Non-breast Cancer Mortality Research Articles

Abstract P2-02-03: Efficacy and Safety of the Addition of Internal Mammary Irradiation to Standard Adjuvant Radiation in Early-Stage Breast Cancer: A Systematic Review and Meta-analysis

Abstract Background: Adjuvant regional nodal irradiation together with whole breast or chest wall irradiation is considered standard of care in most node positive early breast cancer. Existing data on adding internal mammary irradiation (IMNI) to the regional nodal fields are inconsistent. The objective of this study was to conduct a meta-analysis to explore the efficacy and safety of adding IMNI to adjuvant radiotherapy in early-stage, high risk breast cancer. Methods: A search of PubMed and EMBASE identified randomized trials that investigated the addition of IMNI to standard adjuvant radiation in early-stage breast cancer. Hazard ratios (HRs) and 95% confidence intervals (CI) were extracted for overall survival (OS), breast cancer specific survival (BCSS), disease-free survival (DFS) and distant-metastasis free survival (DMFS). The odds ratios (ORs) for regional and loco-regional recurrence, non-breast cancer mortality, secondary non-breast cancer, contralateral breast cancer and cardiovascular morbidity and mortality were also extracted. These data where pooled in a meta-analysis using RevMan 5.4. Results: Analysis included 5 trials comprising 10,994 patients. Compared to the control group, IMNI was associated with a small, but statistically significant improvement in OS (HR=0.91, 95% 0.85-0.97, p=0.004), BCSS (HR=0.84, 95%0.77-0.92, p< 0.001), DFS (HR=0.89, 95% CI 0.82-0.98, p= 0.01) and DMFS (HR=0.89, 95% 0.81-0.98, p=0.02). IMNI was also associated with reduced odds for regional (OR=0.58, 95% 0.44-0.75, p< 0.001) and loco-regional recurrence (OR=0.85, 95% CI 0.72-1.00, p=0.04). Subgroup analyses for OS by tumor location (medial/central vs. lateral) and by nodal burden showed similar benefit is all subgroups. The odds for cardiotoxicity were higher, but did not reach statistical significance (OR=1.23, 95% 0.99-1.53, p=0.07). There was no association with cardiovascular mortality (OR=1.00, 95% 0.69-1.46, p=1.00). There were also comparable odds for non-breast cancer mortality (OR=1.05, 95% 0.79-1.41, p=0.74), secondary cancer (OR=0.95, 95% 0.82-1.10, p=0.51) and contra-lateral breast cancer (OR=1.07, 95% 0.77-1.51, p=0.68). Conclusions: Compared to the control group the addition of IMNI in high-risk patients is associated with a statistically significant improvement in survival, albeit with a magnitude of questionable clinical meaningfulness. Non-significant association with increased cardiovascular toxicity requires further study in longer-term studies. Citation Format: Yasmin Korzets, Dina Levitas, Ahuva Grubstein, Ben W Corn, Eitan Amir, Hadar Goldvaser. Efficacy and Safety of the Addition of Internal Mammary Irradiation to Standard Adjuvant Radiation in Early-Stage Breast Cancer: A Systematic Review and Meta-analysis [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 P2-02-03.

Efficacy and Safety of the Addition of Internal Mammary Irradiation to Standard Adjuvant Radiation in Early-Stage Breast Cancer: A Systematic Review and Meta-Analysis.

Background: Existing data on adding internal mammary nodal irradiation (IMNI) to the regional nodal fields are inconsistent. Methods: Randomized trials investigating the addition of IMNI to standard adjuvant radiation were identified. Hazard ratios (HRs) and 95% confidence intervals (CI) were extracted for overall-survival (OS), breast cancer specific-survival (BCSS), and disease-free survival (DFS) as well as distant-metastasis free survival (DMFS). The odds ratios (ORs) for regional and loco-regional recurrence, non-breast cancer mortality, secondary non-breast cancer, contralateral breast cancer, and cardiovascular morbidity and mortality were also extracted. Results: Analysis included five trials comprising 10,994 patients, predominantly with higher risk, lymph node positive disease. Compared to the control group, IMNI was associated with significant improvement in OS (HR = 0.91, p = 0.004), BCSS (HR = 0.84, p < 0.001), DFS (HR = 0.89, p= 0.01), and DMFS (HR = 0.89, p = 0.02). IMNI was also associated with reduced odds for regional (OR = 0.58, p < 0.001) and loco-regional recurrence (OR = 0.85, p = 0.04). The odds for cardiotoxicity were not statistically significantly higher (OR = 1.23, p = 0.07). There were comparable odds for cardiovascular mortality (OR = 1.00, p = 1.00), non-breast cancer mortality (OR = 1.05, p = 0.74), secondary cancer (OR = 0.95, p = 0.51), and contra-lateral breast cancer (OR = 1.07, 95% 0.77–1.51, p = 0.68). Conclusions: Compared to the control group, the addition of IMNI in high-risk patients is associated with a statistically significant improvement in survival, albeit with a magnitude of questionable clinical meaningfulness.

Tools for Contralateral Prophylactic Mastectomy Decision Making.

