Article

Key clinical point: Human epidermal growth factor receptor 2 (HER2)-low vs HER2-0 expression was associated with improved breast cancer-specific survival (BCSS) outcomes in patients with early-stage triple-negative breast cancer (TNBC), particularly in the high-risk subgroups.

Major finding: Patients with HER2-low vs HER2-0 BC had significantly better BCSS rates in the overall population (96.6% vs 93.7%; log-rank P = .027) and in high-risk subpopulations comprising patients without a pathological complete response despite neoadjuvant chemotherapy (log-rank P = .047) or those with stage-III BC (log-rank P = .010).

Study details: Findings are from a study including 1445 female patients with early-stage TNBC, of whom 51.7% and 48.3% showed HER2-0 and HER2-low status, respectively.

Disclosures: This study was sponsored by the Health Commission of Henan Province, China. The authors declared no conflicts of interest.

Source: Ma Y et al. HER2-low status was associated with better breast cancer-specific survival in early-stage triple-negative breast cancer. Oncologist. 2023 (Sep 28). doi: 10.1093/oncolo/oyad275

Key clinical point: Human epidermal growth factor receptor 2 (HER2)-low vs HER2-0 expression was associated with improved breast cancer-specific survival (BCSS) outcomes in patients with early-stage triple-negative breast cancer (TNBC), particularly in the high-risk subgroups.

Major finding: Patients with HER2-low vs HER2-0 BC had significantly better BCSS rates in the overall population (96.6% vs 93.7%; log-rank P = .027) and in high-risk subpopulations comprising patients without a pathological complete response despite neoadjuvant chemotherapy (log-rank P = .047) or those with stage-III BC (log-rank P = .010).

Study details: Findings are from a study including 1445 female patients with early-stage TNBC, of whom 51.7% and 48.3% showed HER2-0 and HER2-low status, respectively.

Disclosures: This study was sponsored by the Health Commission of Henan Province, China. The authors declared no conflicts of interest.

Source: Ma Y et al. HER2-low status was associated with better breast cancer-specific survival in early-stage triple-negative breast cancer. Oncologist. 2023 (Sep 28). doi: 10.1093/oncolo/oyad275

Key clinical point: Human epidermal growth factor receptor 2 (HER2)-low vs HER2-0 expression was associated with improved breast cancer-specific survival (BCSS) outcomes in patients with early-stage triple-negative breast cancer (TNBC), particularly in the high-risk subgroups.

Major finding: Patients with HER2-low vs HER2-0 BC had significantly better BCSS rates in the overall population (96.6% vs 93.7%; log-rank P = .027) and in high-risk subpopulations comprising patients without a pathological complete response despite neoadjuvant chemotherapy (log-rank P = .047) or those with stage-III BC (log-rank P = .010).

Study details: Findings are from a study including 1445 female patients with early-stage TNBC, of whom 51.7% and 48.3% showed HER2-0 and HER2-low status, respectively.

Disclosures: This study was sponsored by the Health Commission of Henan Province, China. The authors declared no conflicts of interest.

Source: Ma Y et al. HER2-low status was associated with better breast cancer-specific survival in early-stage triple-negative breast cancer. Oncologist. 2023 (Sep 28). doi: 10.1093/oncolo/oyad275

Key clinical point: This real-world study confirmed the effectiveness of tucatinib across all treatment lines in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (BC).

Major finding: Median real-world time-to-treatment discontinuation was 6.5 months (95% CI 5.4-8.8 months) for the overall population but was longer in patients who received tucatinib in combination with trastuzumab and capecitabine in a metastatic setting (8.1 months; 95% CI 5.7-9.5 months) or as second-line or third-line therapy (9.4 months; 95% CI 6.3-14.1 months). Median real-world overall survival was 26.6 months (95% CI 20.2-not reached).

Study details: Findings are from a retrospective cohort study including 216 patients with HER2+ metastatic BC who received tucatinib in any line of therapy.

Disclosures: This study was sponsored by Seagen Inc. and Merck Sharp & Dohme LLC. Seven authors declared being employees of and holding stock or stock options in Seagen Inc., and the other authors declared ties with various sources, including Seagen and Merck Sharp & Dohme.

Source: Kaufman PA et al. Real-world patient characteristics, treatment patterns, and clinical outcomes associated with tucatinib therapy in HER2-positive metastatic breast cancer. Front Oncol. 2023;13:1264861 (Oct 2). doi: 10.3389/fonc.2023.1264861

Key clinical point: This real-world study confirmed the effectiveness of tucatinib across all treatment lines in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (BC).

Major finding: Median real-world time-to-treatment discontinuation was 6.5 months (95% CI 5.4-8.8 months) for the overall population but was longer in patients who received tucatinib in combination with trastuzumab and capecitabine in a metastatic setting (8.1 months; 95% CI 5.7-9.5 months) or as second-line or third-line therapy (9.4 months; 95% CI 6.3-14.1 months). Median real-world overall survival was 26.6 months (95% CI 20.2-not reached).

Study details: Findings are from a retrospective cohort study including 216 patients with HER2+ metastatic BC who received tucatinib in any line of therapy.

Disclosures: This study was sponsored by Seagen Inc. and Merck Sharp & Dohme LLC. Seven authors declared being employees of and holding stock or stock options in Seagen Inc., and the other authors declared ties with various sources, including Seagen and Merck Sharp & Dohme.

Source: Kaufman PA et al. Real-world patient characteristics, treatment patterns, and clinical outcomes associated with tucatinib therapy in HER2-positive metastatic breast cancer. Front Oncol. 2023;13:1264861 (Oct 2). doi: 10.3389/fonc.2023.1264861

Key clinical point: This real-world study confirmed the effectiveness of tucatinib across all treatment lines in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (BC).

Major finding: Median real-world time-to-treatment discontinuation was 6.5 months (95% CI 5.4-8.8 months) for the overall population but was longer in patients who received tucatinib in combination with trastuzumab and capecitabine in a metastatic setting (8.1 months; 95% CI 5.7-9.5 months) or as second-line or third-line therapy (9.4 months; 95% CI 6.3-14.1 months). Median real-world overall survival was 26.6 months (95% CI 20.2-not reached).

Study details: Findings are from a retrospective cohort study including 216 patients with HER2+ metastatic BC who received tucatinib in any line of therapy.

