Effects of Exercise during Adjuvant Chemotherapy on Breast Cancer Outcomes

Background: Observational studies suggest that physical activity following a diagnosis of breast cancer may be associated with a lower risk of recurrence and death. Some studies also suggest possible effect modification by disease stage, body mass index, and receptor status. To date, however, there are no randomized trials examining the effects of exercise on disease outcomes in any cancer patient group. Here, we report an exploratory follow-up of disease outcomes from the Supervised Trial of Aerobic versus Resistance Training (START). Patients and Methods: The START Trial was a Canadian multicenter trial that randomized 242 breast cancer patients starting adjuvant chemotherapy to either usual care (n = 82) or supervised aerobic (n = 78) or resistance (n = 82) exercise for the duration of their chemotherapy. The primary efficacy endpoint for this exploratory analysis was disease-free survival (DFS). Secondary endpoints were overall survival (OS), distant disease-free survival (DDFS), and recurrence-free interval (RFI). The two exercise arms were combined for the analysis (n = 160) and selected subgroups were explored. Results: After a median follow-up of 89 months (IQR 81 to 96), there were 25/160 (15.6%) DFS events in the exercise groups and 18/82 (22.0%) in the control group (log-rank p = 0.21). Eight-year DFS was 82.7% for the exercise groups compared with 75.6% for the control group (Hazard ratio [HR] = 0.68, 95% CI = 0.37-1.24). There were 13/160 (8.1%) deaths in the exercise groups and 11/82 (13.4%) in the control group (log-rank p = 0.21). Eight-year OS was 91.2% in the exercise groups compared with 82.7% in the control group (HR = 0.60, 95% CI = 0.27 to 1.33. There were 20/160 (12.5%) DDFS events in the exercise groups and 16/82 (19.5%) in the control group (log-rank p = 0.15). Eight-year DDFS was 86.7% in the exercise groups compared with 78.3% in the control group (HR = 0.62, 95% CI = 0.32 to 1.19). Finally, there were 20/160 (12.5%) RFI events in the exercise groups and 17/82 (20.7%) in the control group (Gray's p = 0.095). Eight-year cumulative incidence of RFI was 12.6% in the exercise groups compared with 21.6% in the control group (HR = 0.58, 95% CI = 0.30 to 1.11). Subgroup analyses for DFS and RFI suggested stronger effects for women who were overweight/obese, had stage II/III cancer, receptor positive tumors, HER2 positive tumors, received taxane-based chemotherapies, and received at least 85% of their intended chemotherapy dose-intensity. The most notable subgroup effect was for patients who received optimal chemotherapy dosing with a borderline significant effect for DFS (HR = 0.50, 95% CI = 0.25 to 1.01) and a significant effect for RFI (HR = 0.38, 95% CI = 0.18 to 0.81). Conclusions: In this exploratory follow-up of the START Trial, there was a suggestion that exercise during adjuvant chemotherapy may improve several efficacy endpoints although none achieved statistical significance. Nevertheless, the magnitude of the effects appear to be meaningful with absolute 8-year survival differences between 7% and 9% and relative rate reductions between 30% and 40%. The START Trial provides the first randomized data to suggest that adding exercise to standard chemotherapy for breast cancer may improve outcomes. A definitive phase III trial is warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-08-01.