Women with unilateral breast cancer are increasingly opting for the removal of not only the involved breast, but also for the removal of the opposite uninvolved breast (contralateral prophylactic mastectomy [CPM]), although the risk of contralateral breast cancer (CBC) has decreased in recent years. Models to predict the absolute risk of CBC can help a woman decide whether to undergo CPM. Our objective is to illustrate that a better decision can be made if the patient and doctor also have estimates of the absolute risks of regional and distant recurrences and mortality from non-breast cancer causes. We based our analyses on two published models for CBC and published information on the hazards of regional and distant recurrences and non-breast cancer mortality. Assuming that CPM eliminates CBC but has no effect on other events, we calculated how much CPM reduces a woman's CBC risk and total risk from all these events for 10 hypothetical women with various subtypes of breast cancer and risk factors. The risk of CBC and total risk vary greatly, depending on the breast cancer subtype. In some cases, a decision for or against CPM can be based on CBC risk alone, but in others, additional consideration of total risk may cause a woman to decline CPM. There is a potential to develop more informative tools for deciding on CPM. Realizing this potential will require more and better data to validate existing models of absolute CBC risk and to characterize the hazards of regional and distant recurrences and deaths from non-breast cancer causes for women with various subtypes of breast cancers and risk factors.

Abstract P3-19-09: Impact of intraoperative radiation therapy and external beam radiation therapy on non-breast cancer mortality in early-stage breast cancer

Abstract Purpose: The TARGIT-A trial of kilovoltage intraoperative radiation therapy (IORT) versus external beam radiation therapy (EBRT) demonstrated a significant reduction in non-breast cancer mortality (nBCM) in women that received IORT, largely attributed to an increase in cardiac mortality in patients that received EBRT. Further, If EBRT does result in excess nBCM due to cardiac or other causes, then treatment with lumpectomy (Lump) alone or mastectomy (Mast) alone should result in lower rates of nBCM rates compared to Lump+EBRT. Our primary objective was to determine whether Lump+EBRT results in increased nBCM compared to Lump+IORT in women with early-stage breast cancer (BC) with a hypothesis that the two approaches should result in equivalent nBCM. We also tested the hypotheses that Lump+EBRT should have the same rates of nBCM as Lump alone or Mast alone. Materials/Methods: We used the Surveillance Epidemiology and End Results (SEER) database to identify women with early-stage BC treated with Lump alone, Lump+EBRT, Lump+IORT, or Mast alone from 2000-2016. SEER does not distinguish between kilovoltage IORT and electron IORT. We included patients with characteristics similar to the TARGIT-A study: age≥45 years; ductal carcinoma in situ (DCIS) or T1; lymph-node negative. We excluded patients that: received chemotherapy; received postmastectomy radiation therapy; had unknown cause of death; and had ≤1 month of follow-up. The primary endpoint was nBCM which is captured in the SEER database (patients were censored if they were alive or dead due to cancer at last follow-up). Cox-proportional hazards multivariate regression models were used to compare nBCM between Lump+EBRT and Lump+IORT adjusting for confounders that were statistically significant on univariate analysis. We secondarily compared nBCM in the Lump+EBRT vs. Lump population and Lump+EBRT vs. Mast population. Results: We identified 219,470 women that met the inclusion criteria: 121,776 Lump+EBRT; 1,735 Lump+IORT; 41,900 Lump; 54,059 Mast. Median follow-up time was 61 months for the entire cohort (IQR, 30-99 months) but was shorter for Lump+IORT patients (29 months) compared to the other groups (63 months Lump+EBRT; 62 months Mast; 57 months Lump). There were a total of 16,640 nBCM events: 6,210 Lump+EBRT; 5,708 Lump; 4,704 Mast; 18 Lump+IORT. The 5-year cumulative incidence of nBCM was 3.1% for Lump+EBRT vs. 1.6% for Lump+IORT (p=0.034). After adjustment for potential confounders (age, tumor location, marital status, race/ethnicity, DCIS vs. invasive, tumor grade, hormone receptor status, and receipt of axillary surgery), patients treated with Lump+IORT had a 38% relative reduction in the risk of nBCM compared to those treated with Lump+EBRT (HR=0.62, 95% CI 0.39-0.99, p=0.045). Other factors associated with increased nBCM included older age, divorced/single/widowed status (vs. married), Black race, high tumor grade, receipt of axillary lymph node dissection (vs. sentinel lymph node biopsy), no axillary surgery (vs. sentinel node biopsy), and ER-/PR- disease (vs. ER+ or PR+). In contrast, patients treated with Lulmp+EBRT had lower nBCM compared to those that received Lump alone (adjusted HR=0.55, 95% CI 0.53-0.57, p&amp;lt;0.0001) and compared to those that received Mast alone (adjusted HR=0.59, 95% CI 0.56-0.61, p&amp;lt;0.0001). Conclusion: In summary, contrary to our hypothesis, we found that Lump+IORT was associated with lower nBCM compared to Lump+EBRT possibly reflecting underlying selection bias. However, Lump+EBRT was not associated with an increased nBCM relative to patients treated with Lump alone or Mast alone. This suggests that the underlying mechanism for the reduced nBCM seen in patients treated with IORT in the TARGIT-A trial and this SEER analysis is not due to the potentially harmful effects of EBRT. Citation Format: Jose G Bazan, Jay Fisher, Sachin Jhawar, Erin Healy, Sasha Beyer, Julia R. White. Impact of intraoperative radiation therapy and external beam radiation therapy on non-breast cancer mortality in early-stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-19-09.