Disclosures: This study was sponsored by Seagen Inc. and Merck Sharp & Dohme LLC. Seven authors declared being employees of and holding stock or stock options in Seagen Inc., and the other authors declared ties with various sources, including Seagen and Merck Sharp & Dohme.

Source: Kaufman PA et al. Real-world patient characteristics, treatment patterns, and clinical outcomes associated with tucatinib therapy in HER2-positive metastatic breast cancer. Front Oncol. 2023;13:1264861 (Oct 2). doi: 10.3389/fonc.2023.1264861

Key clinical point: Unlike partial breast irradiation (PBI), intraoperative radiation therapy (IORT) was associated with higher ipsilateral breast tumor recurrence (IBTR) rates than whole breast irradiation (WBI) in patients with early-stage breast cancer (BC) who underwent breast-conserving surgery (BCS).

Major finding: The risk for IBTR was comparable in patients treated with PBI and WBI (hazard ratio [HR] 1.20; P = .12) but was significantly higher in patients treated with IORT vs WBI (HR 1.46; P < .01).

Study details: Findings are from a meta-analysis of 11 randomized controlled trials including 15,460 patients with early-stage BC who underwent BCS, of whom 7190 patients, 4931 patients, and 2372 patients received WBI, PBI, and IORT, respectively.

Disclosures: This study did not receive any specific funding. Some authors declared serving as consultants for or receiving grants from various sources.

Source: Ravani LV et al. Comparison of partial-breast irradiation and intraoperative radiation to whole-breast irradiation in early-stage breast cancer patients: A Kaplan-Meier-derived patient data meta-analysis. Breast Cancer Res Treat. 2023 (Sep 22). doi: 10.1007/s10549-023-07112-w

Key clinical point: Unlike partial breast irradiation (PBI), intraoperative radiation therapy (IORT) was associated with higher ipsilateral breast tumor recurrence (IBTR) rates than whole breast irradiation (WBI) in patients with early-stage breast cancer (BC) who underwent breast-conserving surgery (BCS).

Major finding: The risk for IBTR was comparable in patients treated with PBI and WBI (hazard ratio [HR] 1.20; P = .12) but was significantly higher in patients treated with IORT vs WBI (HR 1.46; P < .01).

Study details: Findings are from a meta-analysis of 11 randomized controlled trials including 15,460 patients with early-stage BC who underwent BCS, of whom 7190 patients, 4931 patients, and 2372 patients received WBI, PBI, and IORT, respectively.

Disclosures: This study did not receive any specific funding. Some authors declared serving as consultants for or receiving grants from various sources.

Source: Ravani LV et al. Comparison of partial-breast irradiation and intraoperative radiation to whole-breast irradiation in early-stage breast cancer patients: A Kaplan-Meier-derived patient data meta-analysis. Breast Cancer Res Treat. 2023 (Sep 22). doi: 10.1007/s10549-023-07112-w

Key clinical point: Unlike partial breast irradiation (PBI), intraoperative radiation therapy (IORT) was associated with higher ipsilateral breast tumor recurrence (IBTR) rates than whole breast irradiation (WBI) in patients with early-stage breast cancer (BC) who underwent breast-conserving surgery (BCS).

Major finding: The risk for IBTR was comparable in patients treated with PBI and WBI (hazard ratio [HR] 1.20; P = .12) but was significantly higher in patients treated with IORT vs WBI (HR 1.46; P < .01).

Study details: Findings are from a meta-analysis of 11 randomized controlled trials including 15,460 patients with early-stage BC who underwent BCS, of whom 7190 patients, 4931 patients, and 2372 patients received WBI, PBI, and IORT, respectively.

Disclosures: This study did not receive any specific funding. Some authors declared serving as consultants for or receiving grants from various sources.

Source: Ravani LV et al. Comparison of partial-breast irradiation and intraoperative radiation to whole-breast irradiation in early-stage breast cancer patients: A Kaplan-Meier-derived patient data meta-analysis. Breast Cancer Res Treat. 2023 (Sep 22). doi: 10.1007/s10549-023-07112-w

Key clinical point: Compared with good or low adherence to adjuvant hormone therapy (HT), excellent adherence was associated with a significantly reduced risk for subsequent breast tumors (SBT) in older women with ductal carcinoma in situ (DCIS) of the breast.

Major finding: In patients with excellent vs low adherence to adjuvant HT, both breast-conserving surgery (BCS) and BCS + radiation therapy (RT) significantly reduced the risks for SBT (−10.54 and −6.24 percentage points, respectively; both P < .00001) or subsequent invasive breast cancer (−8.85 and −4.28 percentage points, respectively; both P < .00001). Similar results were obtained in patients with excellent vs good adherence to adjuvant HT.

Study details: Findings are from an analysis of a population-based study including 3075 women with DCIS who were age ≥ 65 years and underwent BCS either with (75%) or without RT (25%).

Disclosures: This study was supported by the US National Cancer Institute. Two authors declared serving as consultants for various sources.

Source: Mitchell JM et al. Adherence to hormonal therapy after surgery among older women with ductal carcinoma in situ: Implications for breast cancer-related adverse health events. Cancer. 2023 (Sep 26). Doi: 10.1002/cncr.35009

Key clinical point: Compared with good or low adherence to adjuvant hormone therapy (HT), excellent adherence was associated with a significantly reduced risk for subsequent breast tumors (SBT) in older women with ductal carcinoma in situ (DCIS) of the breast.

Major finding: In patients with excellent vs low adherence to adjuvant HT, both breast-conserving surgery (BCS) and BCS + radiation therapy (RT) significantly reduced the risks for SBT (−10.54 and −6.24 percentage points, respectively; both P < .00001) or subsequent invasive breast cancer (−8.85 and −4.28 percentage points, respectively; both P < .00001). Similar results were obtained in patients with excellent vs good adherence to adjuvant HT.

Study details: Findings are from an analysis of a population-based study including 3075 women with DCIS who were age ≥ 65 years and underwent BCS either with (75%) or without RT (25%).

Disclosures: This study was supported by the US National Cancer Institute. Two authors declared serving as consultants for various sources.