Background The human epidermal growth factor receptor 2 (ERBB2) can be altered by somatic mutations (with/without ERRB2 amplification) that likely drive tumorigenesis. Here, we present the first study that thoroughly investigates the behavior of patients with ERBB2 mutated tumors in a large unselected cohort of metastatic breast cancer (MBC) patients. Patients and Methods We included retrospectively all MBC patients with sufficient tumor material available, independent of hormone receptor or ERBB2 amplification status, diagnosed between 2000 and 2015 at the Multidisciplinary Breast Center of University Hospitals Leuven. Genomic DNA extracted from primary breast tumors was subjected to deep targeted re-sequencing using an assay covering 5 exons (exons 8, 17, 19, 20 and 21) known to accumulate ERBB2 hotspot mutations. Clinical characteristics, treatment response and outcomes (excluding bilateral BC) were compared between patients with and without ERBB2 mutations. Results We established and validated a research use only next-generation sequencing assay across five exons of ERBB2. Somatic ERBB2 mutations with an allelic frequency of ≥5% in at least one independent analysis, were observed in 1.8% (13/721) of MBC patients. MBC patients with ERBB2 mutant primary tumors appear to have similar patient and tumor characteristics (TNM stage, grade, and receptor and HER2 status) compared to non-mutant patients and ERBB2 mutations occur in all molecular subtypes (7 ER+/HER2-, 4 HER2+, 2 triple negative). However, we see a small trend towards enrichment in the invasive lobular carcinomas (ILC) in the ERBB2 mutant patients vs. the non-mutant patients (4/13 (31%) vs. 97/695 (14%), p=0.086). ER+ patients with an ERBB2 mutant tumor who received first line aromatase inhibitor (AI) (n=3) had a worse median time to progression (TTP) compared to non-mutant patients (n=156) (TTP 103 vs. 311 days, p=0.04), AI use in any line had also a worse TTP (n=8 vs. 376; TTP 74 vs. 213 days, p=0.006). TTP was not significantly different for other standard therapies, but numbers were small. Median distant disease free survival (DDFS) defined as time from primary diagnosis to first metastasis, was slightly shorter for ERBB2 mutant tumors (n=9 vs 514; DDFS 1.4 vs. 2.9 years, p=0.066). However, in ER+/HER2- ERBB2 mutant tumors, median DDFS was significantly shorter in non-mutant patients (n=5 vs. 328; DDFS 0.8 vs. 4.0 years, p=0.02). Median overall survival (OS) after diagnosis of MBC was numerically lower for mutant patients in all subtypes vs. non-mutant patients (n=11 vs. 669; OS 1.1 vs. 2.3 years, p=0.457), and in ER+/HER2- disease (n=6 vs. 431; OS 1.0 vs. 2.9 years, p=0.07). Conclusion In our large MBC cohort, patients with ERBB2 mutant tumors appear to have similar tumor and patient characteristics as ERBB2 non-mutant tumors. ERBB2 mutations do not seem to occur more or less often in specific breast cancer subtypes except for a slight increase for ILC. In ER+/HER2- MBC, patients with ERBB2 mutant tumors appear to be adversely prognostic; having a shorter DDFS after early breast cancer treatment, and in metastatic disease, they respond worse on AI and have a trend for worse OS compared to non-mutant cases. Citation Format: Jongen L, Floris G, Lambrechts D, Laenen A, Neven P, Mann G, Cutler Jr. RE, Lalani AS, Wildiers H. Identification, clinical characteristics and treatment outcomes of somatic human epidermal growth factor receptor 2 (ERBB2) mutations in metastatic breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-04-03.

Background: Postmastectomy radiotherapy (PMRT) has been shown to be beneficial in node-positive breast cancer patients. However, the role of PMRT for patients receiving modern neoadjuvant chemotherapy (NAC) are controversial. We aimed to evaluate the efficacy of radiotherapy for breast cancer patients treated with NAC and mastectomy in the Japanese Breast Cancer Registry. Methods: Patients who received NAC and mastectomy for cT1-4 cN0-2 M0 breast cancer were included in this analysis. We assessed locoregional recurrence (LRR), distant disease-free survival (DDFS), and overall survival (OS) using the Kaplan-Meier method and compared them between the groups with and without PMRT by nodal status after NAC; ypN0, ypN1, and ypN2-3. We also performed multivariable cox regression analysis to evaluate the association of radiotherapy and these outcomes adjusting for baseline patient and cancer characteristics. Results: Of the 145,530 patients registered from 2004 to 2009, we identified 3,226 patients who met our inclusion criteria with the 5-year follow-up information including 1,299 ypN0, 1,036 ypN1, and 879 ypN2-3 cases. PMRT was performed in 185 patients (14.2%) with ypN0, 265 patients (25.6%) with ypN1, and 543 patients (61.8%) with ypN2-3. There was no difference in LRR, DDFS, and OS between the groups with and without radiotherapy for ypN1 patients who received NAC (P=0.72, P=0.29, and P=0.36, respectively). For patients with ypN2-3 breast cancer, radiotherapy significantly improved LRR (P<0.001), DDFS (P=0.01), and OS (P<0.001) on univariate analysis. No difference in LRR, DDFS, and OS was observed for ypN0 patients (P=0.81, P=0.15, and P=0.05, respectively). In multivariable analysis, the use of radiotherapy was independently associated with improved LRR [hazard ratio (HR): 0.608, 95% confidence interval (CI): 0.452–0.818, P=0.001] and OS [HR: 0.685, 95% CI: 0.531–0.885, P=0.004] for ypN2-3 patients. Effect of PMRT on locoregional recurrence by the ypN subgroupsypN subgroupHazard ratio95%CI Low95%CI HighP valueypN00.8550.4581.5960.623ypN10.8320.5491.2620.387ypN2-30.6080.4520.8180.001 Effect of PMRT on overall survival by the ypN subgroupsypN subgroupHazard ratio95%CI Low95%CI HighP valueypN01.3250.8412.0870.224ypN10.8800.5991.2930.514ypN2-30.6850.5310.8850.004 Radiotherapy was not associated with OS among patients with ypN0 [HR: 1.325, 95% CI: 0.841–2.087, P=0.224] and ypN1 [HR: 0.880, 95% CI: 0.599–1.293, P=0.514]. There was no significant difference in DDFS with the addition of radiotherapy for all ypN subgroups. Conclusions: The results from this nationwide database study of breast cancer patients following modern NAC showed that PMRT did not improve survival for patients with ypN1 and ypN0. Radiotherapy might be only beneficial for ypN2-3 breast cancer patients who received NAC and mastectomy in the modern era. Randomized clinical trials are needed to optimize the use of PMRT for breast cancer patients treated with neoadjuvant chemotherapy. Citation Format: Miyashita M, Niikura N, Kumamaru H, Miyata H, Ishida T, Kinoshita T, Tsuda H, Nakamura S, Tokuda Y. Role of postmastectomy radiotherapy after neoadjuvant chemotherapy in breast cancer patients: A study from the Japanese breast cancer registry [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-11.

