Clinical Edge Journal Scan

Key clinical point: Adjuvant endocrine therapy (ET) significantly reduces the incidence of distant metastasis in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) T1a/bN0M0 breast cancer (BC).

Major finding: The 9-year cumulative incidence of distant metastasis was significantly lower in patients who did vs did not receive adjuvant ET (1.5% vs 2.6%; adjusted subdistribution hazard ratio 0.54; P = .027), with the risk factors for distant metastasis being mastectomy (P = .022), no prior receipt of ET (P = .027), lymphatic invasion (P = .004), and higher nuclear grade (P = .047).

Study details: Findings are from a multicenter cohort study including 4758 patients with ER+ /HER2− T1a/bN0M0 BC who underwent surgery, of whom 3991 patients were administered adjuvant ET.

Disclosures: This study was partly supported by the National Cancer Center Research and Development Fund and the Practical Research for Innovative Cancer Control, Japan. The authors declared no conflicts of interest.

Source: Sasada S et al. Prognostic impact of adjuvant endocrine therapy for estrogen receptor-positive and HER2-negative T1a/bN0M0 breast cancer. Breast Cancer Res Treat. 2023 (Sep 9). doi: 10.1007/s10549-023-07097-6

Key clinical point: Adjuvant endocrine therapy (ET) significantly reduces the incidence of distant metastasis in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) T1a/bN0M0 breast cancer (BC).

Major finding: The 9-year cumulative incidence of distant metastasis was significantly lower in patients who did vs did not receive adjuvant ET (1.5% vs 2.6%; adjusted subdistribution hazard ratio 0.54; P = .027), with the risk factors for distant metastasis being mastectomy (P = .022), no prior receipt of ET (P = .027), lymphatic invasion (P = .004), and higher nuclear grade (P = .047).

Study details: Findings are from a multicenter cohort study including 4758 patients with ER+ /HER2− T1a/bN0M0 BC who underwent surgery, of whom 3991 patients were administered adjuvant ET.

Disclosures: This study was partly supported by the National Cancer Center Research and Development Fund and the Practical Research for Innovative Cancer Control, Japan. The authors declared no conflicts of interest.

Source: Sasada S et al. Prognostic impact of adjuvant endocrine therapy for estrogen receptor-positive and HER2-negative T1a/bN0M0 breast cancer. Breast Cancer Res Treat. 2023 (Sep 9). doi: 10.1007/s10549-023-07097-6

Key clinical point: Adjuvant endocrine therapy (ET) significantly reduces the incidence of distant metastasis in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) T1a/bN0M0 breast cancer (BC).

Major finding: The 9-year cumulative incidence of distant metastasis was significantly lower in patients who did vs did not receive adjuvant ET (1.5% vs 2.6%; adjusted subdistribution hazard ratio 0.54; P = .027), with the risk factors for distant metastasis being mastectomy (P = .022), no prior receipt of ET (P = .027), lymphatic invasion (P = .004), and higher nuclear grade (P = .047).

Study details: Findings are from a multicenter cohort study including 4758 patients with ER+ /HER2− T1a/bN0M0 BC who underwent surgery, of whom 3991 patients were administered adjuvant ET.

Disclosures: This study was partly supported by the National Cancer Center Research and Development Fund and the Practical Research for Innovative Cancer Control, Japan. The authors declared no conflicts of interest.

Source: Sasada S et al. Prognostic impact of adjuvant endocrine therapy for estrogen receptor-positive and HER2-negative T1a/bN0M0 breast cancer. Breast Cancer Res Treat. 2023 (Sep 9). doi: 10.1007/s10549-023-07097-6

Key clinical point: Neoadjuvant high-dose alkylating chemotherapy did not improve the Neoadjuvant Response Index (NRI) scores in patients with BRCA1- or BRCA2-pathway-altered (BRCA-altered) triple-negative breast cancer (TNBC).

Major finding: The NRI scores were comparable between the conventional and high-dose chemotherapy treatment groups (0.72 vs 0.78; P = .41). Adverse events, such as fatigue, infections, nausea, oral mucositis, and diarrhea, were more prevalent in the high-dose vs conventional chemotherapy group, although no treatment-related deaths occurred in either group.