Source: Mitchell JM et al. Adherence to hormonal therapy after surgery among older women with ductal carcinoma in situ: Implications for breast cancer-related adverse health events. Cancer. 2023 (Sep 26). Doi: 10.1002/cncr.35009

Key clinical point: Compared with good or low adherence to adjuvant hormone therapy (HT), excellent adherence was associated with a significantly reduced risk for subsequent breast tumors (SBT) in older women with ductal carcinoma in situ (DCIS) of the breast.

Major finding: In patients with excellent vs low adherence to adjuvant HT, both breast-conserving surgery (BCS) and BCS + radiation therapy (RT) significantly reduced the risks for SBT (−10.54 and −6.24 percentage points, respectively; both P < .00001) or subsequent invasive breast cancer (−8.85 and −4.28 percentage points, respectively; both P < .00001). Similar results were obtained in patients with excellent vs good adherence to adjuvant HT.

Study details: Findings are from an analysis of a population-based study including 3075 women with DCIS who were age ≥ 65 years and underwent BCS either with (75%) or without RT (25%).

Disclosures: This study was supported by the US National Cancer Institute. Two authors declared serving as consultants for various sources.

Source: Mitchell JM et al. Adherence to hormonal therapy after surgery among older women with ductal carcinoma in situ: Implications for breast cancer-related adverse health events. Cancer. 2023 (Sep 26). Doi: 10.1002/cncr.35009

Key clinical point: Prophylactic salpingo-oophorectomy (PSO) after breast surgery leads to significantly improved overall survival (OS) outcomes and can be considered in patients with BRCA1/2 breast cancer (BC), particularly in those with the BRCA1 variant.

Major finding: Patients who did vs did not undergo PSO had significantly improved OS outcomes in the overall population (hazard ratio [HR] 0.40; P < .001) and in subgroups of patients with BRCA1 BC (HR 0.35;  95% CI 0.20-0.63), triple-negative BC (HR 0.21;  95% CI 0.09-0.46), and invasive ductal carcinoma (HR 0.51;  95% CI 0.31-0.84).

Study details: Findings are from a retrospective cohort study including 480 patients with BRCA1 (n = 290) or BRCA2 (n = 190) BC who underwent surgical resection, of whom 300 and 163 patients underwent PSO and prophylactic mastectomy, respectively.

Disclosures: This study did not disclose any funding source. Two authors declared being advisory board members of or receiving grants or personal fees from various sources unrelated to this study.

Source: Martelli G et al. Prophylactic salpingo-oophorectomy and survival after BRCA1/2 breast cancer resection. JAMA Surg. 2023 (Oct 4). doi: 10.1001/jamasurg.2023.4770

Key clinical point: Prophylactic salpingo-oophorectomy (PSO) after breast surgery leads to significantly improved overall survival (OS) outcomes and can be considered in patients with BRCA1/2 breast cancer (BC), particularly in those with the BRCA1 variant.

Major finding: Patients who did vs did not undergo PSO had significantly improved OS outcomes in the overall population (hazard ratio [HR] 0.40; P < .001) and in subgroups of patients with BRCA1 BC (HR 0.35;  95% CI 0.20-0.63), triple-negative BC (HR 0.21;  95% CI 0.09-0.46), and invasive ductal carcinoma (HR 0.51;  95% CI 0.31-0.84).

Study details: Findings are from a retrospective cohort study including 480 patients with BRCA1 (n = 290) or BRCA2 (n = 190) BC who underwent surgical resection, of whom 300 and 163 patients underwent PSO and prophylactic mastectomy, respectively.

Disclosures: This study did not disclose any funding source. Two authors declared being advisory board members of or receiving grants or personal fees from various sources unrelated to this study.

Source: Martelli G et al. Prophylactic salpingo-oophorectomy and survival after BRCA1/2 breast cancer resection. JAMA Surg. 2023 (Oct 4). doi: 10.1001/jamasurg.2023.4770

Key clinical point: Prophylactic salpingo-oophorectomy (PSO) after breast surgery leads to significantly improved overall survival (OS) outcomes and can be considered in patients with BRCA1/2 breast cancer (BC), particularly in those with the BRCA1 variant.

Major finding: Patients who did vs did not undergo PSO had significantly improved OS outcomes in the overall population (hazard ratio [HR] 0.40; P < .001) and in subgroups of patients with BRCA1 BC (HR 0.35;  95% CI 0.20-0.63), triple-negative BC (HR 0.21;  95% CI 0.09-0.46), and invasive ductal carcinoma (HR 0.51;  95% CI 0.31-0.84).

Study details: Findings are from a retrospective cohort study including 480 patients with BRCA1 (n = 290) or BRCA2 (n = 190) BC who underwent surgical resection, of whom 300 and 163 patients underwent PSO and prophylactic mastectomy, respectively.

Disclosures: This study did not disclose any funding source. Two authors declared being advisory board members of or receiving grants or personal fees from various sources unrelated to this study.

Source: Martelli G et al. Prophylactic salpingo-oophorectomy and survival after BRCA1/2 breast cancer resection. JAMA Surg. 2023 (Oct 4). doi: 10.1001/jamasurg.2023.4770

Key clinical point: The development of contralateral breast cancer (CBC) was associated with worsened survival outcomes if the primary breast cancer (PBC) subtype was hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (ERBB2−) or if the patients had CBC onset within 1.5 years after PBC surgery.

Major finding: Compared with patients who did not develop CBC, the risk for death was higher in patients who developed CBC within 1.5 years after PBC surgery (hazard ratio 2.014; P = .04) and in those with HR+/ERBB2− PBC (hazard ratio 1.882; P = .01).

Study details: Findings are from a cohort study including 16,251 patients with stages 0-III PBC, of whom 418 patients developed CBC.

Disclosures: This study did not report any funding source. The authors declared no conflicts of interest.

Source: Kim H et al. Survival after development of contralateral breast cancer in Korean patients with breast cancer. JAMA Netw Open. 2023;6(9):e2333557 (Sep 14). doi: 10.1001/jamanetworkopen.2023.33557

Key clinical point: The development of contralateral breast cancer (CBC) was associated with worsened survival outcomes if the primary breast cancer (PBC) subtype was hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (ERBB2−) or if the patients had CBC onset within 1.5 years after PBC surgery.

Major finding: Compared with patients who did not develop CBC, the risk for death was higher in patients who developed CBC within 1.5 years after PBC surgery (hazard ratio 2.014; P = .04) and in those with HR+/ERBB2− PBC (hazard ratio 1.882; P = .01).