Abstract P3-19-16: Impact of targeted intraoperative (TARGIT-IORT) tumor bed boost during breast conserving surgery for early breast cancer on breast cancer associated and non-breast cancer associated mortality and morbidity

Abstract Introduction: Targeted intraoperative radiotherapy (TARGIT - IORT) as a tumor bed boost during breast conserving surgery is an established option for women with early breast cancer. In a previous study our group could demonstrate a beneficial effect of TARGIT-IORT on overall survival after neoadjuvant chemotherapy driven by non-breast cancer mortality, especially from cardiac or pulmonary diseases. This was in line with results of TARGIT-A trial that demonstrated an improved overall survival after TARGIT-IORT that was driven by other causes of death than breast cancer but in our analysis we could not exclude a selection bias because we had no data regarding pulmonary and cardiac co-morbidities. In this study we present an analysis of breast cancer associated and non-breast cancer associated mortality and morbidity in a lower risk population treated with TARGIT-IORT boost or external boost (EBRT) and with a complete dataset of pulmonary and cardiac co-morbidities at baseline. Material/Methods: In this non-randomized cohort study involving 125 patients with early breast cancer we compared outcomes of 59 patients who received a tumor bed boost with IORT (TARGIT-IORT) during lumpectomy versus 66 patients with external (EBRT) boost. All patients received whole breast radiotherapy. Local recurrence rates, distant recurrence rates, mortality, causes of death and incidence of new pulmonary and cardiac morbidity were compared. The small event rate did not allow a formal comparison, so the results are reported descriptively. Results: There were no statistically significant differences between the two groups regarding age, menopausal status, nodal status, ER status, PR status, HER2 status, tumor size, grading, cardiac or pulmonary diseases and hypertension. Median follow up was 60 months. Local recurrence occurred in 3 cases in the EBRT group (4.5%) and 4 cases in the TARGIT-IORT group (6.8%). Distant recurrences were observed in 5 cases in the EBR group (7.6%) and 3 cases in the TARGIT-IORT group (5.1%). 9 patients in the EBRT group (13.6%) died in the follow-up of 60 months and 6 patients (10.2%) in the TARGIT-IORT group. No death from a pulmonary disease occurred and the incidence of new pulmonary and new cardiac diseases showed no difference between both groups with 3 cases in the EBRT group (4.5%) and 2 cases in the TARGIT-IORT group (3.4%). Death from cardiac disease occurred with an incidence of 7 cases in the EBRT group (10.6%) and only 2 cases in the TARGIT-IORT group (3.4%). 2 patients in the EBRT group died of breast cancer (3.0%) whereas this did not happen at all in the TARGIT-IORT group. Conclusion: This analysis of an average risk group of breast cancer patients well balanced for pulmonary and cardiac co-morbidities demonstrates that TARGIT-IORT as an anticipated boost is not inferior to external beam radiotherapy boost. Trends for an improved overall survival after TARGIT-IORT have been reported before. The trend for a lower incidence of death from cardiac disease is in line with earlier considerations that TARGIT-IORT may induce miR-223 in the peritumoral breast tissue resulting in a downregulation of the local expression of epidermal growth factor (EGF) and a decreased activation of epidermal growth factor receptor (EGFR). This mechanism could explain an effect of TARGIT-IORT on the vascular system. In the currently recruiting TARGIT-B study this aspect will be prospectively investigated. Citation Format: Hans-Christin Kolberg, Stephanie Gutberlet, Jayant S Vaidya, Maja Krajewska, György Lövey, Oliver Hoffmann, Miltiades Stephanou, Cornelia Kolberg-Liedtke. Impact of targeted intraoperative (TARGIT-IORT) tumor bed boost during breast conserving surgery for early breast cancer on breast cancer associated and non-breast cancer associated mortality and morbidity [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-19-16.

Identifying Equitable Screening Mammography Strategies for Black Women in the United States Using Simulation Modeling.

Screening mammography guidelines do not explicitly consider racial differences in breast cancer epidemiology, treatment, and survival. To compare tradeoffs of screening strategies in Black women versus White women under current guidelines. An established model from the Cancer Intervention and Surveillance Modeling Network simulated screening outcomes using race-specific inputs for subtype distribution; breast density; mammography performance; age-, stage-, and subtype-specific treatment effects; and non-breast cancer mortality. United States. A 1980 U.S. birth cohort of Black and White women. Screening strategies until age 74 years with varying initiation ages and intervals. Outcomes included benefits (life-years gained [LYG], breast cancer deaths averted, and mortality reduction), harms (mammographies, false positives, and overdiagnoses), and benefit-harm ratios (tradeoffs) by race. Efficiency (benefits per unit resource), mortality disparity reduction, and equity in tradeoffs were evaluated. Equitable strategies for Black women were defined as those with tradeoffs closest to benchmark values for screening White women biennially from ages 50 to 74 years. Biennial screening from ages 45 to 74 years was most efficient for Black women, whereas biennial screening from ages 40 to 74 years was most equitable. Initiating screening 10 years earlier in Black versus White women reduced Black-White mortality disparities by 57% with similar LYG per mammogram for both populations. Selection of the most equitable strategy was sensitive to assumptions about disparities in real-world treatment effectiveness: The less effective treatment was for Black women, the more intensively Black women could be screened before tradeoffs fell short of those experienced by White women. Single model. Initiating biennial screening in Black women at age 40 years reduces breast cancer mortality disparities and yields benefit-harm ratios that are similar to tradeoffs of White women screened biennially from ages 50 to 74 years. National Cancer Institute at the National Institutes of Health.