Study details: Findings are from the phase 3 neo-TN study that included 122 patients with BRCA-altered TNBC who were randomly assigned to receive either conventional or high-dose chemotherapy.

Disclosures: This study was supported by The Dutch Cancer Foundation and the Schumacher Kramer Foundation, Amsterdam. The authors declared no conflicts of interest.

Source: Vliek S et al. High-dose alkylating chemotherapy in BRCA-altered triple-negative breast cancer: The randomized phase III NeoTN trial. NPJ Breast Cancer. 2023;9:75 (Sep 9). doi: 10.1038/s41523-023-00580-9

Key clinical point: Neoadjuvant high-dose alkylating chemotherapy did not improve the Neoadjuvant Response Index (NRI) scores in patients with BRCA1- or BRCA2-pathway-altered (BRCA-altered) triple-negative breast cancer (TNBC).

Major finding: The NRI scores were comparable between the conventional and high-dose chemotherapy treatment groups (0.72 vs 0.78; P = .41). Adverse events, such as fatigue, infections, nausea, oral mucositis, and diarrhea, were more prevalent in the high-dose vs conventional chemotherapy group, although no treatment-related deaths occurred in either group.

Study details: Findings are from the phase 3 neo-TN study that included 122 patients with BRCA-altered TNBC who were randomly assigned to receive either conventional or high-dose chemotherapy.

Disclosures: This study was supported by The Dutch Cancer Foundation and the Schumacher Kramer Foundation, Amsterdam. The authors declared no conflicts of interest.

Source: Vliek S et al. High-dose alkylating chemotherapy in BRCA-altered triple-negative breast cancer: The randomized phase III NeoTN trial. NPJ Breast Cancer. 2023;9:75 (Sep 9). doi: 10.1038/s41523-023-00580-9

Key clinical point: Neoadjuvant high-dose alkylating chemotherapy did not improve the Neoadjuvant Response Index (NRI) scores in patients with BRCA1- or BRCA2-pathway-altered (BRCA-altered) triple-negative breast cancer (TNBC).

Major finding: The NRI scores were comparable between the conventional and high-dose chemotherapy treatment groups (0.72 vs 0.78; P = .41). Adverse events, such as fatigue, infections, nausea, oral mucositis, and diarrhea, were more prevalent in the high-dose vs conventional chemotherapy group, although no treatment-related deaths occurred in either group.

Study details: Findings are from the phase 3 neo-TN study that included 122 patients with BRCA-altered TNBC who were randomly assigned to receive either conventional or high-dose chemotherapy.

Disclosures: This study was supported by The Dutch Cancer Foundation and the Schumacher Kramer Foundation, Amsterdam. The authors declared no conflicts of interest.

Source: Vliek S et al. High-dose alkylating chemotherapy in BRCA-altered triple-negative breast cancer: The randomized phase III NeoTN trial. NPJ Breast Cancer. 2023;9:75 (Sep 9). doi: 10.1038/s41523-023-00580-9

Key clinical point: In women with high levels of background parenchymal enhancement (BPE), a simultaneous high-temporal/high-spatial resolution (HTHS) magnetic resonance imaging (MRI) protocol detected an additional 15.7 cases of breast cancer (BC) per 1000 patients than the standard high-spatial resolution MRI protocol while concomitantly decreasing the rate of unnecessary biopsies by ~10%.

Major finding: HTHS vs standard protocol improved the BC detection rate per 1000 patients (23.6 vs 7.9; P = .021), increased the positive predictive value of biopsy (16.0% vs 6.3%; P = .014), and decreased the rate of unnecessary biopsies by 9.8%.

Study details: This retrospective study included 1414 women with 1481 high-BPE examinations.

Disclosures: This study was supported partly by the US National Cancer Institute. JS Sung, K Feigin, and K Pinker declared serving in leadership roles and consulting roles or as members of speakers’ bureaus of or receiving research funding from various sources.

