Breast Cancer

Key clinical point: Neoadjuvant radiation therapy (NART) led to similar survival outcomes as postoperation radiation therapy (PORT) in patients with invasive ductal carcinoma (IDC) who underwent breast-conserving surgery (BCS) and were treated with neoadjuvant chemotherapy.

Major finding: NART vs PORT led to comparable breast cancer-specific survival (BCCS) and overall survival (OS) outcomes (both log-rank P > .05) in patients undergoing BCS or implant-based immediate breast reconstruction. However, NART vs PORT led to significantly lower BCCS (hazard ratio [HR] 1.407; log-rank P = .003) and OS (HR 1.383; log-rank P = .004) outcomes in those undergoing mastectomy.

Study details: This retrospective study included 14,515 women with IDC (age ≤ 80 years) from the Surveillance, Epidemiology, and End Results (SEER) database who were treated with neoadjuvant chemotherapy, of whom 386 and 14,129 patients underwent NART and PORT, respectively.

Disclosures: This study was supported by Shanghai Science and Technology Commission and Fudan University, China. The authors declared no conflicts of interest.

Source: Yuan J, Zhang M, Wang M, et al. Neoadjuvant radiochemotherapy is safe and feasible for breast conserving surgery or immediate reconstruction. Sci Rep. 2024;14:9208 (Apr 22). doi: 10.1038/s41598-024-59961-0 Source

Key clinical point: Neoadjuvant radiation therapy (NART) led to similar survival outcomes as postoperation radiation therapy (PORT) in patients with invasive ductal carcinoma (IDC) who underwent breast-conserving surgery (BCS) and were treated with neoadjuvant chemotherapy.

Major finding: NART vs PORT led to comparable breast cancer-specific survival (BCCS) and overall survival (OS) outcomes (both log-rank P > .05) in patients undergoing BCS or implant-based immediate breast reconstruction. However, NART vs PORT led to significantly lower BCCS (hazard ratio [HR] 1.407; log-rank P = .003) and OS (HR 1.383; log-rank P = .004) outcomes in those undergoing mastectomy.

Study details: This retrospective study included 14,515 women with IDC (age ≤ 80 years) from the Surveillance, Epidemiology, and End Results (SEER) database who were treated with neoadjuvant chemotherapy, of whom 386 and 14,129 patients underwent NART and PORT, respectively.

Disclosures: This study was supported by Shanghai Science and Technology Commission and Fudan University, China. The authors declared no conflicts of interest.

Source: Yuan J, Zhang M, Wang M, et al. Neoadjuvant radiochemotherapy is safe and feasible for breast conserving surgery or immediate reconstruction. Sci Rep. 2024;14:9208 (Apr 22). doi: 10.1038/s41598-024-59961-0 Source

Key clinical point: Neoadjuvant radiation therapy (NART) led to similar survival outcomes as postoperation radiation therapy (PORT) in patients with invasive ductal carcinoma (IDC) who underwent breast-conserving surgery (BCS) and were treated with neoadjuvant chemotherapy.

Major finding: NART vs PORT led to comparable breast cancer-specific survival (BCCS) and overall survival (OS) outcomes (both log-rank P > .05) in patients undergoing BCS or implant-based immediate breast reconstruction. However, NART vs PORT led to significantly lower BCCS (hazard ratio [HR] 1.407; log-rank P = .003) and OS (HR 1.383; log-rank P = .004) outcomes in those undergoing mastectomy.

Study details: This retrospective study included 14,515 women with IDC (age ≤ 80 years) from the Surveillance, Epidemiology, and End Results (SEER) database who were treated with neoadjuvant chemotherapy, of whom 386 and 14,129 patients underwent NART and PORT, respectively.

Disclosures: This study was supported by Shanghai Science and Technology Commission and Fudan University, China. The authors declared no conflicts of interest.

