These findings in the face of unaltered circulating cytokines tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6, as well as the tumor necrosis factor receptor-I s, suggest that PAF may influence some endotoxin-induced, counterregulatory hormonal responses and symptoms through cytokine-independent mechanisms. This study further supports the role of PAF antagonists as an adjunct to cytokine blockade in the treatment of gram-negative sepsis.
In tailoring treatment for DCIS, the goal is to avoid overtreatment while minimizing risk of recurrence. This necessitates estimation of recurrence risk and assessment of efficacy of each intervention in reducing risk. There are several clinicopathologic and treatment factors that have been proven in prospective trials to affect risk. These have been combined into a multivariable nomogram that estimates 10-year risk of recurrence (DCIS Nomogram). It is available online and free-of-charge, and has been validated in at least 5 independent populations with assessments of calibration and discrimination to assess its utility. There have also been attempts to develop genomic predictors of risk. The Oncotype DCIS score originally was based on a purely genomic analysis, but was “refined” to include clinicopathologic factors. DCISionRT was initially created with the inclusion of clinicopathologic factors. Neither has been prospectively validated and neither has published any assessments of calibration and discrimination. It is unclear what proportion of either risk estimate is due to the inclusion of clinicopathologic factors vs the actual genomic analysis. Both cost thousands of dollars. Furthermore, neither the refined Oncotype DCIS score nor the DCISionRT score incorporates the use of endocrine therapy. Tamoxifen and aromatase inhibitors have been proven to reduce the risk of recurrence by about 30-50%, and their use should be expected to decrease risk of recurrence. Yet, neither score accounts for this fact, and therefore the risk predictions are too high for those that take endocrine therapy, and too low for those that do not. In a sample of 59 women age ≥50 years old, with DCIS ≤2.5cm in size and clear margins, 10-year recurrence risk estimates from the DCIS Nomogram and refined Oncotype DCIS score (RDS) were compared. Overall, RDS risk estimates were in agreement (within 1-2% of the nomogram risk estimate range, calculated with and without the use of endocrine therapy) in 92% of cases. Among the 5 patients for which the Nomogram and RDS estimates disagreed, all had close margins (≤2mm). Close margins are associated with a statistically significant doubling of risk of recurrence. Nevertheless, the Oncotype DCIS score 10-year recurrence estimate was only 5-8% for these patients with close margins, while the Nomogram estimates were 11-14% (assuming use of endocrine therapy) or 21-27% (without endocrine therapy). From all published data, it seems clear that the refined Oncotype DCIS score markedly underestimates risk for those with close margins. And for those with clear margins, there was excellent (100%) agreement between the Nomogram and the refined Oncotype DCIS score. Given the need for cost-based value in health care, and given the cost-free availability of a validated predictive online DCIS nomogram, rigorous evaluation of predictive accuracy and proof of significant added clinical benefit should be performed and made available before any new expensive commercially available test is adopted for clinical use. Citation Format: Kimberly Van Zee. Defining recurrence risk for DCIS: How do we tailor therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr F1-3.
Background Breast conserving therapy (BCT) is accepted as a preferred option for unifocal breast cancer. However, the oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC), has not been demonstrated in a prospective study. The ACOSOG (Alliance) Z11102 phase II single arm prospective trial was designed to evaluate outcomes with BCT for MIBC. Methods Women age 40+ with 2 or 3 foci of biopsy proven breast cancer (BC) (each site < 5cm in size with at least 1 site invasive) separated by >2-3 cm of normal breast tissue and disease limited to two quadrants of the breast with cN0 or cN1 disease were eligible. All patients had pre-operative mammogram and breast MRI was initially required and subsequently made optional. Neoadjuvant therapy was not allowed. Patients were treated with lumpectomy resected to negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary endpoint of Z11102 is the cumulative incidence of local recurrence (LR, defined as histologic evidence of ductal carcinoma in situ or invasive BC in the ipsilateral breast or chest wall) at 5 years (treating death and distant and nodal/regional recurrence as competing risks) to assess whether the rate is greater than 8%. Data were frozen 5/25/2022. Results From 11/2012-8/2016, 270 women were enrolled. Of these, 33 were ineligible, 14 converted to mastectomy, 11 were unable to meet protocol-specific radiation endpoints, 1 had no definable tumor, 1 had 4 sites of cancer and 16 withdrew before completing surgery and radiation, leaving 194 patients [median age 61 (range 40-87)] eligible who completed breast conserving surgery and radiation therapy. With median follow-up of alive patients of 66.6 months (range: 4.1, 90.6), 6 patients have developed LR (5 ipsilateral breast and 1 chest wall), corresponding to an estimated cumulative incidence of local recurrence of 3.2% (95% CI: 1.3, 6.4) at 5 years. No patients have developed regional recurrence, 5 patients developed distant recurrence, 0 patients developed local and distant recurrence, 5 patients developed contralateral BC, 3 new non-BC primaries and 8 patients have died (1 related to BC). The rate of local recurrence in patients without a breast pre-op MRI (n=14) was 22.6% at 5 years compared to 1.7% among the 180 patients with a preop MRI (p=0.002). Patient age, number of sites of preoperative biopsy proven BC, HER2 status, pathologic T and N category were not statistically significantly associated with risk of LR. Conclusion The Z11102 clinical trial demonstrates that for women with MIBC breast conserving surgery with adjuvant radiation with lumpectomy site boosts has an acceptably low LR rate (3.2% at 5 years), making this a reasonable consideration for women with 2-3 ipsilateral foci. The LR rate was significantly higher in the small cohort of patients without preoperative breast MRI. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT01556243 Table 1: Factors associated with LR after BCT for MIBC Citation Format: Judy C. Boughey, Kari M. Rosenkranz, Karla V. Ballman, Linda McCall, Bruce G. Haffty, Laurie W. Cuttino, Charlotte D. Kubicky, H. T. Carisa Le-Petross, Kimberly Van Zee, Armando E. Giuliano, Olwen M. Hahn, Kelly K. Hunt, Lisa Carey, Ann Partridge. Impact of Breast Conservation Therapy on Local Recurrence in Patients with Multiple Ipsilateral Breast Cancer – Results from ACOSOG Z11102 (Alliance) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-01.
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