Source: Eskreis-Winkler S et al. High-temporal/high-spatial resolution breast magnetic resonance imaging improves diagnostic accuracy compared with standard breast magnetic resonance imaging in patients with high background parenchymal enhancement. J Clin Oncol. 2023 (Aug 10). doi: 10.1200/JCO.22.00635

Key clinical point: In women with high levels of background parenchymal enhancement (BPE), a simultaneous high-temporal/high-spatial resolution (HTHS) magnetic resonance imaging (MRI) protocol detected an additional 15.7 cases of breast cancer (BC) per 1000 patients than the standard high-spatial resolution MRI protocol while concomitantly decreasing the rate of unnecessary biopsies by ~10%.

Major finding: HTHS vs standard protocol improved the BC detection rate per 1000 patients (23.6 vs 7.9; P = .021), increased the positive predictive value of biopsy (16.0% vs 6.3%; P = .014), and decreased the rate of unnecessary biopsies by 9.8%.

Study details: This retrospective study included 1414 women with 1481 high-BPE examinations.

Disclosures: This study was supported partly by the US National Cancer Institute. JS Sung, K Feigin, and K Pinker declared serving in leadership roles and consulting roles or as members of speakers’ bureaus of or receiving research funding from various sources.

Source: Eskreis-Winkler S et al. High-temporal/high-spatial resolution breast magnetic resonance imaging improves diagnostic accuracy compared with standard breast magnetic resonance imaging in patients with high background parenchymal enhancement. J Clin Oncol. 2023 (Aug 10). doi: 10.1200/JCO.22.00635

Key clinical point: In women with high levels of background parenchymal enhancement (BPE), a simultaneous high-temporal/high-spatial resolution (HTHS) magnetic resonance imaging (MRI) protocol detected an additional 15.7 cases of breast cancer (BC) per 1000 patients than the standard high-spatial resolution MRI protocol while concomitantly decreasing the rate of unnecessary biopsies by ~10%.

Major finding: HTHS vs standard protocol improved the BC detection rate per 1000 patients (23.6 vs 7.9; P = .021), increased the positive predictive value of biopsy (16.0% vs 6.3%; P = .014), and decreased the rate of unnecessary biopsies by 9.8%.

Study details: This retrospective study included 1414 women with 1481 high-BPE examinations.

Disclosures: This study was supported partly by the US National Cancer Institute. JS Sung, K Feigin, and K Pinker declared serving in leadership roles and consulting roles or as members of speakers’ bureaus of or receiving research funding from various sources.

Source: Eskreis-Winkler S et al. High-temporal/high-spatial resolution breast magnetic resonance imaging improves diagnostic accuracy compared with standard breast magnetic resonance imaging in patients with high background parenchymal enhancement. J Clin Oncol. 2023 (Aug 10). doi: 10.1200/JCO.22.00635

Key clinical point: In patients with locally advanced triple-negative breast cancer (TNBC), neoadjuvant apatinib (Apa) plus dose-dense paclitaxel and carboplatin (ddTCb) was more effective in improving clinical outcomes than ddTCb alone and showed an acceptable safety profile.

Major finding: A significantly higher proportion of patients in the Apa + ddTCb vs ddTCb treatment group achieved pathological complete response (60.9% vs 30.4%; P = .009) and underwent breast-conserving surgery (47.8% vs 21.7%; P = .016). The incidence of adverse events was higher in the Apa + ddTCb treatment arm, but they were generally acceptable.

Study details: This prospective cohort study included 23 patients with stages I-IIIC TNBC who received neoadjuvant Apa + ddTCb therapy matched with 69 patients with stages I-IIIC TNBC who received neoadjuvant ddTCb therapy only.

Disclosures: This study was supported by CAMS Innovation Fund for Medical Sciences and the Translational research project of Medical Oncology Key Foundation of Cancer Hospital, Chinese Academy of Medical Sciences. The authors declared no conflicts of interest.

Source: Liu J, Xu B, Zhang P, et al. Efficacy and safety of apatinib combined with dose-dense paclitaxel and carboplatin in neoadjuvant therapy for locally advanced triple-negative breast cancer: A prospective cohort study with propensity-matched analysis. Int J Cancer. 2023 (Sep 7). doi: 10.1002/ijc.34717

Key clinical point: In patients with locally advanced triple-negative breast cancer (TNBC), neoadjuvant apatinib (Apa) plus dose-dense paclitaxel and carboplatin (ddTCb) was more effective in improving clinical outcomes than ddTCb alone and showed an acceptable safety profile.