Source: Yuan J, Zhang M, Wang M, et al. Neoadjuvant radiochemotherapy is safe and feasible for breast conserving surgery or immediate reconstruction. Sci Rep. 2024;14:9208 (Apr 22). doi: 10.1038/s41598-024-59961-0 Source

Key clinical point: Use of a statin after breast cancer (BC) diagnosis improved survival in older women (age ≥ 66 years) with localized and regional stage disease, particularly in those with the hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) subtype.

Major finding: Use vs no use of a statin postdiagnosis was associated with a 15% reduced risk for BC-specific mortality (hazard ratio 0.85; 95% CI 0.75-0.96), with the effect being more pronounced women with HR+/HER2− BC (hazard ratio 0.71; 95% CI 0.57-0.88). There was no significant association between postdiagnosis statin use and the risk for BC recurrence (hazard ratio 1.05; 95% CI 0.91-1.21).

Study details: This retrospective cohort study included women with localized and regional stage BC from the Surveillance, Epidemiology, and End Results (SEER)–Medicare database who were assessed for mortality (n = 38,858) and recurrence (n = 28,522), of whom 8836 and 6475 used a statin postdiagnosis, respectively.

Disclosures: This study was supported by the US National Cancer Institute, National Institutes of Health. The authors declared no conflicts of interest.

Source: Guo H, Malone KE, Heckbert SR, Li CI. Statin use and risks of breast cancer recurrence and mortality. Cancer. 2024 (May 6). doi: 10.1002/cncr.35362 Source

Key clinical point: Use of a statin after breast cancer (BC) diagnosis improved survival in older women (age ≥ 66 years) with localized and regional stage disease, particularly in those with the hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) subtype.

Major finding: Use vs no use of a statin postdiagnosis was associated with a 15% reduced risk for BC-specific mortality (hazard ratio 0.85; 95% CI 0.75-0.96), with the effect being more pronounced women with HR+/HER2− BC (hazard ratio 0.71; 95% CI 0.57-0.88). There was no significant association between postdiagnosis statin use and the risk for BC recurrence (hazard ratio 1.05; 95% CI 0.91-1.21).

Study details: This retrospective cohort study included women with localized and regional stage BC from the Surveillance, Epidemiology, and End Results (SEER)–Medicare database who were assessed for mortality (n = 38,858) and recurrence (n = 28,522), of whom 8836 and 6475 used a statin postdiagnosis, respectively.

Disclosures: This study was supported by the US National Cancer Institute, National Institutes of Health. The authors declared no conflicts of interest.

Source: Guo H, Malone KE, Heckbert SR, Li CI. Statin use and risks of breast cancer recurrence and mortality. Cancer. 2024 (May 6). doi: 10.1002/cncr.35362 Source

Key clinical point: Use of a statin after breast cancer (BC) diagnosis improved survival in older women (age ≥ 66 years) with localized and regional stage disease, particularly in those with the hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) subtype.

Major finding: Use vs no use of a statin postdiagnosis was associated with a 15% reduced risk for BC-specific mortality (hazard ratio 0.85; 95% CI 0.75-0.96), with the effect being more pronounced women with HR+/HER2− BC (hazard ratio 0.71; 95% CI 0.57-0.88). There was no significant association between postdiagnosis statin use and the risk for BC recurrence (hazard ratio 1.05; 95% CI 0.91-1.21).

Study details: This retrospective cohort study included women with localized and regional stage BC from the Surveillance, Epidemiology, and End Results (SEER)–Medicare database who were assessed for mortality (n = 38,858) and recurrence (n = 28,522), of whom 8836 and 6475 used a statin postdiagnosis, respectively.

Disclosures: This study was supported by the US National Cancer Institute, National Institutes of Health. The authors declared no conflicts of interest.