In 1982, the National Surgical Adjuvant Breast and Bowel Project initiated a randomized, double-blinded, placebo-controlled trial (B-14) to determine the effectiveness of adjuvant tamoxifen therapy in patients with primary operable breast cancer who had estrogen receptor-positive tumors and no axillary lymph node involvement. The findings indicated that tamoxifen therapy provided substantial benefit to patients with early stage disease. However, questions arose about how long the observed benefit would persist, about the duration of therapy necessary to maintain maximum benefit, and about the nature and severity of adverse effects from prolonged treatment. We evaluated the outcome of patients in the B-14 trial through 10 years of follow-up. In addition, the effects of 5 years versus more than 5 years of tamoxifen therapy were compared. In the trial, patients were initially assigned to receive either tamoxifen at 20 mg/day (n = 1404) or placebo (n = 1414). Tamoxifen-treated patients who remained disease free after 5 years of therapy were then reassigned to receive either another 5 years of tamoxifen (n = 322) or 5 years of placebo (n = 321). After the study began, another group of patients who met the same protocol eligibility requirements as the randomly assigned patients were registered to receive tamoxifen (n = 1211). Registered patients who were disease free after 5 years of treatment were also randomly assigned to another 5 years of tamoxifen (n = 261) or to 5 years of placebo (n = 249). To compare 5 years with more than 5 years of tamoxifen therapy, data relating to all patients reassigned to an additional 5 years of the drug were combined. Patients who were not reassigned to either tamoxifen or placebo continued to be followed in the study. Survival, disease-free survival, and distant disease-free survival (relating to failure at distant sites) were estimated by use of the Kaplan-Meier method; differences between the treatment groups were assessed by use of the logrank test. The relative risks of failure (with 95% confidence intervals [CIs]) were determined by use of the Cox proportional hazards model. Reported P values are two-sided. Through 10 years of follow-up, a significant advantage in disease-free survival (69% versus 57%, P < .0001; relative risk = 0.66; 95% CI = 0.58-0.74), distant disease-free survival (76% versus 67%, P < .0001; relative risk = 0.70; 95% CI = 0.61-0.81), and survival (80% versus 76%, P = .02; relative risk = 0.84; 95% CI = 0.71-0.99) was found for patients in the group first assigned to receive tamoxifen. The survival benefit extended to those 49 years of age or younger and to those 50 years of age or older. Tamoxifen therapy was associated with a 37% reduction in the incidence of contralateral (opposite) breast cancer (P = .007). Through 4 years after the reassignment of tamoxifen-treated patients to either continued-therapy or placebo groups, advantages in disease-free survival (92% versus 86%, P = .003) and distant disease-free survival (96% versus 90%, P = .01) were found for those who discontinued tamoxifen treatment. Survival was 96% for those who discontinued tamoxifen compared with 94% for those who continued tamoxifen treatment (P = .08). A higher incidence of thromboembolic events was seen in tamoxifen-treated patients (through 5 years, 1.7% versus 0.4%). Except for endometrial cancer, the incidence of second cancers was not increased with tamoxifen therapy. The benefit from 5 years of tamoxifen therapy persists through 10 years of follow-up. No additional advantage is obtained from continuing tamoxifen therapy for more than 5 years.