Study details: Findings are from a cohort study including 16,251 patients with stages 0-III PBC, of whom 418 patients developed CBC.

Disclosures: This study did not report any funding source. The authors declared no conflicts of interest.

Source: Kim H et al. Survival after development of contralateral breast cancer in Korean patients with breast cancer. JAMA Netw Open. 2023;6(9):e2333557 (Sep 14). doi: 10.1001/jamanetworkopen.2023.33557

Key clinical point: The development of contralateral breast cancer (CBC) was associated with worsened survival outcomes if the primary breast cancer (PBC) subtype was hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (ERBB2−) or if the patients had CBC onset within 1.5 years after PBC surgery.

Major finding: Compared with patients who did not develop CBC, the risk for death was higher in patients who developed CBC within 1.5 years after PBC surgery (hazard ratio 2.014; P = .04) and in those with HR+/ERBB2− PBC (hazard ratio 1.882; P = .01).

Study details: Findings are from a cohort study including 16,251 patients with stages 0-III PBC, of whom 418 patients developed CBC.

Disclosures: This study did not report any funding source. The authors declared no conflicts of interest.

Source: Kim H et al. Survival after development of contralateral breast cancer in Korean patients with breast cancer. JAMA Netw Open. 2023;6(9):e2333557 (Sep 14). doi: 10.1001/jamanetworkopen.2023.33557

Key clinical point: Women who were exposed to fine particulate matter, ie, airborne particles with an aerodynamic diameter ≤ 2.5 μm (PM_2.5), showed an increased risk of developing breast cancer (BC), particularly estrogen receptor-positive (ER+) BC.

Major finding: As little as a 10 µg/m³ increase in PM_2.5 concentration during 1980-1984 increased the incident risk for BC by 8% (hazard ratio [HR] 1.08;  95% CI 1.02-1.13), with the risk being even higher in case of ER+ BC (HR 1.10;  95% CI 1.04-1.17).

Study details: Findings are from an analysis of a prospective, US-based cohort including 196,905 women with no prior history of cancer, of whom 15,870 developed incident BC.

Disclosures: This study was funded by the US National Institutes of Environmental Health Sciences and the US National Cancer Institute Intramural Program. The authors declared no conflicts of interest.

Source: White AJ et al. Ambient fine particulate matter and breast cancer incidence in a large prospective US cohort. J Natl Cancer Inst. 2023 (Sep 11). doi: 10.1093/jnci/djad170

Key clinical point: Women who were exposed to fine particulate matter, ie, airborne particles with an aerodynamic diameter ≤ 2.5 μm (PM_2.5), showed an increased risk of developing breast cancer (BC), particularly estrogen receptor-positive (ER+) BC.

Major finding: As little as a 10 µg/m³ increase in PM_2.5 concentration during 1980-1984 increased the incident risk for BC by 8% (hazard ratio [HR] 1.08;  95% CI 1.02-1.13), with the risk being even higher in case of ER+ BC (HR 1.10;  95% CI 1.04-1.17).

Study details: Findings are from an analysis of a prospective, US-based cohort including 196,905 women with no prior history of cancer, of whom 15,870 developed incident BC.

Disclosures: This study was funded by the US National Institutes of Environmental Health Sciences and the US National Cancer Institute Intramural Program. The authors declared no conflicts of interest.

Source: White AJ et al. Ambient fine particulate matter and breast cancer incidence in a large prospective US cohort. J Natl Cancer Inst. 2023 (Sep 11). doi: 10.1093/jnci/djad170

Key clinical point: Women who were exposed to fine particulate matter, ie, airborne particles with an aerodynamic diameter ≤ 2.5 μm (PM_2.5), showed an increased risk of developing breast cancer (BC), particularly estrogen receptor-positive (ER+) BC.

Major finding: As little as a 10 µg/m³ increase in PM_2.5 concentration during 1980-1984 increased the incident risk for BC by 8% (hazard ratio [HR] 1.08;  95% CI 1.02-1.13), with the risk being even higher in case of ER+ BC (HR 1.10;  95% CI 1.04-1.17).

Study details: Findings are from an analysis of a prospective, US-based cohort including 196,905 women with no prior history of cancer, of whom 15,870 developed incident BC.

Disclosures: This study was funded by the US National Institutes of Environmental Health Sciences and the US National Cancer Institute Intramural Program. The authors declared no conflicts of interest.

Source: White AJ et al. Ambient fine particulate matter and breast cancer incidence in a large prospective US cohort. J Natl Cancer Inst. 2023 (Sep 11). doi: 10.1093/jnci/djad170

Key clinical point: Women who survived cancer during childhood and received ≥ 200 mg/m² cumulative doxorubicin dose as a part of the treatment may have an increased risk of developing subsequent breast cancer (SBC).

Major finding: A ≥200 mg/m² cumulative doxorubicin dose vs no doxorubicin treatment led to > 2-fold increase in the risk for SBC (hazard ratio [HR] for 200-299  mg/m²: 2.50, 95% CI 1.85-3.40; HR for 300-399  mg/m²: 2.33, 95% CI 1.68-3.23; and HR for ≥ 400  mg/m²: 2.78, 95% CI 1.99-3.88). Every 100 mg/m² increase in the cumulative doxorubicin dose increased SBC risk in patients who survived cancer and either received (HR 1.11;  95% CI 1.02-1.21) or did not receive chest radiotherapy (HR 1.26;  95% CI 1.17-1.36).

<Study details: Findings are from an analysis of a pooled cohort including 17,903 females who survived cancer for ≥ 5 years, of whom 782 survivors developed SBC.

Disclosures: This study was supported by the Children Cancer Free Foundation (aka Foundation KiKa, Stichting Kinderen Kankervrij), Amsterdam. The authors declared no conflicts of interest.

Source: Wang Y et al for The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer. Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer. Nat Med. 2023;29(9):2268-2277 (Sep 11). doi: 10.1038/s41591-023-02514-1

Key clinical point: Women who survived cancer during childhood and received ≥ 200 mg/m² cumulative doxorubicin dose as a part of the treatment may have an increased risk of developing subsequent breast cancer (SBC).