Source: Guo H, Malone KE, Heckbert SR, Li CI. Statin use and risks of breast cancer recurrence and mortality. Cancer. 2024 (May 6). doi: 10.1002/cncr.35362 Source

Key clinical point: Sentinel lymph node biopsy (SLNB) performed before vs after neoadjuvant chemotherapy (NACT) showed a higher axillary lymph node dissection rate and no overall survival (OS) benefits in patients with clinically lymph node-negative (cN0) breast cancer (BC).

Major finding: The axillary lymph node dissection rate was significantly higher for SLNB performed before vs after NACT (29.9% vs 7.4%; P < .001; odds ratio 5.35; P = .002). Moreover, the 4-year overall survival rate was significantly compromised when SLNB was performed before vs after NACT (88.4% vs 95.7%; hazard ratio 0.21; P = .009).

Study details: This retrospective observational study included 310 patients with cN0 BC, of whom 107 and 203 patients underwent SLNB before and after NACT, respectively.

Disclosures: This study did not receive any specific funding except Open Access funding from Springer Nature. The authors declared no financial conflicts of interest. Two authors declared non-financial ties with various sources.

Source: Fernandez-Gonzalez S, Falo C, Pla MJ, et al. Sentinel lymph node biopsy before and after neoadjuvant chemotherapy in cN0 breast cancer patients: Impact on axillary morbidity and survival—A propensity score cohort study. Breast Cancer Res Treat. 2024 (Apr 18). doi: 10.1007/s10549-024-07274-1 Source

Key clinical point: Sentinel lymph node biopsy (SLNB) performed before vs after neoadjuvant chemotherapy (NACT) showed a higher axillary lymph node dissection rate and no overall survival (OS) benefits in patients with clinically lymph node-negative (cN0) breast cancer (BC).

Major finding: The axillary lymph node dissection rate was significantly higher for SLNB performed before vs after NACT (29.9% vs 7.4%; P < .001; odds ratio 5.35; P = .002). Moreover, the 4-year overall survival rate was significantly compromised when SLNB was performed before vs after NACT (88.4% vs 95.7%; hazard ratio 0.21; P = .009).

Study details: This retrospective observational study included 310 patients with cN0 BC, of whom 107 and 203 patients underwent SLNB before and after NACT, respectively.

Disclosures: This study did not receive any specific funding except Open Access funding from Springer Nature. The authors declared no financial conflicts of interest. Two authors declared non-financial ties with various sources.

Source: Fernandez-Gonzalez S, Falo C, Pla MJ, et al. Sentinel lymph node biopsy before and after neoadjuvant chemotherapy in cN0 breast cancer patients: Impact on axillary morbidity and survival—A propensity score cohort study. Breast Cancer Res Treat. 2024 (Apr 18). doi: 10.1007/s10549-024-07274-1 Source

Key clinical point: Sentinel lymph node biopsy (SLNB) performed before vs after neoadjuvant chemotherapy (NACT) showed a higher axillary lymph node dissection rate and no overall survival (OS) benefits in patients with clinically lymph node-negative (cN0) breast cancer (BC).

Major finding: The axillary lymph node dissection rate was significantly higher for SLNB performed before vs after NACT (29.9% vs 7.4%; P < .001; odds ratio 5.35; P = .002). Moreover, the 4-year overall survival rate was significantly compromised when SLNB was performed before vs after NACT (88.4% vs 95.7%; hazard ratio 0.21; P = .009).

Study details: This retrospective observational study included 310 patients with cN0 BC, of whom 107 and 203 patients underwent SLNB before and after NACT, respectively.

Disclosures: This study did not receive any specific funding except Open Access funding from Springer Nature. The authors declared no financial conflicts of interest. Two authors declared non-financial ties with various sources.

Source: Fernandez-Gonzalez S, Falo C, Pla MJ, et al. Sentinel lymph node biopsy before and after neoadjuvant chemotherapy in cN0 breast cancer patients: Impact on axillary morbidity and survival—A propensity score cohort study. Breast Cancer Res Treat. 2024 (Apr 18). doi: 10.1007/s10549-024-07274-1 Source

Key clinical point: Trastuzumab deruxtecan demonstrated superior efficacy over trastuzumab emtansine as second-line treatment in patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with or without brain metastases.