&lt;p&gt;Supplementary Figures S1-6. Supplementary Fig. S1. Kaplan-Meier estimates of disease-free survival and distant disease-free survival according to the PIK3CA mutations in different hotspots. Disease-free survival (Panel A); Distant disease-free survival (Panel B). Supplementary Fig. S2. Kaplan-Meier estimates of disease-free survival and distant disease-free survival according to the PIK3CA status in the entire study population (n=729). Disease-free survival (Panel A); Distant disease-free survival (Panel B). Supplementary Fig. S3. Kaplan-Meier estimates of disease-free survival and distant disease-free survival according to the PIK3CA status in the luminal subgroup (n=376). Disease-free survival (Panel A); Distant disease-free survival (Panel B). Supplementary Fig. S4. Kaplan-Meier estimates of disease-free survival and distant disease-free survival according to the PIK3CA status in the HER2-positive patients who did not receive trastuzumab treatment (n=181). Disease-free survival (Panel A); Distant disease-free survival (Panel B). Supplementary Fig. S5. Kaplan-Meier estimates of disease-free survival and distant disease-free survival according to the PIK3CA status in the HER2-positive patients who received trastuzumab treatment (n=41). Disease-free survival (Panel A); Distant disease-free survival (Panel B). Supplementary Fig. S6. Kaplan-Meier estimates of disease-free survival and distant disease-free survival according to the PIK3CA status in TN subgroup (n=128). Disease-free survival (Panel A); Distant disease-free survival (Panel B).&lt;/p&gt;

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; Breast cancers in carriers of inactivating mutations of the &lt;i&gt;BRCA1&lt;/i&gt; gene carry a specific DNA copy-number signature (“&lt;i&gt;BRCA1&lt;/i&gt;-like”). This signature is shared with cancers that inactivate &lt;i&gt;BRCA1&lt;/i&gt; through other mechanisms. Because BRCA1 is important in repair of DNA double-strand breaks through error-free homologous recombination, patients with a &lt;i&gt;BRCA1&lt;/i&gt;-like tumor may benefit from high-dose alkylating (HD) chemotherapy, which induces DNA double-strand breaks.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; We investigated a single institution cohort of high-risk patients that received tandem HD chemotherapy schedule comprising ifosfamide, epirubicin, and carboplatin or conventional chemotherapy. We classified copy-number profiles to be &lt;i&gt;BRCA1&lt;/i&gt;-like or non–&lt;i&gt;BRCA1&lt;/i&gt;-like and analyzed clinical associations and performed survival analysis with a treatment by biomarker interaction design.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; &lt;i&gt;BRCA1&lt;/i&gt;-like status associated with high-grade and triple-negative breast cancers. &lt;i&gt;BRCA1&lt;/i&gt;-like cases benefitted from the HD compared with a conventional regimen on disease-free survival (DFS): [hazard ratio (HR), 0.05; 95% confidence interval (CI), 0.01–0.38; &lt;i&gt;P&lt;/i&gt; = 0.003]; distant DFS (DDFS): (HR, 0.06; 95% CI, 0.01–0.43; &lt;i&gt;P&lt;/i&gt; = 0.01); and overall survival (OS; HR, 0.15; 95% CI, 0.03–0.83; &lt;i&gt;P&lt;/i&gt; = 0.03) after correction for prognostic factors. No such benefit was observed in the non–&lt;i&gt;BRCA1&lt;/i&gt;-like cases on DFS (HR, 0.74; 95% CI, 0.38–1.46; &lt;i&gt;P&lt;/i&gt; = 0.39), DDFS (HR, 0.79; 95% CI, 0.41–1.52; &lt;i&gt;P&lt;/i&gt; = 0.47), and OS (HR, 0.93; 95% CI, 0.52–1.64; &lt;i&gt;P&lt;/i&gt; = 0.79). The &lt;i&gt;P&lt;/i&gt; values for interaction were 0.01 (DFS), 0.01 (DDFS), and 0.045 (OS).&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; &lt;i&gt;BRCA1&lt;/i&gt;-like tumors recurred significantly less often after HD than conventional chemotherapy. &lt;i&gt;BRCA1&lt;/i&gt;-like copy-number profile classification may be a predictive marker for HD alkylating chemotherapy. &lt;i&gt;Clin Cancer Res; 21(4); 763–70. ©2014 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

Purpose Previous studies have suggested an association between metformin use and improved outcome in patients with diabetes and breast cancer. In the current study, we aimed to explore this association in human epidermal growth factor receptor 2 (HER2 ) -positive primary breast cancer in the context of a large, phase III adjuvant trial. Patients and Methods The ALTTO trial randomly assigned patients with HER2-positive breast cancer to receive 1 year of either trastuzumab alone, lapatinib alone, their sequence, or their combination. In this substudy, we evaluated whether patients with diabetes at study entry-with or without metformin treatment-were associated with different disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) compared with patients without diabetes. Results A total of 8,381 patients were included in the current analysis: 7,935 patients (94.7%) had no history of diabetes at diagnosis, 186 patients (2.2%) had diabetes with no metformin treatment, and 260 patients (3.1%) were diabetic and had been treated with metformin. Median follow-up was 4.5 years (0.16 to 6.31 years), at which 1,205 (14.38%), 929 (11.08%), and 528 (6.3%) patients experienced DFS, DDFS, and OS events, respectively. Patients with diabetes who had not been treated with metformin experienced worse DFS (multivariable hazard ratio [HR], 1.40; 95% CI, 1.01 to 1.94; P = .043), DDFS (multivariable HR, 1.56; 95% CI, 1.10 to 2.22; P = .013), and OS (multivariable HR, 1.87; 95% CI, 1.23 to 2.85; P = .004). This effect was limited to hormone receptor-positive patients. Whereas insulin treatment was associated with a detrimental effect, metformin had a salutary effect in patients with diabetes who had HER2-positive and hormone receptor-positive breast cancer. Conclusion Metformin may improve the worse prognosis that is associated with diabetes and insulin treatment, mainly in patients with primary HER2-positive and hormone receptor-positive breast cancer.