252Development and validation of a breast cancer absolute risk prediction model in Chinese population

Abstract Background Compared with developed countries, breast cancer in China is characterized by a rapidly escalating incidence rate, lower survival rate, and vast geographic variation. However, there is no national validated model in China to aid early detection yet. Methods A large nation-wide prospective cohort, China Kadoorie Biobank (CKB), was used to evaluate relative and attributable risks. A total of 300,824 women free of prior cancer were recruited during 2004-2008 and followed up to 31 December 2016. Absolute risks were calculated by incorporating national age- and residence-specific incidence and non-breast cancer mortality rates. We used an independent large prospective cohort, Shanghai Women's Health Study (SWHS), to externally validate the calibration and discriminating accuracy. Results During a median of 10.2 years of follow-up in the CKB, 2,287 cases were observed. The final model included education, BMI, height, family history of cancer, parity, and age at menarche. The model was well-calibrated in both the CKB and the SWHS, yielding expected/observed ratios of 1.00 (95% confidence interval (CI), 0.96-1.04) and 0.94 (95% CI, 0.89-0.99), respectively. After eliminating the effect of age and residence, the adjusted areas under the curve were 0.615 (95% CI, 0.600-0.630) and 0.585 (95% CI, 0.564-0.605), respectively. Conclusions Based only on non-laboratory predictors, our model has an excellent calibration and moderate discriminating capacity. The model may be a useful tool to raise individuals’ awareness and aid risk-stratified screening and prevention strategies. Key messages We developed a breast cancer prediction model for Chinese women, which performed well in internal and external validation.

Development and external validation of a breast cancer absolute risk prediction model in Chinese population

BackgroundsIn contrast to developed countries, breast cancer in China is characterized by a rapidly escalating incidence rate in the past two decades, lower survival rate, and vast geographic variation. However, there is no validated risk prediction model in China to aid early detection yet.MethodsA large nationwide prospective cohort, China Kadoorie Biobank (CKB), was used to evaluate relative and attributable risks of invasive breast cancer. A total of 300,824 women free of any prior cancer were recruited during 2004–2008 and followed up to Dec 31, 2016. Cox models were used to identify breast cancer risk factors and build a relative risk model. Absolute risks were calculated by incorporating national age- and residence-specific breast cancer incidence and non-breast cancer mortality rates. We used an independent large prospective cohort, Shanghai Women’s Health Study (SWHS), with 73,203 women to externally validate the calibration and discriminating accuracy.ResultsDuring a median of 10.2 years of follow-up in the CKB, 2287 cases were observed. The final model included age, residence area, education, BMI, height, family history of overall cancer, parity, and age at menarche. The model was well-calibrated in both the CKB and the SWHS, yielding expected/observed (E/O) ratios of 1.01 (95% confidence interval (CI), 0.94–1.09) and 0.94 (95% CI, 0.89–0.99), respectively. After eliminating the effect of age and residence, the model maintained moderate but comparable discriminating accuracy compared with those of some previous externally validated models. The adjusted areas under the receiver operating curve (AUC) were 0.634 (95% CI, 0.608–0.661) and 0.585 (95% CI, 0.564–0.605) in the CKB and the SWHS, respectively.ConclusionsBased only on non-laboratory predictors, our model has a good calibration and moderate discriminating capacity. The model may serve as a useful tool to raise individuals’ awareness and aid risk-stratified screening and prevention strategies.

New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer

BackgroundThe TARGIT-A trial reported risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer to be as effective as whole-breast external beam radiotherapy (EBRT). Here, we present further detailed analyses.MethodsIn total, 2298 women (≥45 years, invasive ductal carcinoma ≤3.5 cm, cN0–N1) were randomised. We investigated the impact of tumour size, grade, ER, PgR, HER2 and lymph node status on local recurrence-free survival, and of local recurrence on distant relapse and mortality. We analysed the predictive factors for recommending supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach, using regression modelling. Non-breast cancer mortality was compared between TARGIT-IORT plus EBRT vs. EBRT.ResultsLocal recurrence-free survival was no different between TARGIT-IORT and EBRT, in every tumour subgroup. Unlike in the EBRT arm, local recurrence in the TARGIT-IORT arm was not a predictor of a higher risk of distant relapse or death. Our new predictive tool for recommending supplemental EBRT after TARGIT-IORT is at https://targit.org.uk/addrt. Non-breast cancer mortality was significantly lower in the TARGIT-IORT arm, even when patients received supplemental EBRT, HR 0.38 (95% CI 0.17–0.88) P = 0.0091.ConclusionTARGIT-IORT is as effective as EBRT in all subgroups. Local recurrence after TARGIT-IORT, unlike after EBRT, has a good prognosis. TARGIT-IORT might have a beneficial abscopal effect.Trial registrationISRCTN34086741 (21/7/2004), NCT00983684 (24/9/2009).

Diet Quality and Breast Cancer Recurrence and Survival: The Pathways Study.

BackgroundPrior research suggests a relationship between overall diet quality and breast cancer survival, although few studies have reported on this topic. We evaluated whether 4 dietary quality indices consistent with healthy eating recommendations around the time of breast cancer diagnosis were associated with risk of recurrence, cause-specific, and all-cause mortality.MethodsA total of 3660 women diagnosed with invasive breast cancer were included. Diet was assessed an average of 2.3 (range = 0.7-18.7) months after diagnosis, from which 4 dietary quality indices were derived: the American Cancer Society guidelines (ACS), the alternate Mediterranean Diet Index (aMED), the Dietary Approaches to Stop Hypertension (DASH), and the 2015 Healthy Eating Index (HEI). Over 40 888 person-years of follow-up, 461 breast cancer recurrences, and 655 deaths were ascertained. Cox models were used to estimate hazards ratios (HRs) and 95% confidence intervals (CIs).ResultsAdjusted comparisons between extreme quintiles showed all 4 dietary quality indices to be inversely associated with all-cause mortality, suggesting a 21%-27% lower risk (ACS HR = 0.73, 95% CI = 0.56 to 0.95; aMED HR = 0.79, 95% CI = 0.61 to 1.03; DASH HR = 0.76, 95% CI = 0.58 to 1.00; HEI HR = 0.77, 95% CI = 0.60 to 1.01). Similar patterns were noted for non-breast cancer mortality (ACS HR = 0.69, 95% CI = 0.48 to 0.98; aMED HR = 0.73, 95% CI = 0.50 to 1.05; DASH HR = 0.55, 95% CI = 0.38 to 0.79; HEI HR = 0.67, 95% CI = 0.48 to 0.94). None of the dietary quality indices were associated with recurrence or breast cancer–specific mortality.ConclusionFood intake patterns concordant with dietary quality indices consistent with recommendations for healthy eating may be beneficial for women with breast cancer.