Major finding: Trastuzumab deruxtecan led to significantly longer median progression-free survival (15.0 vs 3.0 months; hazard ratio 0.25; 95% CI 0.13-0.45) and higher systemic (67.4% vs 20.5%) and intracranial (65.7% vs 34.3%) objective response rates than trastuzumab emtansine in patients with brain metastases. Outcomes were similar in patients without brain metastases.

Study details: This exploratory analysis of the phase 3 DESTINY-Breast03 trial included 524 patients with HER2+ metastatic BC with or without brain metastases who were randomly assigned to receive trastuzumab deruxtecan or trastuzumab emtansine after their disease progressed with trastuzumab and taxane treatment.

Disclosures: This study was supported by Daiichi Sankyo and AstraZeneca. Six authors declared being current or former employees or holding stock or stock options of Daiichi Sankyo or AstraZeneca. Several authors declared having ties to various sources, including Daiichi Sankyo and AstraZeneca.

Source: Hurvitz SA, Kim SB, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial. ESMO Open. 2024;109294 (Apr 24). doi: 10.1016/j.esmoop.2024.102924 Source

Key clinical point: Trastuzumab deruxtecan demonstrated superior efficacy over trastuzumab emtansine as second-line treatment in patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with or without brain metastases.

Major finding: Trastuzumab deruxtecan led to significantly longer median progression-free survival (15.0 vs 3.0 months; hazard ratio 0.25; 95% CI 0.13-0.45) and higher systemic (67.4% vs 20.5%) and intracranial (65.7% vs 34.3%) objective response rates than trastuzumab emtansine in patients with brain metastases. Outcomes were similar in patients without brain metastases.

Study details: This exploratory analysis of the phase 3 DESTINY-Breast03 trial included 524 patients with HER2+ metastatic BC with or without brain metastases who were randomly assigned to receive trastuzumab deruxtecan or trastuzumab emtansine after their disease progressed with trastuzumab and taxane treatment.

Disclosures: This study was supported by Daiichi Sankyo and AstraZeneca. Six authors declared being current or former employees or holding stock or stock options of Daiichi Sankyo or AstraZeneca. Several authors declared having ties to various sources, including Daiichi Sankyo and AstraZeneca.

Source: Hurvitz SA, Kim SB, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial. ESMO Open. 2024;109294 (Apr 24). doi: 10.1016/j.esmoop.2024.102924 Source

Key clinical point: Trastuzumab deruxtecan demonstrated superior efficacy over trastuzumab emtansine as second-line treatment in patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with or without brain metastases.

Major finding: Trastuzumab deruxtecan led to significantly longer median progression-free survival (15.0 vs 3.0 months; hazard ratio 0.25; 95% CI 0.13-0.45) and higher systemic (67.4% vs 20.5%) and intracranial (65.7% vs 34.3%) objective response rates than trastuzumab emtansine in patients with brain metastases. Outcomes were similar in patients without brain metastases.

Study details: This exploratory analysis of the phase 3 DESTINY-Breast03 trial included 524 patients with HER2+ metastatic BC with or without brain metastases who were randomly assigned to receive trastuzumab deruxtecan or trastuzumab emtansine after their disease progressed with trastuzumab and taxane treatment.

Disclosures: This study was supported by Daiichi Sankyo and AstraZeneca. Six authors declared being current or former employees or holding stock or stock options of Daiichi Sankyo or AstraZeneca. Several authors declared having ties to various sources, including Daiichi Sankyo and AstraZeneca.