Background / Aim: To analyze oncological outcome of breast cancer (BC) subtypes in routine clinical care in specialized breast care units (BCU). Patients and methods: A prospectively followed cohort of 4110 female cases with primary, non-bilateral, non-metastatic BC treated between 01.01.2003 and 31.12.2012 has been analyzed for the whole cohort and separately for the five routinely used clinico-pathological subtypes (i.e. Luminal A, Luminal B (=Her2 neg.), Luminal B (=Her2 pos.), HER-2, triple negative). The median follow-up of the cohort was 51 month. We calculated estimates for local control rate (LCR), disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS) and relative overall survival (ROS). 5 year outcome results referred to 5 different endpoints (using Kaplan-Meier method) of all patients with primary, non-metastatic, non-bilateral breast cancer treated at Heidelberg Breast Care Unit between 01.01.2003 and 31.12.2012 All patients (including in-situ)Patients with invasive cancer (excluding in-situ) n=4102 (including 499 in-situ cases)n = 3603LCR [%] (95% CI)96.1 (95.6 ; 96.6)96.1 (95.7 ; 96.5)DFS [%] (95% CI)85.0 (84.2 ; 85.8)83.7 (82.8 ; 84.6)DDFS [%] (95% CI)86.9 (86.1 ; 87.7)85.7 (84.8 ; (86.6)OS [%] (95% CI)91.3 (90.5 ; 92.2)90.5 (89.6 ; 91.4)ROS [%] (95% CI)95.5 (94.3 ; 96.7)94.7 (93.4 ; 96.0)CI, confidence interval; LCR, local recurrence rate; DFS, disease-free survival; DDFS, distant disease-free survival; OS, observed overall survival; ROS, relative (age adjusted) overall survival Outcome results referred to 5 different endpoints (using Kaplan-Meier method) according to clinico-pathological tumor subtype or in-situ tumor. Results in percent at 5 years (95% CI).invasive cancer (n = 34541) Lum A-likeLum B1-likeLum B2-likeHER2+Triple negativeCIS (n = 499)LCR [%] (95% CI)99.1 (98.7 ; 99.5)95.2 (-)**95.0 (86.3 ; 100)90.5 (-)89.6 (87.1 ; 92.1)96.2 (94.3 ; 98.1)DFS [%] (95% CI)92.2 (90.9 ; 93.5)80.1 (78.6 ; 81.6)79.0 (71.0 ; 86.0)77.0 (-)69.1 (66.4 ; 71.8)93.0 (91.3 ; 94.7)DDFS [%] (95% CI)92.9 (91.6 ; 94.2)82.2 (80.5 ; 83.9)82.8 (76.5 ; 89.1)83.3 (-)72.2 (70.7 ; 73.7)95.6 (94.4 ; 96.8)OS [%] (95% CI)95.1 (94.1 ; 96.1)88.7 (86.6 ; 90.8)92.5 (87.5 ; 97.5)85.6 (79.9 ; 91.3)78.5 (76.4 ; 80.6)96.9 (95.2 ; 98.6)ROS [%] (95% CI)100.0 (98.5 ; 100)93.4 (90.7 ; 96.1)96.0 (91.2 ; 100)88.8 (81.4 ; 96.2)80.1 (75.1 ; 85.1)100.0 (97.8 ; 100) Results: LCR, DFS, DDFS, OS and ROS over 5 years for the whole cohort of invasive cases were 96.1%, 83.7%, 85.7%, 90.5% and 94.7%, respectively. Luminal A tumors were the most frequent (44.7%) and showed the best outcome with LCR, OS and ROS over 5 years at 99.1%, 95.1% and 100.0%, respectively; while triple negative tumors presented the poorest outcome with LCR, OS and ROS over 5 years at 89.6%, 78.5% and 80.1%, respectively. Conclusions: This outcome analysis of a large cohort of patients with primary BC diagnosed, treated and prospectively followed on a routine basis at a specialized BCU in Germany confirmed general and detailed clinico-pathological subtype outcome data of clinical trials. Citation Format: Hennigs A, Heil J, Gondos A, Riedel F, Marme F, Sinn H-P, Schirmacher P, Kauczor H-U, Debus J, Golatta M, Schtz F, Sohn C, Schneeweiss A. Prognosis of clinico-pathological breast cancer subtypes in routine clinical care. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-12.

