Sensitivity of the clinical target volume (CTV) V95% is -5%/cm of expansion for the proposed technique, which is identical to the IMRT technique and much lower than the -22%/cm for cVMAT. Results are similar for setup errors. OAR doses are mostly insensitive to anatomical variations and the OAR sensitivity to setup variations does not depend on the planning technique. The results are confirmed by dose distributions recalculated on cone-beam CT, showing that for VMAT + SWO the CTV V95% remains within 2.5% of the planned value, whereas it deviates by up to 7% for cVMAT. A practical VMAT planning technique is developed, which is robust to daily anatomical variations and setup errors.

Geometrical and dosimetric evaluation of breast target volume auto-contouring.

BACKGROUND AND PURPOSE: Automatic delineations are often used as a starting point in the radiotherapy contouring workflow, after which they are manually reviewed and adapted. The purpose of this work was to quantify the geometric differences between automatic and manually edited breast clinical target volume (CTV) contours and evaluate the dosimetric impact of such differences. MATERIALS AND METHODS: Eighty-seven automatically generated and manually edited contours of the left breast were retrieved from our clinical database. The automatic contours were obtained with a commercial auto-segmentation toolbox. The geometrical comparison was performed both locally and globally using the Dice score and the 95% Hausdorff distance (HD). Two treatment plans were generated for each patient and the obtained dosimetric differences were quantified using dose-volume histogram (DVH) parameters in the lungs, heart and planning target volume (PTV). An inter-observer variability study with four observers was performed on a subset of ten patients. RESULTS: A median Dice score of 0.95 and a median 95% HD of 9.7 mm were obtained. Larger breasts were consistently under-contoured. Cranial under-contouring resulted in more than 5% relative decrease in PTV coverage in 15% of the patients while lateroposterior over-contouring increased the lung V20Gy by a maximum of 2%. The inter-observer variability of the PTV coverage was smaller than the difference between PTV coverage achieved by the automatic and the consensus contours. CONCLUSIONS: Cranial under-contouring resulted in under-treatment, while lateroposterior over-contouring resulted in an increased lung dosage that is clinically irrelevant, showing the need to consider dose distributions to assess the clinical impact of local geometrical differences.

Concurrent chemoradiotherapy for large-volume locally-advanced non-small cell lung cancer.

PURPOSE: Patients with large volume stage III non-small cell lung cancer (NSCLC) are often excluded from concurrent chemoradiotherapy (CRT) protocols due to fears about excessive toxicity and poor survival. Patients with N3 nodal disease may be excluded for the same reason. We have routinely accepted fit patients in both the above groups for CRT if they met our planning parameters. We analyzed toxicity and survival outcomes for patients undergoing CRT with a planning target volume (PTV) exceeding 700 cc, either with or without N3 nodal disease, or a PTV less then 700 cc with N3 disease. MATERIALS AND METHODS: Single center, retrospective study of patients with stage III NSCLC treated with CRT between 2004 and 2011. RESULTS: 121 patients were eligible, with 81% (98/121) having a PTV>700 cc (of whom 33% (32/98) had N3 nodal disease) and 19% (23/121) having N3 disease and a PTV≤700 cc. Grade ≥3 esophagitis and pneumonitis were recorded in respectively 34% and 4% of all patients. Median follow-up for all patients was 37.6 months (mo). Median overall (OS) and progression-free (PFS) survivals were 15.7 mo and 11.6 mo, respectively, OS for all patients with PTV>700 cc was 14.5 mo (19.5 mo with N3 and 13.2 mo without N3), compared to 26.5 mo for PTV≤700 cc with N3 (p=0.009). About 1 in 4 patients with PTV>700 cc died within 6 mo of starting radiotherapy (this was associated with Charlson comorbidity index [CCI]≥1), while about 18% were alive at 3 years. CONCLUSION: Patients undergoing CRT for stage III NSCLC with a PTV>700 cc, with or without N3 nodal disease, had a significantly shorter OS than patients with PTV≤700 cc with N3. Patients with PTV>700 cc and with CCI≥1, had a significantly higher risk of early death but longer-term survivors with PTV>700 cc are observed. The PTV and CCI should be considered in clinical decision making and used as stratification factors in future trials.