Major finding: A significantly higher proportion of patients in the Apa + ddTCb vs ddTCb treatment group achieved pathological complete response (60.9% vs 30.4%; P = .009) and underwent breast-conserving surgery (47.8% vs 21.7%; P = .016). The incidence of adverse events was higher in the Apa + ddTCb treatment arm, but they were generally acceptable.

Study details: This prospective cohort study included 23 patients with stages I-IIIC TNBC who received neoadjuvant Apa + ddTCb therapy matched with 69 patients with stages I-IIIC TNBC who received neoadjuvant ddTCb therapy only.

Disclosures: This study was supported by CAMS Innovation Fund for Medical Sciences and the Translational research project of Medical Oncology Key Foundation of Cancer Hospital, Chinese Academy of Medical Sciences. The authors declared no conflicts of interest.

Source: Liu J, Xu B, Zhang P, et al. Efficacy and safety of apatinib combined with dose-dense paclitaxel and carboplatin in neoadjuvant therapy for locally advanced triple-negative breast cancer: A prospective cohort study with propensity-matched analysis. Int J Cancer. 2023 (Sep 7). doi: 10.1002/ijc.34717

Key clinical point: In patients with locally advanced triple-negative breast cancer (TNBC), neoadjuvant apatinib (Apa) plus dose-dense paclitaxel and carboplatin (ddTCb) was more effective in improving clinical outcomes than ddTCb alone and showed an acceptable safety profile.

Major finding: A significantly higher proportion of patients in the Apa + ddTCb vs ddTCb treatment group achieved pathological complete response (60.9% vs 30.4%; P = .009) and underwent breast-conserving surgery (47.8% vs 21.7%; P = .016). The incidence of adverse events was higher in the Apa + ddTCb treatment arm, but they were generally acceptable.

Study details: This prospective cohort study included 23 patients with stages I-IIIC TNBC who received neoadjuvant Apa + ddTCb therapy matched with 69 patients with stages I-IIIC TNBC who received neoadjuvant ddTCb therapy only.

Disclosures: This study was supported by CAMS Innovation Fund for Medical Sciences and the Translational research project of Medical Oncology Key Foundation of Cancer Hospital, Chinese Academy of Medical Sciences. The authors declared no conflicts of interest.

Source: Liu J, Xu B, Zhang P, et al. Efficacy and safety of apatinib combined with dose-dense paclitaxel and carboplatin in neoadjuvant therapy for locally advanced triple-negative breast cancer: A prospective cohort study with propensity-matched analysis. Int J Cancer. 2023 (Sep 7). doi: 10.1002/ijc.34717

Key clinical point: Trifluridine/tipiracil (FTD/TPI) showed promising anti-tumor activity with a manageable safety profile regardless of prior exposure to fluoropyrimidine therapy in patients with metastatic breast cancer (BC).

Major finding: The median durations of progression-free survival were 5.7 months and 9.4 months in patients with and without prior exposure to fluoropyrimidine therapy, respectively. Neutropenia (81.8%), fatigue (29.7%), anorexia (25.7%), and nausea (25.7%) were the most common all-grade treatment-related adverse events.

Study details: Findings are from a phase 2 study including 74 patients with metastatic BC with or without prior exposure to fluoropyrimidine therapy who received FTD/TPI.

Disclosures: This study was funded by a grant from the National Medical Research Council, Singapore. Some authors declared receiving research funding, honoraria, consulting fees, or travel support from or having other ties with various sources.

Source: Lim JSJ et al. Phase II study of trifluridine/tipiracil (FTD/TPI) in metastatic breast cancers with or without prior exposure to fluoropyrimidines. Eur J Cancer. 2023;113311 (Aug 25). doi: 10.1016/j.ejca.2023.113311

Key clinical point: Trifluridine/tipiracil (FTD/TPI) showed promising anti-tumor activity with a manageable safety profile regardless of prior exposure to fluoropyrimidine therapy in patients with metastatic breast cancer (BC).