Source: Hurvitz SA, Kim SB, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial. ESMO Open. 2024;109294 (Apr 24). doi: 10.1016/j.esmoop.2024.102924 Source

Key clinical point: Axillary lymph node dissection (ALND) can be omitted in node-positive breast cancer (BC) as only 1% of patients who achieved nodal pathological complete response (pCR) with neoadjuvant chemotherapy reported axillary recurrence (AR) in 5 years.

Major finding: The AR rate was very low at 0.65% (95% CI 0.29%-1.30%) and 1.0% (95% CI 0.49%-2.00%) at 3 years and 5 years, respectively, in patients who omitted ALND and underwent targeted axillary dissection (TAD) or sentinel lymph node biopsy (SLNB). AR rates were comparable in both surgical cohorts at 3 years (P = .55).

Study details: This retrospective cohort study included 1144 patients with node-positive BC who achieved nodal pCR with neoadjuvant chemotherapy, of whom 58.2% and 41.8% underwent SLNB and TAD, respectively.

Disclosures: This study was supported in part by a US National Institutes of Health and US National Cancer Institute Cancer Center support grant. Several authors declared receiving personal fees, grants, or consulting fees from or having other ties with various sources.

Source: Montagna G, Mrdutt MM, Sun SX, et al. Omission of axillary dissection following nodal downstaging with neoadjuvant chemotherapy. JAMA Oncol. 2024 (Apr 25). doi: 10.1001/jamaoncol.2024.0578 Source

Key clinical point: Axillary lymph node dissection (ALND) can be omitted in node-positive breast cancer (BC) as only 1% of patients who achieved nodal pathological complete response (pCR) with neoadjuvant chemotherapy reported axillary recurrence (AR) in 5 years.

Major finding: The AR rate was very low at 0.65% (95% CI 0.29%-1.30%) and 1.0% (95% CI 0.49%-2.00%) at 3 years and 5 years, respectively, in patients who omitted ALND and underwent targeted axillary dissection (TAD) or sentinel lymph node biopsy (SLNB). AR rates were comparable in both surgical cohorts at 3 years (P = .55).

Study details: This retrospective cohort study included 1144 patients with node-positive BC who achieved nodal pCR with neoadjuvant chemotherapy, of whom 58.2% and 41.8% underwent SLNB and TAD, respectively.

Disclosures: This study was supported in part by a US National Institutes of Health and US National Cancer Institute Cancer Center support grant. Several authors declared receiving personal fees, grants, or consulting fees from or having other ties with various sources.

Source: Montagna G, Mrdutt MM, Sun SX, et al. Omission of axillary dissection following nodal downstaging with neoadjuvant chemotherapy. JAMA Oncol. 2024 (Apr 25). doi: 10.1001/jamaoncol.2024.0578 Source

Key clinical point: Axillary lymph node dissection (ALND) can be omitted in node-positive breast cancer (BC) as only 1% of patients who achieved nodal pathological complete response (pCR) with neoadjuvant chemotherapy reported axillary recurrence (AR) in 5 years.

Major finding: The AR rate was very low at 0.65% (95% CI 0.29%-1.30%) and 1.0% (95% CI 0.49%-2.00%) at 3 years and 5 years, respectively, in patients who omitted ALND and underwent targeted axillary dissection (TAD) or sentinel lymph node biopsy (SLNB). AR rates were comparable in both surgical cohorts at 3 years (P = .55).

Study details: This retrospective cohort study included 1144 patients with node-positive BC who achieved nodal pCR with neoadjuvant chemotherapy, of whom 58.2% and 41.8% underwent SLNB and TAD, respectively.

Disclosures: This study was supported in part by a US National Institutes of Health and US National Cancer Institute Cancer Center support grant. Several authors declared receiving personal fees, grants, or consulting fees from or having other ties with various sources.