Major finding: A ≥200 mg/m² cumulative doxorubicin dose vs no doxorubicin treatment led to > 2-fold increase in the risk for SBC (hazard ratio [HR] for 200-299  mg/m²: 2.50, 95% CI 1.85-3.40; HR for 300-399  mg/m²: 2.33, 95% CI 1.68-3.23; and HR for ≥ 400  mg/m²: 2.78, 95% CI 1.99-3.88). Every 100 mg/m² increase in the cumulative doxorubicin dose increased SBC risk in patients who survived cancer and either received (HR 1.11;  95% CI 1.02-1.21) or did not receive chest radiotherapy (HR 1.26;  95% CI 1.17-1.36).

<Study details: Findings are from an analysis of a pooled cohort including 17,903 females who survived cancer for ≥ 5 years, of whom 782 survivors developed SBC.

Disclosures: This study was supported by the Children Cancer Free Foundation (aka Foundation KiKa, Stichting Kinderen Kankervrij), Amsterdam. The authors declared no conflicts of interest.

Source: Wang Y et al for The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer. Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer. Nat Med. 2023;29(9):2268-2277 (Sep 11). doi: 10.1038/s41591-023-02514-1

Key clinical point: Women who survived cancer during childhood and received ≥ 200 mg/m² cumulative doxorubicin dose as a part of the treatment may have an increased risk of developing subsequent breast cancer (SBC).

Major finding: A ≥200 mg/m² cumulative doxorubicin dose vs no doxorubicin treatment led to > 2-fold increase in the risk for SBC (hazard ratio [HR] for 200-299  mg/m²: 2.50, 95% CI 1.85-3.40; HR for 300-399  mg/m²: 2.33, 95% CI 1.68-3.23; and HR for ≥ 400  mg/m²: 2.78, 95% CI 1.99-3.88). Every 100 mg/m² increase in the cumulative doxorubicin dose increased SBC risk in patients who survived cancer and either received (HR 1.11;  95% CI 1.02-1.21) or did not receive chest radiotherapy (HR 1.26;  95% CI 1.17-1.36).

<Study details: Findings are from an analysis of a pooled cohort including 17,903 females who survived cancer for ≥ 5 years, of whom 782 survivors developed SBC.

Disclosures: This study was supported by the Children Cancer Free Foundation (aka Foundation KiKa, Stichting Kinderen Kankervrij), Amsterdam. The authors declared no conflicts of interest.

Source: Wang Y et al for The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer. Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer. Nat Med. 2023;29(9):2268-2277 (Sep 11). doi: 10.1038/s41591-023-02514-1

Key clinical point: The omission of axillary surgery leads to non-inferior outcomes compared to sentinel lymph node biopsy (SLNB) and may not be necessary in patients with early breast cancer (BC) having a tumor diameter ≤ 2 cm and negative results for preoperative axillary lymph node ultrasonography.

Major finding: The rates of 5-year distant disease-free survival were comparable in patients who underwent SLNB and those who did not undergo axillary surgery (97.7% vs 98.0%; hazard ratio 0.84; noninferiority P = .02).

Study details: Findings are from the phase 3 SOUND trial including 1405 women with BC having a tumor diameter ≤ 2 cm and negative preoperative axillary ultrasonography results who were randomly assigned to undergo either SLNB or no axillary surgery.

Disclosures: This study did not disclose any funding source. Some authors declared receiving personal fees from various sources.

Source: Gentilini OD et al for the SOUND Trial Group. Sentinel lymph node biopsy vs no axillary surgery in patients with small breast cancer and negative results on ultrasonography of axillary lymph nodes: The SOUND randomized clinical trial. JAMA Oncol. 2023 (Sep 21). doi: 10.1001/jamaoncol.2023.3759

Key clinical point: The omission of axillary surgery leads to non-inferior outcomes compared to sentinel lymph node biopsy (SLNB) and may not be necessary in patients with early breast cancer (BC) having a tumor diameter ≤ 2 cm and negative results for preoperative axillary lymph node ultrasonography.

Major finding: The rates of 5-year distant disease-free survival were comparable in patients who underwent SLNB and those who did not undergo axillary surgery (97.7% vs 98.0%; hazard ratio 0.84; noninferiority P = .02).

Study details: Findings are from the phase 3 SOUND trial including 1405 women with BC having a tumor diameter ≤ 2 cm and negative preoperative axillary ultrasonography results who were randomly assigned to undergo either SLNB or no axillary surgery.

Disclosures: This study did not disclose any funding source. Some authors declared receiving personal fees from various sources.

Source: Gentilini OD et al for the SOUND Trial Group. Sentinel lymph node biopsy vs no axillary surgery in patients with small breast cancer and negative results on ultrasonography of axillary lymph nodes: The SOUND randomized clinical trial. JAMA Oncol. 2023 (Sep 21). doi: 10.1001/jamaoncol.2023.3759

Key clinical point: The omission of axillary surgery leads to non-inferior outcomes compared to sentinel lymph node biopsy (SLNB) and may not be necessary in patients with early breast cancer (BC) having a tumor diameter ≤ 2 cm and negative results for preoperative axillary lymph node ultrasonography.

Major finding: The rates of 5-year distant disease-free survival were comparable in patients who underwent SLNB and those who did not undergo axillary surgery (97.7% vs 98.0%; hazard ratio 0.84; noninferiority P = .02).

Study details: Findings are from the phase 3 SOUND trial including 1405 women with BC having a tumor diameter ≤ 2 cm and negative preoperative axillary ultrasonography results who were randomly assigned to undergo either SLNB or no axillary surgery.

Disclosures: This study did not disclose any funding source. Some authors declared receiving personal fees from various sources.

Source: Gentilini OD et al for the SOUND Trial Group. Sentinel lymph node biopsy vs no axillary surgery in patients with small breast cancer and negative results on ultrasonography of axillary lymph nodes: The SOUND randomized clinical trial. JAMA Oncol. 2023 (Sep 21). doi: 10.1001/jamaoncol.2023.3759

PHOTO:PEAKSTOCK/SHUTTERSTOCK

Richman IB, Long JB, Soulos PR, et al. Estimating breast cancer overdiagnosis after screening mammography among older women in the United States. Ann Intern Med. 2023;176:1172-1180. doi:10.7326/M23-0133

EXPERT COMMENTARY

A screening test is performed to detect potential health disorders or diseases in people who do not have any symptoms of disease. The goal of screening is to detect the condition early enough to treat it most effectively, and ultimately to decrease morbidity and mortality related to the disease. Overdiagnosis refers to the finding of a cancer that would not have caused clinical problems during a person’s lifetime.