Major finding: The median durations of progression-free survival were 5.7 months and 9.4 months in patients with and without prior exposure to fluoropyrimidine therapy, respectively. Neutropenia (81.8%), fatigue (29.7%), anorexia (25.7%), and nausea (25.7%) were the most common all-grade treatment-related adverse events.

Study details: Findings are from a phase 2 study including 74 patients with metastatic BC with or without prior exposure to fluoropyrimidine therapy who received FTD/TPI.

Disclosures: This study was funded by a grant from the National Medical Research Council, Singapore. Some authors declared receiving research funding, honoraria, consulting fees, or travel support from or having other ties with various sources.

Source: Lim JSJ et al. Phase II study of trifluridine/tipiracil (FTD/TPI) in metastatic breast cancers with or without prior exposure to fluoropyrimidines. Eur J Cancer. 2023;113311 (Aug 25). doi: 10.1016/j.ejca.2023.113311

Key clinical point: Trifluridine/tipiracil (FTD/TPI) showed promising anti-tumor activity with a manageable safety profile regardless of prior exposure to fluoropyrimidine therapy in patients with metastatic breast cancer (BC).

Major finding: The median durations of progression-free survival were 5.7 months and 9.4 months in patients with and without prior exposure to fluoropyrimidine therapy, respectively. Neutropenia (81.8%), fatigue (29.7%), anorexia (25.7%), and nausea (25.7%) were the most common all-grade treatment-related adverse events.

Study details: Findings are from a phase 2 study including 74 patients with metastatic BC with or without prior exposure to fluoropyrimidine therapy who received FTD/TPI.

Disclosures: This study was funded by a grant from the National Medical Research Council, Singapore. Some authors declared receiving research funding, honoraria, consulting fees, or travel support from or having other ties with various sources.

Source: Lim JSJ et al. Phase II study of trifluridine/tipiracil (FTD/TPI) in metastatic breast cancers with or without prior exposure to fluoropyrimidines. Eur J Cancer. 2023;113311 (Aug 25). doi: 10.1016/j.ejca.2023.113311

Key clinical point: Giredestrant demonstrated stronger anti-proliferative activity than anastrozole and was well-tolerated in patients with estrogen receptor-positive (ER+ ), human epidermal growth factor receptor 2-negative (HER2−), untreated early breast cancer (BC).

Major finding: At week 2, giredestrant vs anastrozole had a stronger anti-proliferative effect as indicated by greater relative geometric mean reduction of Ki67 scores (−75% vs −67%; P = .043). Neutropenia (26% and 27%, respectively) and decreased neutrophil count (15% and 15%, respectively) were the most common grade 3-4 adverse events observed in the giredestrant + palbociclib and anastrozole + palbociclib treatment arms.

Study details: Findings are from the phase 2 coopERA Breast Cancer trial including 221 postmenopausal patients with clinical T stage (cT)1c to cT4a-c, ER+ /HER2− early BC who were randomly assigned to receive giredestrant or anastrozole in combination with palbociclib.

Disclosures: This study was funded by F Hoffmann-La Roche. Seven authors declared being employees or stockholders of F Hoffmann-La Roche, and the other authors declared ties with various sources.

Source: Hurvitz SA et al on behalf of thecoopERA Breast Cancer study group. Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): An open-label, randomised, controlled, phase 2 study. Lancet Oncol. 2023;24(9):1029-1041 (Aug 29). doi: 10.1016/S1470-2045(23)00268-1

Key clinical point: Giredestrant demonstrated stronger anti-proliferative activity than anastrozole and was well-tolerated in patients with estrogen receptor-positive (ER+ ), human epidermal growth factor receptor 2-negative (HER2−), untreated early breast cancer (BC).

Major finding: At week 2, giredestrant vs anastrozole had a stronger anti-proliferative effect as indicated by greater relative geometric mean reduction of Ki67 scores (−75% vs −67%; P = .043). Neutropenia (26% and 27%, respectively) and decreased neutrophil count (15% and 15%, respectively) were the most common grade 3-4 adverse events observed in the giredestrant + palbociclib and anastrozole + palbociclib treatment arms.