Source: Montagna G, Mrdutt MM, Sun SX, et al. Omission of axillary dissection following nodal downstaging with neoadjuvant chemotherapy. JAMA Oncol. 2024 (Apr 25). doi: 10.1001/jamaoncol.2024.0578 Source

Key clinical point: Breast cancer (BC) diagnosed between five to <10 years postpartum (PP) was associated with a high mortality risk in women with young-onset BC (age ≤ 45 years) who had germline BRCA1/2 pathogenic variants (PV), particularly the BRCA1 mutation.

Major finding: Women with PPBC diagnosed within 5-10 years had an almost 1.5-fold higher mortality risk than nulliparous women (adjusted hazard ratio [aHR] 1.56; P = .03), with the risk being even more prominent in BRCA1 carriers (aHR 2.03; P = .02) and those with estrogen receptor-negative BC (aHR 3.12; P = .02).

Study details: This prospective cohort study included 903 women with germline BRCA1/2 PV diagnosed with stages I-III BC at age ≤ 45 years, of whom 224 were nulliparous at the time of BC diagnosis.

Disclosures: This study was supported by Oregon Health & Science University's Knight Cancer Institute, US National Institutes of Health, US National Cancer Institute, and other sources. Two authors declared receiving personal fees from various sources.

Source: Zhang Z, Ye S, Bernhardt SM, et al. Postpartum breast cancer and survival in women with germline BRCA pathogenic variants. JAMA Netw Open. 2024;7(4):e247421. doi: 10.1001/jamanetworkopen.2024.7421 Source

Key clinical point: Breast cancer (BC) diagnosed between five to <10 years postpartum (PP) was associated with a high mortality risk in women with young-onset BC (age ≤ 45 years) who had germline BRCA1/2 pathogenic variants (PV), particularly the BRCA1 mutation.

Major finding: Women with PPBC diagnosed within 5-10 years had an almost 1.5-fold higher mortality risk than nulliparous women (adjusted hazard ratio [aHR] 1.56; P = .03), with the risk being even more prominent in BRCA1 carriers (aHR 2.03; P = .02) and those with estrogen receptor-negative BC (aHR 3.12; P = .02).

Study details: This prospective cohort study included 903 women with germline BRCA1/2 PV diagnosed with stages I-III BC at age ≤ 45 years, of whom 224 were nulliparous at the time of BC diagnosis.

Disclosures: This study was supported by Oregon Health & Science University's Knight Cancer Institute, US National Institutes of Health, US National Cancer Institute, and other sources. Two authors declared receiving personal fees from various sources.

Source: Zhang Z, Ye S, Bernhardt SM, et al. Postpartum breast cancer and survival in women with germline BRCA pathogenic variants. JAMA Netw Open. 2024;7(4):e247421. doi: 10.1001/jamanetworkopen.2024.7421 Source

Key clinical point: Breast cancer (BC) diagnosed between five to <10 years postpartum (PP) was associated with a high mortality risk in women with young-onset BC (age ≤ 45 years) who had germline BRCA1/2 pathogenic variants (PV), particularly the BRCA1 mutation.

Major finding: Women with PPBC diagnosed within 5-10 years had an almost 1.5-fold higher mortality risk than nulliparous women (adjusted hazard ratio [aHR] 1.56; P = .03), with the risk being even more prominent in BRCA1 carriers (aHR 2.03; P = .02) and those with estrogen receptor-negative BC (aHR 3.12; P = .02).

Study details: This prospective cohort study included 903 women with germline BRCA1/2 PV diagnosed with stages I-III BC at age ≤ 45 years, of whom 224 were nulliparous at the time of BC diagnosis.

Disclosures: This study was supported by Oregon Health & Science University's Knight Cancer Institute, US National Institutes of Health, US National Cancer Institute, and other sources. Two authors declared receiving personal fees from various sources.