Asian women with breast cancer are often studied in aggregate, belying significant intragroup diversity. The authors sought to examine differences in breast cancer characteristics and outcomes among Asian women. Asian, non-Hispanic Black, Hispanic, and non-Hispanic White women aged 18 years and older who were diagnosed with breast cancer from 1990 to 2016 were identified in the Surveillance, Epidemiology, and End Results 18 database. Asian patients were subclassified as Chinese, Japanese, Korean, Filipino, Vietnamese, South Asian (Asian Indian or Pakistani), Southeast Asian (SEA, i.e., Cambodian, Laotian, Hmong, or Thai), or other Asian. Unadjusted overall survival (OS) and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method. Cox proportional hazards models were used to estimate adjusted OS and CSS. In total, 910,415 women were included (Asian, n = 63,405; Black, n = 92,226; Hispanic, n = 84,451; White, n = 670,333). Asian women had higher rates of human epidermal growth factor receptor 2 (HER2)-positive disease compared with White women (18.7% vs 13.8%) and had the highest 10-year unadjusted OS and CSS among all racial/ethnic groups (all P < .001). SEA women had the highest rates of stage IV disease at presentation, whereas Japanese women had the lowest rates (5.9% vs 2.7%; P < .001). Japanese women had the highest 10-year unadjusted CSS (89.4%; 95% confidence interval, 88.7%-90.1%) of any distinct Asian group, whereas SEA women had the worst unadjusted CSS (78%; 95% confidence interval, 74.1%-81.3%; P < .001). After adjustment, SEA women had the worst OS of any Asian group and were the only Asian group without improved OS compared with White women (reference category; P = .08). Breast cancer characteristics and outcomes vary significantly among Asian women. Future research should consider disaggregation by country or region of origin to identify subgroups that are at risk for worse outcomes than aggregated data may suggest. Asian women with breast cancer are frequently studied as a single entity. However, Asian ethnic groups differ greatly by country of origin, genetic ancestry, disease frequency, socioeconomic status, patterns of immigration, as well as dietary and cultural practices. Women of different Asian ethnicities vary significantly with regard to cancer characteristics, such as mortality and tumor subtype. Future research should disaggregate these populations to better understand, treat, and counsel Asian patients with breast cancer.

Neratinib as extended adjuvant therapy in patients with copositive early breast cancer: German health technology assessment–driven analyses from the ExteNET study

Objectives and rationale: Breast cancer (BC) arising at a young age is relatively uncommon; however, approximately 6 to 10% of women diagnosed with BC are younger than the age 40. This subgroup of young women presents different risk factors, tumor biology, and clinical outcomes. Moreover, the interpretation of the effects of inherited genetic factors on the prognosis of young patients with BC remains a subject of debate. The primary aim of this study was to evaluate the characteristics of young patients with BC and to compare the long-term oncological results between BRCA-mutation carriers and non-carriers. We retrospectively reviewed all the consecutive young (≤ 40 years old) BC patients treated at the Breast Unit of IRCCS Humanitas Research Hospital (Milan, Italy). All young patients underwent BRCA-mutation analysis. For further analysis young BC patients were divided into two groups: BRCA-mutation carriers versus non-carriers. Tumor, surgical treatment, and post-operative data were compared between the two groups. Primary end-points were: disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). The Kaplan-Meier method was used to generate the recurrence and survival curves. Multivariate analyses were performed using the Cox proportional hazards model to identify independent risk and protective factors for DFS, DDFS, and OS. Results: The characteristics of 63 young BC patients with BRCA-mutation were compared with 339 young BC patients without BRCA-mutation. BRCA-mutation carriers tend to be younger (60.3% versus 34.8% if age ≤ 35 years, odds ratio (OR) = 17.699, 95% confidence interval (95%CI) = 33.871-35.568, p = 0.001) and present more aggressive tumors (66.7% versus 40.7% if G3, OR = 17.119, 95%CI = 2.549-2.828, p = 0.001; 57.2% versus 12.4% if biological subtype triple negative, OR = 52.727, 95%CI = 2.042-2.417, p = 0.001; 73.0% versus 39.2% if Ki67 ≥ 25%, OR = 58.981, 95%CI = 47.135-58.505, p = 0.001). Young BC patients without BRCA-mutation presented significantly better long-term oncological results in terms of DFS, DDFS, and OS compared with young BRCA-mutation carriers (10-years DFS rate 91.1% versus 58.1%, p &amp;lt; 0.001; 10-year DDFS rate 91.2% versus 76.1%, p = 0.003; 10-year OS rate 98.0% versus 87.8%, p = 0.002, respectively). Neo-adjuvant chemotherapy was found to be an independent protective factor for OS in young BRCA-mutated BC patients (hazard radio = 14.885, 95%CI = 2.343-94.566, p = 0.004). Conclusions: Breast cancer is more likely to present at a younger age (≤ 35 years) and with more aggressive characteristics (G3, triple negative, Ki67 ≥ 25%) in patients with BRCA-mutation compared with their non-mutated counterpart. Young BRCA-mutation carriers show a poorer prognosis in terms of recurrence and survival compared with non-carriers. The implementation of neo-adjuvant chemotherapy may improve survival in young BC patients with BRCA-mutation. Citation Format: Damiano Gentile, Simone Di Maria Grimaldi, Andrea Sagona, Erika Barbieri, Alberto Bottini, Giuseppe Canavese, Giulia Caraceni, Shadya Darwish, Corrado Tinterri. Comparison of long-term oncological outcomes in young women with breast cancer between BRCA-mutation carriers versus non-carriers: How genetic risk factors and tumor characteristics influence the prognosis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-22-08.