Current guidelines for the early detection of breast cancer vary considerably, including recommendations for what age to initiate screening, the cadence of screening (annual or biannual), the use of ancillary screening for people with dense breasts, and importantly the upper age limit for which screening is advised. The US Preventive Services Task Force recommends continuing screening to age 74. The American Cancer Society suggests ongoing screening if life expectancy is estimated at more than 10 years, and the American College of Physicians recommends stopping screening at age 75, or younger if life expectancy is less than 10 years. The American College of Obstetricians and Gynecologists states that women at average risk of breast cancer should continue screening mammography until at least age 75.

Overdiagnosis is a difficult concept for clinicians to understand let alone explain to our patients. Recently, Richman and colleagues published the results of their study aimed at estimating overdiagnosis associated with breast cancer screening among older women.¹ As Dr. Otis Brawley, former Chief Medical and Scientific Officer of the American Cancer Society and current Distinguished Professor of Oncology and Epidemiology at Johns Hopkins University, states in the editorial that accompanies the study by Richman and colleagues, “Some tumors are not destined to grow, spread, and kill due to their genomics or their microenvironment. A second type of overdiagnosis involves small tumors that do have the potential to grow but will not grow fast enough to bother the patient within their natural lifetime.”²

Although screening mammography in older women results in frequent false positives that require additional imaging as well as biopsies, we have become more aware of the potential of overdiagnosis as an important downside of screening mammography in an elderly population.

Continue to: Details of the study...

Details of the study

Using the SEER registry to identify breast cancers linked to a 5% sample of Medicare beneficiaries, Richman and colleagues (funded by the National Cancer Institute and based at Yale University) conducted a retrospectivecohort study to estimate the likelihood of overdiagnosis associated with screening mammography among older women over 15 years of follow-up. Specifically, they assessed the difference in cumulative incidence of in situ and invasive breast cancer among women aged 70 years and older without a history of breast cancer when screened in 2002. During the subsequent 3 years, participants either continued screening (screened group) or did not (unscreened group). Women were followed through 2017.

Among almost 55,000 women followed, 88% were White, 6% were Black, and 3% were Hispanic. Mean follow-up was 13.7 years among women aged 70 to 74 years at baseline. For those aged 75 to 84 at baseline, mean follow-up was 10 years, and for those aged 85 years and older, mean follow-up was 5.7 years.

Estimated rates of overdiagnosis. Overall, among women aged 70 to 74 at baseline who were eventually diagnosed with breast cancer, the investigators estimated that 31% of these cancers were overdiagnosed. The corresponding percentage of breast cancers estimated to represent overdiagnosis climbed to 47% for those aged 75 to 84 years at baseline and to 54% for those aged 85 years and older at baseline.

The investigators assessed the impact of greater screening among women with a first-degree relative with a diagnosis of breast cancer and determined that this did not explain their results. With respect to cancer stage, the investigators noted that overdiagnosis was more prevalent among in situ and localized invasive cancers compared with those with regional or distant spread. Of note, the incidence of cancer with regional or distant spread was neither higher nor lower among those who were screened. Finally, the investigators did not observe significant differences in breast cancer–specific mortality by screening status.

The proportion of cancers that were overdiagnosed was particularly high among women with in situ as well as those with localized invasive disease. The investigators pointed out that as many as 90% of women aged 80 and older diagnosed with localized cancer undergo surgery, and almost two-thirds of those older than 70 years have radiation therapy for early-stage disease. In addition to the burdens associated with these treatments for overdiagnosed cancers in older women, simply being diagnosed with breast cancer profoundly affects the health and well-being of women, resulting in anxiety and substantial reductions in quality of life.

The authors also noted that some studies suggest that, among breast cancers diagnosed with screening, chemotherapy is less likely to be employed among older women, a screening benefit that must be weighed against the high likelihood of overdiagnosis. However, this benefit is unlikely to be meaningful for the majority of patients in this study who presented with in situ or early invasive lesions since chemotherapy often is not recommended for such women.

Study strengths and limitations

If screening mammography is effective, the incidence of advanced-stage tumors and breast cancer–specific mortality should be reduced in screened populations. Accordingly, in this large, long-term study using reliable sources of data, the findings that the incidence of advanced-stage disease as well as breast cancer–specific mortality were similar in the screened and unscreened cohorts provides powerful evidence that screening mammography is not effective in older women.³

As the authors pointed out, their findings regarding a high prevalence of overdiagnosis associated with screening mammography in older women are consistent with findings of other studies, some of which used different methodology.

The authors acknowledged that some women in their Medicare cohort who initially continued screening likely stopped screening subsequently, while some who initially did not continue screening might have been screened subsequently. They went on to indicate that if patients were completely adherent with subsequent screening (or not getting screened) the likelihood that cancers among screened women were overdiagnosed would be even higher.

Lead-time bias occurs when screening finds a cancer earlier than that cancer would have been diagnosed because of symptoms. This study followed the cohorts over a long timeframe to reduce the possibility that lead time was inappropriately identified as overdiagnosis. They also observed that, among women aged 85 and older, most cohort members had died by the end of study follow-up; accordingly, lead time is not likely to have explained their findings.

Limitations. The authors acknowledged that miscoding the mammogram type (screening vs diagnostic) could result in higher estimates of overdiagnosis. In their most conservative sensitivity analysis, the overdiagnosis rates could be as low as 15% for women aged 70 to 74, 36% for those aged 75 to 84, and 44% for people aged 85 and older.

Because this was an observational cohort study, unmeasured differences in breast cancer risk and underlying health factors may have been confounders. Specifically, people with severe life-threatening conditions that limited their expected life span may have chosen not to undergo regular screening. Although the authors did attempt to adjust for these factors, there may have been unrecognized confounders. This study was designed to estimate overdiagnosis, and therefore the specific benefits and harms of screening could not be addressed based on the data collected. ●

PHOTO:PEAKSTOCK/SHUTTERSTOCK

Richman IB, Long JB, Soulos PR, et al. Estimating breast cancer overdiagnosis after screening mammography among older women in the United States. Ann Intern Med. 2023;176:1172-1180. doi:10.7326/M23-0133

EXPERT COMMENTARY

A screening test is performed to detect potential health disorders or diseases in people who do not have any symptoms of disease. The goal of screening is to detect the condition early enough to treat it most effectively, and ultimately to decrease morbidity and mortality related to the disease. Overdiagnosis refers to the finding of a cancer that would not have caused clinical problems during a person’s lifetime.