Source: Zhang Z, Ye S, Bernhardt SM, et al. Postpartum breast cancer and survival in women with germline BRCA pathogenic variants. JAMA Netw Open. 2024;7(4):e247421. doi: 10.1001/jamanetworkopen.2024.7421 Source

Key clinical point: Young breast cancer (BC) survivors with a germline pathogenic variant had a higher risk for second primary breast cancer (SPBC) in the first 10 years after diagnosis than those without any mutation.

Major finding: Over a median follow-up of 10 years, 2.5% of BC survivors developed an SPBC. The SPBC risk was around five times higher in carriers vs noncarriers of germline pathogenic variants (subdistribution hazard ratio [sHR] 5.27; P = .01) and in women with primary in situ vs invasive BC (10.4% vs 2.1%; sHR 5.61; P = .01).

Study details: This prospective cohort study included 685 women diagnosed with stages 0-III BC at age ≤ 40 years who underwent unilateral mastectomy or lumpectomy as the primary surgery.

Disclosures: This study was funded by Susan G. Komen and the Breast Cancer Research Foundation. Four authors declared receiving grants or author royalties from various sources.

Source: Brantley KD, Rosenberg SM, Collins LC, et al. Second primary breast cancer in young breast cancer survivors. JAMA Oncol. 2024 (Apr 11). doi: 10.1001/jamaoncol.2024.0286 Source

Key clinical point: Young breast cancer (BC) survivors with a germline pathogenic variant had a higher risk for second primary breast cancer (SPBC) in the first 10 years after diagnosis than those without any mutation.

Major finding: Over a median follow-up of 10 years, 2.5% of BC survivors developed an SPBC. The SPBC risk was around five times higher in carriers vs noncarriers of germline pathogenic variants (subdistribution hazard ratio [sHR] 5.27; P = .01) and in women with primary in situ vs invasive BC (10.4% vs 2.1%; sHR 5.61; P = .01).

Study details: This prospective cohort study included 685 women diagnosed with stages 0-III BC at age ≤ 40 years who underwent unilateral mastectomy or lumpectomy as the primary surgery.

Disclosures: This study was funded by Susan G. Komen and the Breast Cancer Research Foundation. Four authors declared receiving grants or author royalties from various sources.

Source: Brantley KD, Rosenberg SM, Collins LC, et al. Second primary breast cancer in young breast cancer survivors. JAMA Oncol. 2024 (Apr 11). doi: 10.1001/jamaoncol.2024.0286 Source

Key clinical point: Young breast cancer (BC) survivors with a germline pathogenic variant had a higher risk for second primary breast cancer (SPBC) in the first 10 years after diagnosis than those without any mutation.

Major finding: Over a median follow-up of 10 years, 2.5% of BC survivors developed an SPBC. The SPBC risk was around five times higher in carriers vs noncarriers of germline pathogenic variants (subdistribution hazard ratio [sHR] 5.27; P = .01) and in women with primary in situ vs invasive BC (10.4% vs 2.1%; sHR 5.61; P = .01).

Study details: This prospective cohort study included 685 women diagnosed with stages 0-III BC at age ≤ 40 years who underwent unilateral mastectomy or lumpectomy as the primary surgery.

Disclosures: This study was funded by Susan G. Komen and the Breast Cancer Research Foundation. Four authors declared receiving grants or author royalties from various sources.

Source: Brantley KD, Rosenberg SM, Collins LC, et al. Second primary breast cancer in young breast cancer survivors. JAMA Oncol. 2024 (Apr 11). doi: 10.1001/jamaoncol.2024.0286 Source

Key clinical point: A once-daily dose of 300 mg aspirin in the adjuvant setting did not reduce risk for breast cancer (BC) recurrence or improve survival outcomes as compared with placebo in patients with high-risk nonmetastatic BC.

Major finding: Treatment with aspirin and placebo led to comparable invasive disease-free survival (hazard ratio [HR] 1.27; P = .06) and overall survival outcomes (HR 1.19; P = .36) along with similar rates of grades 3 and 4 adverse events.