Use of Non-Cancer Medications in New Zealand Women at the Diagnosis of Primary Invasive Breast Cancer: Prevalence, Associated Factors and Effects on Survival.

Background: Assessing the use of multiple medications in cancer patients is crucial as such use may affect cancer outcomes. This study reports the prevalence of non-cancer medication use at breast cancer diagnosis, its associated factors, and its effect on survival. Methods: We identified all women diagnosed with primary invasive breast cancer between 1 January 2007 and 31 December 2016, from four population-based breast cancer registries, in Auckland, Waikato, Wellington, and Christchurch, New Zealand. Through linkage to the pharmaceutical records, we obtained information on non-cancer medications that were dispensed for a minimum of 90 days’ supply between one year before cancer diagnosis and first cancer treatment. We performed ordered logistic regressions to identify associated factors and Cox regressions to investigate its effect on patient survival. Results: Of 14,485 patients, 52% were dispensed at least one drug (mean—1.3 drugs; maximum—13 drugs), with a higher prevalence observed in patients who were older, treated at a public facility, more economically deprived, and screen-detected. The use of 2–3 drugs showed a reduced non-breast cancer mortality (HR = 0.75, 95%CI = 0.60–0.92) in previously hospitalised patients, with other groups showing non-significant associations when adjusted for confounding factors. Drug use was not associated with changes in breast cancer-specific mortality. Conclusions: Non-cancer medication use at breast cancer diagnosis was common in New Zealand, more prevalent in older and disadvantaged women, and showed no effect on breast cancer-specific mortality, but a reduction in other cause mortality with the use of 2–3 drugs.

Does Intraoperative Radiation Therapy Result in Improved Overall Survival in Early-Stage Breast Cancer? An Analysis of the National Cancer Database

The TARGIT-A trial of kilovoltage intraoperative radiation therapy (IORT) vs. external beam radiation therapy (EBRT) demonstrated a significant reduction in non-breast cancer mortality (nBCM) with a trend towards improved overall survival (OS) in women that received IORT. The trend towards improved OS was attributed to an increase in cardiac mortality in EBRT patients. We set to determine whether EBRT results in inferior OS compared to IORT in women with low-risk, early-stage breast cancer (BC) in a United States database with a hypothesis that the two approaches should result in equivalent OS. We used the National Cancer Database (NCDB) to identify women with low-risk BC treated with lumpectomy and either IORT or EBRT from 2004-2016. Low-risk BC included: age≥50 years, stage 0-I (ductal histology), lymph node-negative, ER+. Patients were categorized into 1 of 2 groups: IORT (20 Gy/1 fraction and no further EBRT) or EBRT (4256-6000 cGy to the breast [no regional lymph node irradiation]). The primary endpoint was OS. We compared OS between the IORT and EBRT patients using the Kaplan-Meier method and Cox-regression multivariate analysis (p<.05 considered significant). We used propensity-score matching (PSM) as an independent test of the Cox regression analysis. We identified 81,889 women that met the inclusion criteria (1,321 IORT; 80,568 EBRT). Compared to EBRT patients, IORT patients were older (mean age = 68.3 years vs. 64.8 years, p<.0001), had a similar proportion of patients with no comorbidities (83.1% vs. 84.7%, p = .13), and were less likely to have DCIS (11.3% vs. 27.5%, p<.0001), grade 3 tumors (9.9% vs. 16.8%, p<.0001), or PR- disease (9.3% vs. 14.7%, p<.0001). IORT patients were more often treated at academic medical centers (53.8% vs. 31.4%, p<.0001). Median follow-up was 44.9 months (IQR 23.7 months-75.9 months). The 4-year OS for IORT vs. EBRT was 94.9% vs. 95.7% (HR = 1.24, 95% CI 0.93-1.64, p = .15). Only tumor laterality and receipt of lymph node surgery were not associated with OS on univariate analysis. After adjustment for all other potential confounders (age, comorbidity, race, facility type, insurance status, income level, education level, stage, tumor size, grade, PR status, hormone therapy receipt, and chemotherapy receipt) the HR for OS from IORT vs. EBRT was 0.90 (95% CI 0.67-1.21, p = .48). The PSM cohort included 1320 of a possible 1321 matched pairs. The 4-year OS for IORT vs. EBRT was 94.9% vs. 95.9% with a HR = 1.13 (0.79-1.63, p = 0.51). In summary, we found that there was no significant trend towards improved OS between patients with low-risk BC treated with IORT vs. EBRT. We included only the lowest risk BC patients, including those with DCIS, to allow for the detection a potentially small harmful effect of EBRT. Further study is warranted to determine if IORT or other partial breast irradiation techniques result in reduced nBCM, especially in an era of more precise, conformal EBRT delivery techniques.