Introduction: Patients with triple-negative (TN) or HER2-enriched ipsilateral breast cancer recurrence (IBCR) seem to be excluded from a second breast-conserving surgery (BCS) under the assumption that salvage mastectomy would provide better oncological outcomes. Objectives: The objective of this study was to describe the clinical features of these patients, to compare the two surgical alternatives (salvage mastectomy versus second BCS) in terms of oncological results, and to identify independent factors influencing prognosis and surgical treatment. Methods: We retrospectively reviewed all the consecutive patients with histologically confirmed TN or HER2-enriched IBCR. Disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed and compared between the two groups. Results: Eighty-five patients were affected by TN or HER2-enriched IBCR, with a median age of 60 years (range, 32-87 years). The majority of patients (72.9%) were treated with salvage mastectomy. There was no significant difference in terms of DFS between patients receiving a second BCS or mastectomy (p=0.596). However, patients undergoing a second BCS had significantly better DDFS, OS, and BCSS compared to mastectomy (p=0.009; p=0.002; p=0.001, respectively). Tumor dimension &amp;lt; 16 mm (78.3% versus 38.7%, hazard ratio (HR)=3.602, 95% confidence interval (95% CI)=1.534-8.459, p=0.003) was found to significantly increase the probability of receiving a second BCS and positively affects recurrence and survival outcomes (DFS: HR=8.065, 95% CI=2.320-28.034, p=0.001; DDFS: HR=17.011, 95% CI=3.853-75.099, p=0.001; OS: HR: 13.881, 95% CI=2.730-70.579, p=0.002; BCSS: HR=36.773, 95% CI=4.579-295.322, p=0.001). Second BCS represents an independent protective factor for OS and BCSS (OS: HR=0.246, 95% CI=0.027-0.697, p=0.002; BCSS: HR=0.313, 95% CI=0.092-0.511, p=0.002). Conclusion: Salvage mastectomy is not always necessary and it does not seem to increase survival compared to a second BCS. This reinforces the concept that the prognosis of TN and HER2-enriched BC recurrence is mainly driven by the biology of the disease, rather than by the extent of surgery. In patients with small (&amp;lt; 16 mm) aggressive subtypes of IBCR, a second conservative approach can still be evaluated and offered, presenting acceptable loco-regional control and survival. Citation Format: Damiano Gentile, Andrea Sagona, Erika Barbieri, Simone Di Maria Grimaldi, Ruggero Spoto, Davide Franceschini, Stefano Vaccari, Valeriano Vinci, Ersilia Biondi, Lorenzo Scardina, Corrado Tinterri. Salvage mastectomy is not always necessary for aggressive subtypes of ipsilateral breast cancer recurrence: A single-institution retrospective study [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 P1-09-09.

Overall Survival in Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer Treated with a CDK 4/6 Inhibitor Plus Fulvestrant: A U.S. Food and Drug Administration Pooled Analysis