Study details: This phase 3 trial included 3020 patients with high-risk nonmetastatic BC (age 18 to <70 years) and a history of human epidermal growth factor receptor 2-negative BC who were treated with standard therapy and were randomly assigned to receive 300 mg aspirin or placebo once daily.

Disclosures: This study was supported by the US Department of Defense Breast Cancer Research Program and other sources. Five authors declared receiving grants, royalties, or consulting fees from various sources.

Source: Chen WY, Ballman KV, Partridge AH, et al. Aspirin vs placebo as adjuvant therapy for breast cancer: The Alliance A011502 randomized trial. JAMA. 2024 (Apr 29). doi: 10.1001/jama.2024.4840 Source

Key clinical point: A once-daily dose of 300 mg aspirin in the adjuvant setting did not reduce risk for breast cancer (BC) recurrence or improve survival outcomes as compared with placebo in patients with high-risk nonmetastatic BC.

Major finding: Treatment with aspirin and placebo led to comparable invasive disease-free survival (hazard ratio [HR] 1.27; P = .06) and overall survival outcomes (HR 1.19; P = .36) along with similar rates of grades 3 and 4 adverse events.

Study details: This phase 3 trial included 3020 patients with high-risk nonmetastatic BC (age 18 to <70 years) and a history of human epidermal growth factor receptor 2-negative BC who were treated with standard therapy and were randomly assigned to receive 300 mg aspirin or placebo once daily.

Disclosures: This study was supported by the US Department of Defense Breast Cancer Research Program and other sources. Five authors declared receiving grants, royalties, or consulting fees from various sources.

Source: Chen WY, Ballman KV, Partridge AH, et al. Aspirin vs placebo as adjuvant therapy for breast cancer: The Alliance A011502 randomized trial. JAMA. 2024 (Apr 29). doi: 10.1001/jama.2024.4840 Source

Key clinical point: A once-daily dose of 300 mg aspirin in the adjuvant setting did not reduce risk for breast cancer (BC) recurrence or improve survival outcomes as compared with placebo in patients with high-risk nonmetastatic BC.

Major finding: Treatment with aspirin and placebo led to comparable invasive disease-free survival (hazard ratio [HR] 1.27; P = .06) and overall survival outcomes (HR 1.19; P = .36) along with similar rates of grades 3 and 4 adverse events.

Study details: This phase 3 trial included 3020 patients with high-risk nonmetastatic BC (age 18 to <70 years) and a history of human epidermal growth factor receptor 2-negative BC who were treated with standard therapy and were randomly assigned to receive 300 mg aspirin or placebo once daily.

Disclosures: This study was supported by the US Department of Defense Breast Cancer Research Program and other sources. Five authors declared receiving grants, royalties, or consulting fees from various sources.

Source: Chen WY, Ballman KV, Partridge AH, et al. Aspirin vs placebo as adjuvant therapy for breast cancer: The Alliance A011502 randomized trial. JAMA. 2024 (Apr 29). doi: 10.1001/jama.2024.4840 Source

SAN DIEGO — Compared with medical oncologists, dermatologists were more likely to correctly classify and grade dermatologic adverse events from cancer therapies, results from a multicenter survey showed.

“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.

The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”

To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.

Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).

“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”

Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”

Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.

“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”

Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
 

A version of this article first appeared on Medscape.com.

SAN DIEGO — Compared with medical oncologists, dermatologists were more likely to correctly classify and grade dermatologic adverse events from cancer therapies, results from a multicenter survey showed.

“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.

The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”

To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.

Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).

“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”

Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”

Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.

“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”

Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
 

A version of this article first appeared on Medscape.com.

SAN DIEGO — Compared with medical oncologists, dermatologists were more likely to correctly classify and grade dermatologic adverse events from cancer therapies, results from a multicenter survey showed.

“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.

The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”

To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.

Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).

“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”

Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”

Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.

“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”

Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
 

A version of this article first appeared on Medscape.com.

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.