Ethnic and biological differences in the association between physical activity and survival after breast cancer

Physical activity is recommended for most cancer patients as a nonpharmacological therapy to improve prognosis. Few studies have investigated the association between physical activity and breast cancer prognosis by ethnicity, biological, and modifiable risk factors for mortality. We investigated the association between physical activity and long-term survival among breast cancer survivors. A total of 397 survivors (96 Hispanic and 301 non-Hispanic White (NHW)) from the New Mexico HEAL study contributed baseline and biological data approximately 6 months after diagnosis. Study outcomes included all-cause, breast cancer-specific, and non-breast cancer mortality. The exposure was self-reported physical activity within the past month. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox Proportional Hazards regression. A total of 133 deaths (53 breast cancer-specific deaths) were observed after a median follow-up time of 13 years. Engaging in >6.9 metabolic equivalent hours/week (MET-h/week) of moderate to vigorous physical activity (active) was inversely associated with all-cause mortality among all women (HR 0.66, 95% CI 0.43–0.99) and NHWs (HR 0.58, 95% CI 0.36–0.94). Active NHW women also had a reduced risk of non-breast cancer mortality (HR 0.56, 95% CI 0.31–0.99), compared to inactive women (0 MET-h/week). In subgroups, we observed the inverse associations with all-cause mortality among women >58 years old (p-interaction= 0.03) and with localized stage (p-interaction = 0.046). Our results confirm the protective association between physical activity and mortality after breast cancer diagnosis, and demonstrate that this association significantly differs by age and cancer stage. Larger studies are warranted to substantiate our findings.

Incidence, Characteristics, and Outcomes of Interval Breast Cancers Compared With Screening-Detected Breast Cancers

Breast cancer comprises a highly heterogeneous group of diseases. Many breast cancers, particularly the more lethal ones, may not satisfy the assumptions about biology and natural history of breast cancer necessary for screening mammography to be effective. To compare tumor characteristics of breast cancers diagnosed within 2 years of a normal screening mammogram (interval breast cancer [IBC]) with those of screen-detected breast cancers (SBC) and to compare breast cancer-specific mortality of IBC with SBC. In this registry-based cohort study, we collected data about relevant tumor- and patient-related variables on women diagnosed with breast cancer between January 2004 and June 2010 who participated in the population-based screening program in Manitoba, Canada, and those diagnosed with breast cancer outside the screening program in the province. We performed multinomial logistic regression analysis to assess tumor and patient characteristics associated with a diagnosis of IBC compared with SBC. Competing risk analysis was performed to examine risk of death by cancer detection method. Breast cancer diagnosis. Differences in tumor characteristics and breast cancer-specific mortality. A total of 69 025 women aged 50 to 64 years had 212 screening mammograms during the study period. There were 1687 breast cancer diagnoses (705 SBC, 206 IBC, 275 were noncompliant, and 501 were detected outside the screening program), and 225 deaths (170 breast cancer-specific deaths). Interval cancers were more likely than SBC to be of high grade and estrogen receptor negative (odds ratio [OR], 6.33; 95% CI, 3.73-10.75; P < .001; and OR, 2.88; 95% CI, 2.01-4.13; P < .001, respectively). After a median follow-up of 7 years, breast cancer-specific mortality was significantly higher for IBC compared with SBC cancers (hazard ratio [HR] 3.55; 95% CI, 2.01-6.28; P < .001), for a sojorn time of 2 years. Non-breast cancer mortality was similar between IBC and SBC (HR, 1.33; 95% CI, 0.43-4.15). In this cohort study, interval cancers were highly prevalent in women participating in population screening, represented a worse biology, and had a hazard for breast cancer death more than 3-fold that for SBC. Strategies beyond current mammographic screening practices are needed to reduce incidence, improve detection, and reduce deaths from these potentially lethal breast cancers.

Treatment patterns, risk for hospitalization and mortality in older patients with triple negative breast cancer

ObjectivesTo study the treatment patterns, potential risk factors for hospitalization within one year from diagnosis, and causes of death in older patients with triple negative breast cancer (TNBC). Materials and MethodsWe performed a registry-based cohort study using the BCBaSe database which links cases of breast cancer from three Swedish healthcare regions with socioeconomic factors, hospitalizations and causes of death. Women ≥70 years old with non-metastatic TNBC, between 1/12007 and 31/122012 were included (n = 413). ResultsIn total, 168 patients (40.7%) received chemotherapy after surgery and 123 patients (30.0%) in the whole cohort had at least one hospitalization within one year from diagnosis. The risk of hospitalization overall was increased in the group receiving chemotherapy (Odds Ratio 2.35, 95% Confidence Intervall: 1.30–4.26) mainly due to toxicities. Cumulative incidence of breast cancer mortality was comparable among different age groups (70–74 vs. 75–79 vs. ≥ 80 years old) whereas non-breast cancer mortality was higher in patients ≥80 years old. Stage at diagnosis and comorbidities were independently associated with both breast cancer-specific- and overall mortality whereas age was only associated with overall mortality. ConclusionsThe use of chemotherapy in older patients with TNBC was associated with age, tumor stage, and comorbidities. Chemotherapy use was also associated with increased risk for hospitalization within one year from diagnosis. Although the impact of chemotherapy on mortality was analyzed in a multivariate manner showing neither increased or decreased mortality, no firm conclusion can be drawn due to unmeasured confounders.

Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.