Current guidelines for the early detection of breast cancer vary considerably, including recommendations for what age to initiate screening, the cadence of screening (annual or biannual), the use of ancillary screening for people with dense breasts, and importantly the upper age limit for which screening is advised. The US Preventive Services Task Force recommends continuing screening to age 74. The American Cancer Society suggests ongoing screening if life expectancy is estimated at more than 10 years, and the American College of Physicians recommends stopping screening at age 75, or younger if life expectancy is less than 10 years. The American College of Obstetricians and Gynecologists states that women at average risk of breast cancer should continue screening mammography until at least age 75.

Overdiagnosis is a difficult concept for clinicians to understand let alone explain to our patients. Recently, Richman and colleagues published the results of their study aimed at estimating overdiagnosis associated with breast cancer screening among older women.¹ As Dr. Otis Brawley, former Chief Medical and Scientific Officer of the American Cancer Society and current Distinguished Professor of Oncology and Epidemiology at Johns Hopkins University, states in the editorial that accompanies the study by Richman and colleagues, “Some tumors are not destined to grow, spread, and kill due to their genomics or their microenvironment. A second type of overdiagnosis involves small tumors that do have the potential to grow but will not grow fast enough to bother the patient within their natural lifetime.”²

Although screening mammography in older women results in frequent false positives that require additional imaging as well as biopsies, we have become more aware of the potential of overdiagnosis as an important downside of screening mammography in an elderly population.

Continue to: Details of the study...

Details of the study

Using the SEER registry to identify breast cancers linked to a 5% sample of Medicare beneficiaries, Richman and colleagues (funded by the National Cancer Institute and based at Yale University) conducted a retrospectivecohort study to estimate the likelihood of overdiagnosis associated with screening mammography among older women over 15 years of follow-up. Specifically, they assessed the difference in cumulative incidence of in situ and invasive breast cancer among women aged 70 years and older without a history of breast cancer when screened in 2002. During the subsequent 3 years, participants either continued screening (screened group) or did not (unscreened group). Women were followed through 2017.

Among almost 55,000 women followed, 88% were White, 6% were Black, and 3% were Hispanic. Mean follow-up was 13.7 years among women aged 70 to 74 years at baseline. For those aged 75 to 84 at baseline, mean follow-up was 10 years, and for those aged 85 years and older, mean follow-up was 5.7 years.

Estimated rates of overdiagnosis. Overall, among women aged 70 to 74 at baseline who were eventually diagnosed with breast cancer, the investigators estimated that 31% of these cancers were overdiagnosed. The corresponding percentage of breast cancers estimated to represent overdiagnosis climbed to 47% for those aged 75 to 84 years at baseline and to 54% for those aged 85 years and older at baseline.

The investigators assessed the impact of greater screening among women with a first-degree relative with a diagnosis of breast cancer and determined that this did not explain their results. With respect to cancer stage, the investigators noted that overdiagnosis was more prevalent among in situ and localized invasive cancers compared with those with regional or distant spread. Of note, the incidence of cancer with regional or distant spread was neither higher nor lower among those who were screened. Finally, the investigators did not observe significant differences in breast cancer–specific mortality by screening status.

The proportion of cancers that were overdiagnosed was particularly high among women with in situ as well as those with localized invasive disease. The investigators pointed out that as many as 90% of women aged 80 and older diagnosed with localized cancer undergo surgery, and almost two-thirds of those older than 70 years have radiation therapy for early-stage disease. In addition to the burdens associated with these treatments for overdiagnosed cancers in older women, simply being diagnosed with breast cancer profoundly affects the health and well-being of women, resulting in anxiety and substantial reductions in quality of life.

The authors also noted that some studies suggest that, among breast cancers diagnosed with screening, chemotherapy is less likely to be employed among older women, a screening benefit that must be weighed against the high likelihood of overdiagnosis. However, this benefit is unlikely to be meaningful for the majority of patients in this study who presented with in situ or early invasive lesions since chemotherapy often is not recommended for such women.

Study strengths and limitations

If screening mammography is effective, the incidence of advanced-stage tumors and breast cancer–specific mortality should be reduced in screened populations. Accordingly, in this large, long-term study using reliable sources of data, the findings that the incidence of advanced-stage disease as well as breast cancer–specific mortality were similar in the screened and unscreened cohorts provides powerful evidence that screening mammography is not effective in older women.³

As the authors pointed out, their findings regarding a high prevalence of overdiagnosis associated with screening mammography in older women are consistent with findings of other studies, some of which used different methodology.

The authors acknowledged that some women in their Medicare cohort who initially continued screening likely stopped screening subsequently, while some who initially did not continue screening might have been screened subsequently. They went on to indicate that if patients were completely adherent with subsequent screening (or not getting screened) the likelihood that cancers among screened women were overdiagnosed would be even higher.

Lead-time bias occurs when screening finds a cancer earlier than that cancer would have been diagnosed because of symptoms. This study followed the cohorts over a long timeframe to reduce the possibility that lead time was inappropriately identified as overdiagnosis. They also observed that, among women aged 85 and older, most cohort members had died by the end of study follow-up; accordingly, lead time is not likely to have explained their findings.

Limitations. The authors acknowledged that miscoding the mammogram type (screening vs diagnostic) could result in higher estimates of overdiagnosis. In their most conservative sensitivity analysis, the overdiagnosis rates could be as low as 15% for women aged 70 to 74, 36% for those aged 75 to 84, and 44% for people aged 85 and older.

Because this was an observational cohort study, unmeasured differences in breast cancer risk and underlying health factors may have been confounders. Specifically, people with severe life-threatening conditions that limited their expected life span may have chosen not to undergo regular screening. Although the authors did attempt to adjust for these factors, there may have been unrecognized confounders. This study was designed to estimate overdiagnosis, and therefore the specific benefits and harms of screening could not be addressed based on the data collected. ●

PHOTO:PEAKSTOCK/SHUTTERSTOCK

Richman IB, Long JB, Soulos PR, et al. Estimating breast cancer overdiagnosis after screening mammography among older women in the United States. Ann Intern Med. 2023;176:1172-1180. doi:10.7326/M23-0133

EXPERT COMMENTARY

A screening test is performed to detect potential health disorders or diseases in people who do not have any symptoms of disease. The goal of screening is to detect the condition early enough to treat it most effectively, and ultimately to decrease morbidity and mortality related to the disease. Overdiagnosis refers to the finding of a cancer that would not have caused clinical problems during a person’s lifetime.