4594 Background: Cisplatin based neoadjuvant chemotherapy (NAC) followed by definitive therapy improves survival in patients with muscle invasive bladder cancer (MIBC). However, the clinical benefit of NAC might vary with the choice of definitive therapy. Therefore, we assessed the absolute benefit of NAC followed by radical cystectomy or radical radiotherapy separately using the totality of evidence. Methods: MEDLINE and EMBASE were systematically searched to identify randomized trials assessing cisplatin based neoadjuvant chemotherapy followed by either radical cystectomy or definitive radiotherapy in patients with MIBC. Outcomes of interest included overall survival (OS) and disease-free survival (DFS). Treatment effects were expressed as hazard ratios (HR) with 95% confidence interval (CI). Incidence rate ratios were calculated to estimate time to event outcomes for trials not reporting HR. A random-effects DerSimonian-Laird meta-analysis was conducted. Absolute effects were then obtained using baseline risks from the control arm of RCTs. Results: Of 4887 studies identified, 13 trials with 2529 patients were included in this meta-analysis. Most trials included patients with T2-4 and N0 patients and only 3 trials included patients with node positive disease. Total of 180 (47%) DFS events were observed with NAC+RC compared to 213 (56%) events in RC alone (HR: 0.72; 95% CI: 0.59-0.89) and 346 (58%) OS events were observed with NAC+ RC compared to 385 (52%) events in RC alone (HR: 0.80; 95% CI: 0.69-0.92). Total of 186 (70%) DFS events were observed with NAC + radiotherapy compared to 205 (71%) events in radiotherapy alone (HR: 0.91; 95% CI: 0.74-1.12) and 263 (58%) OS events were observed with NAC+ radiotherapy compared to 294 (61%) events in radiotherapy alone (HR:0.93; 95% CI: 0.79-1.08). Conclusions: The choice of definitive therapy after cisplatin-based NAC impacts survival in patients with MIBC. RC after NAC improved DFS (114 fewer events per 1000 events) and OS (76 fewer per 1000 events) whereas radiotherapy after NAC showed no survival benefit. [Table: see text]

Background: Pathological complete response (pCR) has been used as a primary endpoint in neoadjuvant clinical trials for non-metastatic breast cancer and as a surrogate endpoint for long-term survival outcomes. The U.S. Food and Drug Administration (FDA) accepted pCR as a surrogate endpoint for the approval of new drugs in the neoadjuvant setting in high-risk early-stage breast cancer. However, though the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) pooled analysis in 2014 showed that at the patient level achieving pCR was associated with longer overall survival (OS) and event-free survival (EFS), at the trial-level the association between high pCR rate and better OS and EFS outcomes was weak (coefficient of difference [R2]; 0.03 and 0.24, respectively) among all subtypes of breast cancer. A recent study reported that this association at the trial-level was similarly weak among Human Epidermal Growth Factor Receptor-2 (HER-2) positive breast cancer (R2; 0.02 and 0.23, respectively). However, the potential surrogacy of pCR rate for OS and EFS in triple-negative breast cancer (TNBC) in the neoadjuvant setting has not been well studied in a comprehensive manner. Moreover, because of significant advances in systemic treatment strategies in TNBC over the past decade including a combination of immune checkpoint inhibitors (ICIs) with conventional cytotoxic agents, the trial-level surrogacy needs to be reassessed in recently published neoadjuvant clinical trials for TNBC. Our primary objective is to assess the association between pCR rate and survival outcomes in neoadjuvant clinical trials for TNBC by collecting data from articles published after the CTNeoBC article in 2014. Methods: We performed a systematic literature search based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the PubMed, Cochrane Library, and Web of Science databases. Articles published between January 1, 2014, and March 31, 2023, were searched. We included only randomized control trials of neoadjuvant treatments for clinical stage I-III TNBC that compared two or more regimens followed by curative intent breast surgery. The selected trials had data for odds ratio (OR) for pCR and hazard ratios (HRs) either for OS or for EFS or disease-free survival (DFS). We excluded trials including estrogen receptor positive, progesterone receptor-positive, or HER-2 positive diseases, and those without data enough to obtain ORs for pCR, HRs for OS, EFS, or DFS. Unpublished data as a full article was also excluded. If EFS could not be obtained from the articles, DFS was used in place of EFS. Two independent investigators (TY and TF) searched and extracted data. Any disagreement was resolved by discussion with the third author (ZZ). A linear regression model on a logarithmic scale weighted by the sample size of each trial was performed and the R2 was used to assess the trial-level association between OR for pCR and HRs for OS or EFS. Results: We identified eight trials with a total of 2,926 patients. Three of the eight trials used ICIs in the intervention arm. One trial did not provide OS data and was not included in the OS analysis. In four trials, EFS was not available and DFS was used for EFS analysis. The R2 was 0.191 (95% confidence interval [CI], 0.165 to 0.218) for OS and 0.193 (95% CI, 0.167 to 0.219) for EFS. Conclusions: Similarly to the previous reports, our findings suggest that the surrogacy of the pCR rate for OS and EFS in recent neoadjuvant clinical trials for TNBC is weak. At this moment, there is no strong evidence to support using pCR as a surrogate for long-term survival outcomes in neoadjuvant clinical trials for TNBC. Citation Format: Toru Yoshino, Zao Zhang, Ryota Sato, Stanley Lipkowitz, Takeo Fujii. Revisiting the potential of pathological complete response as a surrogate for long-term survival outcomes in triple-negative breast cancer at the trial-level [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-03-07.