ObjectiveTo determine whether risk adapted intraoperative radiotherapy, delivered as a single dose during lumpectomy, can effectively replace postoperative whole breast external beam radiotherapy for early breast cancer.DesignProspective, open label, randomised controlled clinical trial.Setting32 centres in 10 countries in the United Kingdom, Europe, Australia, the United States, and Canada.Participants2298 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, cN0-N1, eligible for breast conservation and randomised before lumpectomy (1:1 ratio, blocks stratified by centre) to either risk adapted targeted intraoperative radiotherapy (TARGIT-IORT) or external beam radiotherapy (EBRT).InterventionsRandom allocation was to the EBRT arm, which consisted of a standard daily fractionated course (three to six weeks) of whole breast radiotherapy, or the TARGIT-IORT arm. TARGIT-IORT was given immediately after lumpectomy under the same anaesthetic and was the only radiotherapy for most patients (around 80%). TARGIT-IORT was supplemented by EBRT when postoperative histopathology found unsuspected higher risk factors (around 20% of patients).Main outcome measuresNon-inferiority with a margin of 2.5% for the absolute difference between the five year local recurrence rates of the two arms, and long term survival outcomes.ResultsBetween 24 March 2000 and 25 June 2012, 1140 patients were randomised to TARGIT-IORT and 1158 to EBRT. TARGIT-IORT was non-inferior to EBRT: the local recurrence risk at five year complete follow-up was 2.11% for TARGIT-IORT compared with 0.95% for EBRT (difference 1.16%, 90% confidence interval 0.32 to 1.99). In the first five years, 13 additional local recurrences were reported (24/1140 v 11/1158) but 14 fewer deaths (42/1140 v 56/1158) for TARGIT-IORT compared with EBRT. With long term follow-up (median 8.6 years, maximum 18.90 years, interquartile range 7.0-10.6) no statistically significant difference was found for local recurrence-free survival (hazard ratio 1.13, 95% confidence interval 0.91 to 1.41, P=0.28), mastectomy-free survival (0.96, 0.78 to 1.19, P=0.82), distant disease-free survival (0.88, 0.69 to 1.12, P=0.30), overall survival (0.82, 0.63 to 1.05, P=0.13), and breast cancer mortality (1.12, 0.63 to 1.28, P=0.54). Mortality from other causes was significantly lower (0.59, 0.40 to 0.86, P=0.005).ConclusionFor patients with early breast cancer who met our trial selection criteria, risk adapted immediate single dose TARGIT-IORT during lumpectomy was an effective alternative to EBRT, with comparable long term efficacy for cancer control and lower non-breast cancer mortality. TARGIT-IORT should be discussed with eligible patients when breast conserving surgery is planned.Trial registrationISRCTN34086741, NCT00983684.

Abstract A005: Would black women benefit from a screening mammography schedule that differs from that recommended for the overall population? A simulation modeling study

Abstract Background: For breast cancer, black women experience younger mean age at diagnosis, higher incidence of triple negative disease, and higher mortality compared to the overall population. These epidemiological differences raise the question of whether different screening mammography schedules for black women might produce similar benefit-to-harm ratio as those currently recommended for the overall population. Methods: We used the Georgetown-Einstein Cancer Intervention and Surveillance Modeling Network (CISNET) model to compare the benefit-to-harm ratios of a variety of digital mammography screening schedules for black women and white women. We updated the models with a variety of race-specific inputs, including non-breast cancer (competing) mortality, breast density, mammography sensitivity, breast cancer incidence with and without screening, estrogen (ER) and Her-2 receptor distributions, and stage distributions. Within age, stage, and ER/Her-2 receptor strata, we assumed that breast cancer biology was the same across races, as reflected by equal sojourn, stage dwell time and treatment efficacy. The objective of this study was to isolate the impact of screening mammography, not to quantify the impact of differences in screening or treatment completion on disparities. Therefore, in keeping with previously published methods, we assumed 100% dissemination of screening mammography and adjuvant treatment for all races. We investigated annual, biennial, and hybrid screening strategies beginning at age 40, 45, or 50 and concluding at age 74 (e.g. “A40-B50-74” means annually starting at age 40, then biennially at age 50, then stopping at age 74). We quantified the number of mammograms (M), overdiagnoses, false positives (FP), breast cancer deaths averted (BCDA), life years gained (LYG) and their benefit-to-harm ratios (LYG:M, BCDA:M, LYG:FP, BCDA:FP). Results: Biennial strategies (B50-74, B45-74, B40-74) have approximately equal incremental benefit:harm ratios and are superior to annual or hybrid strategies. Hybrid strategies A40B50-74 and B40A50-74 are sometimes efficient, depending on the metric, but have lower incremental benefit:harm ratios than the biennial strategies. Results were similar for black and white women. Conclusions: Despite the fact that black women have a younger mean age at diagnosis, higher incidence of triple negative disease, and higher breast cancer mortality, the relative benefits of different screening mammography schedules do not appear to differ between black and white women. These findings do not support different screening guidelines for black and white women. Future analyses will investigate whether potential racial differences in treatment efficacy might change the relative benefits of different screening mammography schedules. Citation Format: Christina H Chapman, Clyde Schechter, Amy Trentham, Ron Gangnon, Chris Cadham, Jeanne Mandelblatt. Would black women benefit from a screening mammography schedule that differs from that recommended for the overall population? A simulation modeling study [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A005.