Current guidelines for the early detection of breast cancer vary considerably, including recommendations for what age to initiate screening, the cadence of screening (annual or biannual), the use of ancillary screening for people with dense breasts, and importantly the upper age limit for which screening is advised. The US Preventive Services Task Force recommends continuing screening to age 74. The American Cancer Society suggests ongoing screening if life expectancy is estimated at more than 10 years, and the American College of Physicians recommends stopping screening at age 75, or younger if life expectancy is less than 10 years. The American College of Obstetricians and Gynecologists states that women at average risk of breast cancer should continue screening mammography until at least age 75.

Overdiagnosis is a difficult concept for clinicians to understand let alone explain to our patients. Recently, Richman and colleagues published the results of their study aimed at estimating overdiagnosis associated with breast cancer screening among older women.¹ As Dr. Otis Brawley, former Chief Medical and Scientific Officer of the American Cancer Society and current Distinguished Professor of Oncology and Epidemiology at Johns Hopkins University, states in the editorial that accompanies the study by Richman and colleagues, “Some tumors are not destined to grow, spread, and kill due to their genomics or their microenvironment. A second type of overdiagnosis involves small tumors that do have the potential to grow but will not grow fast enough to bother the patient within their natural lifetime.”²

Although screening mammography in older women results in frequent false positives that require additional imaging as well as biopsies, we have become more aware of the potential of overdiagnosis as an important downside of screening mammography in an elderly population.

Continue to: Details of the study...

Details of the study

Using the SEER registry to identify breast cancers linked to a 5% sample of Medicare beneficiaries, Richman and colleagues (funded by the National Cancer Institute and based at Yale University) conducted a retrospectivecohort study to estimate the likelihood of overdiagnosis associated with screening mammography among older women over 15 years of follow-up. Specifically, they assessed the difference in cumulative incidence of in situ and invasive breast cancer among women aged 70 years and older without a history of breast cancer when screened in 2002. During the subsequent 3 years, participants either continued screening (screened group) or did not (unscreened group). Women were followed through 2017.

Among almost 55,000 women followed, 88% were White, 6% were Black, and 3% were Hispanic. Mean follow-up was 13.7 years among women aged 70 to 74 years at baseline. For those aged 75 to 84 at baseline, mean follow-up was 10 years, and for those aged 85 years and older, mean follow-up was 5.7 years.

Estimated rates of overdiagnosis. Overall, among women aged 70 to 74 at baseline who were eventually diagnosed with breast cancer, the investigators estimated that 31% of these cancers were overdiagnosed. The corresponding percentage of breast cancers estimated to represent overdiagnosis climbed to 47% for those aged 75 to 84 years at baseline and to 54% for those aged 85 years and older at baseline.

The investigators assessed the impact of greater screening among women with a first-degree relative with a diagnosis of breast cancer and determined that this did not explain their results. With respect to cancer stage, the investigators noted that overdiagnosis was more prevalent among in situ and localized invasive cancers compared with those with regional or distant spread. Of note, the incidence of cancer with regional or distant spread was neither higher nor lower among those who were screened. Finally, the investigators did not observe significant differences in breast cancer–specific mortality by screening status.

The proportion of cancers that were overdiagnosed was particularly high among women with in situ as well as those with localized invasive disease. The investigators pointed out that as many as 90% of women aged 80 and older diagnosed with localized cancer undergo surgery, and almost two-thirds of those older than 70 years have radiation therapy for early-stage disease. In addition to the burdens associated with these treatments for overdiagnosed cancers in older women, simply being diagnosed with breast cancer profoundly affects the health and well-being of women, resulting in anxiety and substantial reductions in quality of life.

The authors also noted that some studies suggest that, among breast cancers diagnosed with screening, chemotherapy is less likely to be employed among older women, a screening benefit that must be weighed against the high likelihood of overdiagnosis. However, this benefit is unlikely to be meaningful for the majority of patients in this study who presented with in situ or early invasive lesions since chemotherapy often is not recommended for such women.

Study strengths and limitations

If screening mammography is effective, the incidence of advanced-stage tumors and breast cancer–specific mortality should be reduced in screened populations. Accordingly, in this large, long-term study using reliable sources of data, the findings that the incidence of advanced-stage disease as well as breast cancer–specific mortality were similar in the screened and unscreened cohorts provides powerful evidence that screening mammography is not effective in older women.³

As the authors pointed out, their findings regarding a high prevalence of overdiagnosis associated with screening mammography in older women are consistent with findings of other studies, some of which used different methodology.

The authors acknowledged that some women in their Medicare cohort who initially continued screening likely stopped screening subsequently, while some who initially did not continue screening might have been screened subsequently. They went on to indicate that if patients were completely adherent with subsequent screening (or not getting screened) the likelihood that cancers among screened women were overdiagnosed would be even higher.

Lead-time bias occurs when screening finds a cancer earlier than that cancer would have been diagnosed because of symptoms. This study followed the cohorts over a long timeframe to reduce the possibility that lead time was inappropriately identified as overdiagnosis. They also observed that, among women aged 85 and older, most cohort members had died by the end of study follow-up; accordingly, lead time is not likely to have explained their findings.

Limitations. The authors acknowledged that miscoding the mammogram type (screening vs diagnostic) could result in higher estimates of overdiagnosis. In their most conservative sensitivity analysis, the overdiagnosis rates could be as low as 15% for women aged 70 to 74, 36% for those aged 75 to 84, and 44% for people aged 85 and older.

Because this was an observational cohort study, unmeasured differences in breast cancer risk and underlying health factors may have been confounders. Specifically, people with severe life-threatening conditions that limited their expected life span may have chosen not to undergo regular screening. Although the authors did attempt to adjust for these factors, there may have been unrecognized confounders. This study was designed to estimate overdiagnosis, and therefore the specific benefits and harms of screening could not be addressed based on the data collected. ●