Partial-breast irradiation versus whole-breast radiotherapy for early breast cancer: A systematic review and update meta-analysis

PurposeThe purpose of this study was to compare the treatment outcomes of partial-breast irradiation (PBI) versus whole-breast radiotherapy (WBRT) in early breast cancer. Methods and MaterialsEligible randomized clinical trials were identified on Medline, Embase, the Cochrane Library, and the proceedings of annual meetings through December 2019. A meta-analysis for local recurrence (LR), overall mortality (OM), and non-breast cancer mortality (NBCM) was conducted. When possible, the outcomes were calculated for 5, 7, and 10 years of followup. A subgroup analysis by PBI technique (brachytherapy [BT], external beam radiotherapy [EBRT], intraoperative radiotherapy [IORT], and mixed) was performed. A p value < 0.05 was considered significant. ResultsEleven randomized clinical trials with a total of 14,436 patients (7186 PBI vs. 7250 WBRT) were included in the meta-analysis. The odds ratio (OR) for LR in 5 y was 1.46 (95% CI 1.15–2, p = 0.024) for PBI. In the subgroup analysis, no significant difference for LR was observed between PBI and WBRT using BT (p = 0.51), EBRT (p = 0.25), or mixed techniques (p = 0.89). The only subgroup with statistical difference was IORT 3.1 (95% CI 1.2–7.6, p = 0.014). No significant difference in LR was observed with 7 and 10 years among the groups. The OM had no difference at 5, 7, and 10 years of followup for any subgroup. A nonsignificant difference was observed comparing PBI with WBRT for NBCM OR = 1.24 (95% CI 0.98–1.57, p = 0.07). The rates of cardiac death, contralateral breast cancer, and development of second tumor were not significant. ConclusionsThe LR with PBI is low and similar to WBRT in selected early breast cancer with a longer followup. The subgroup analysis detected a significant difference for LR associated with IORT and no significant difference for BT and EBRT. Our results confirm a nonsignificant difference for OM and NBCM between PBI and WBRT.

The Association Between Guideline-concordant Care and Risk for Breast Cancer and Non-breast Cancer Mortality Among Older Women with Breast Cancer

The purpose of this study is to determine how receipt of guideline-concordant care (GCC) is associated with breast cancer-specific mortality (BCSM) and non-breast cancer mortality (NBCM) among older women with breast cancer. The SEER-Medicare data was used to identify 142, 433 women age > 66 diagnosed with stage I-III breast cancer between 2007-2011. Receipt of GCC was determined according to evidence-based treatment guidelines. Cause-specific Cox proportional hazard multivariable regression models were used to estimate the association between GCC and the risk of BCSM, considering NBCM as a competing event, and NBCM, considering BCSM as a competing event, within five years of diagnosis or until end of follow-up. Among older women with breast cancer, 6.5% experienced BCSM and 11.9% experienced NBCM. GCC was associated with a 24% decreased risk of BCSM (AHR, 0.76; 95% CI, 0.71-0.82), but a 80% increased risk of NBCM (AHR, 1.80; 95% CI, 1.70-1.92). Receipt of adjuvant endocrine therapy was associated with an increased risk of BCSM and a decreased risk for NBCM. Receipt of chemotherapy was associated with an increased risk for BCSM and NBCM, while radiation therapy was associated with a decreased risk of NBCM. Women with a pre-existing dementia, arthritis, hypertension, stroke and increased comorbidity burden had an increased risk for BCSM. Most older breast cancer patients do not receive GCC, yet relatively few die from breast cancer. While GCC does decrease the risk of BCSM, the decision to treat should be made considering the patients existing health status, given that pre-existing comorbidity increases the risk for both BCSM and NBCM. Mortality differences associated with specific types of treatment may be attributed to patient selection for treatment based on worse cancer prognostic factors.

Editorial: Doctor's Dilemma or Patient's Choice?

Introduction: It has been estimated that about 50% of screen-detected cases might be over-diagnosed and over-treated. In this paper we analysed the mortality of patients with screen detected cancers in the TARGIT-A trial in which patients >=45 years with an invasive duct carcinoma <=3.5 cm in size and suitable for breast conserving therapy were randomly allocated to receive either risk-adapted TARGIT IORT or conventional course of several weeks of fractionated external beam radiotherapy (EBRT). Method: This was a post-hoc subgroup analysis limited to patients whose cancers were detected by screening mammography, and we compared breast cancer mortality, non-breast cancer mortality and overall mortality between TARGIT and EBRT with Kaplan Meier plots and logrank test. The allocation of cause of death was performed by an independent clinician who was blinded to the randomisation arms of the trial. Results: A total of 3451 patients were recruited into the TARGIT-A trial. Of these, there were 2102 patients whose cancers were diagnosed by mammographic screening (61% of the total). There were 30 deaths recorded: TARGIT 10/1060vs EBRT 20/1042): 7 from breast cancer (TARGIT 4 vs. EBRT 3), 23 from other causes (TARGIT 6, EBRT 17). The overall survival with TARGIT was 2% higher than with EBRT (5-year rates: 98.03% 95%CI 95.97 – 99.04, vs 96.03% 95%CI 93.41 – 97.62, Logrank p = 0.0522), with a doubling of mortality from 2% to 4% in this population. The breast cancer-specific survival was identical between the groups (99%). The difference in overall survival was due to higher non-breast-cancer survival in the TARGIT arm (TARGIT 99.2% and EBRT 96.7%) attributable to deaths in the EBRT arm from cardiac causes and other cancers (TARGIT 3 vs. EBRT 14). Interpretation: Harm from overtreatment of patients with screen detected cancers eligible to receive TARGIT IORT (<3.5 cm ductal cancers), who form a large proportion of the eligible group, in the form of deaths due cardiac causes and other cancers could be potentially avoided if they were instead treated by receive TARGIT IORT instead of conventional external beam radiotherapy. After discussions and volunteers with personal case histories to relate and a break there was a final session to consider the ethical and legal responsibility of doctors in the new era of shared decision-making with a brief run-through of key cases by Suzanne White of Leigh Day solicitors and then a keen Q&A discussion. Should we try for a Judicial Review of the failure to provide IORT in the NHS? Should a case be brought under the Human Rights Act using crowd funding? Something must be done if the medical establishment does not put IORT into practice in the NHS round the country.