Study details: Findings are from the phase 2 coopERA Breast Cancer trial including 221 postmenopausal patients with clinical T stage (cT)1c to cT4a-c, ER+ /HER2− early BC who were randomly assigned to receive giredestrant or anastrozole in combination with palbociclib.

Disclosures: This study was funded by F Hoffmann-La Roche. Seven authors declared being employees or stockholders of F Hoffmann-La Roche, and the other authors declared ties with various sources.

Source: Hurvitz SA et al on behalf of thecoopERA Breast Cancer study group. Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): An open-label, randomised, controlled, phase 2 study. Lancet Oncol. 2023;24(9):1029-1041 (Aug 29). doi: 10.1016/S1470-2045(23)00268-1

Key clinical point: Giredestrant demonstrated stronger anti-proliferative activity than anastrozole and was well-tolerated in patients with estrogen receptor-positive (ER+ ), human epidermal growth factor receptor 2-negative (HER2−), untreated early breast cancer (BC).

Major finding: At week 2, giredestrant vs anastrozole had a stronger anti-proliferative effect as indicated by greater relative geometric mean reduction of Ki67 scores (−75% vs −67%; P = .043). Neutropenia (26% and 27%, respectively) and decreased neutrophil count (15% and 15%, respectively) were the most common grade 3-4 adverse events observed in the giredestrant + palbociclib and anastrozole + palbociclib treatment arms.

Study details: Findings are from the phase 2 coopERA Breast Cancer trial including 221 postmenopausal patients with clinical T stage (cT)1c to cT4a-c, ER+ /HER2− early BC who were randomly assigned to receive giredestrant or anastrozole in combination with palbociclib.

Disclosures: This study was funded by F Hoffmann-La Roche. Seven authors declared being employees or stockholders of F Hoffmann-La Roche, and the other authors declared ties with various sources.

Source: Hurvitz SA et al on behalf of thecoopERA Breast Cancer study group. Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): An open-label, randomised, controlled, phase 2 study. Lancet Oncol. 2023;24(9):1029-1041 (Aug 29). doi: 10.1016/S1470-2045(23)00268-1

Key clinical point: The incidence rate of local recurrence was low even after omitting radiotherapy in women with luminal A breast cancer (BC) age ≥55 years who underwent breast-conserving surgery (BCS) followed by endocrine therapy.

Major finding: At 5 years, the cumulative incidence of local recurrence was low (2.3%; 95% CI 1.2%-4.1%), with 1.9% of patients (90% CI 1.1%-3.2%) reporting contralateral BC recurrences and 2.7% of patients (90% CI 1.6%-4.1%) reporting recurrences of any type.

Study details: This prospective cohort study included 500 women with T1N0 (tumor size < 2 cm and node negative) luminal A BC age ≥ 55 years who had undergone BCS followed by adjuvant endocrine therapy.

Disclosures: This study was supported by the Canadian Cancer Society and Canadian Breast Cancer Foundation. Some authors declared serving as consultants or members of data safety and monitoring boards or having ties with various sources.

Source: Whelan TJ et al for the LUMINA Study Investigators. Omitting radiotherapy after breast-conserving surgery in luminal A breast cancer. N Engl J Med. 2023;389(7):612-619 (Aug 17). doi: 10.1056/NEJMoa2302344

Key clinical point: The incidence rate of local recurrence was low even after omitting radiotherapy in women with luminal A breast cancer (BC) age ≥55 years who underwent breast-conserving surgery (BCS) followed by endocrine therapy.

Major finding: At 5 years, the cumulative incidence of local recurrence was low (2.3%; 95% CI 1.2%-4.1%), with 1.9% of patients (90% CI 1.1%-3.2%) reporting contralateral BC recurrences and 2.7% of patients (90% CI 1.6%-4.1%) reporting recurrences of any type.

Study details: This prospective cohort study included 500 women with T1N0 (tumor size < 2 cm and node negative) luminal A BC age ≥ 55 years who had undergone BCS followed by adjuvant endocrine therapy.

Disclosures: This study was supported by the Canadian Cancer Society and Canadian Breast Cancer Foundation. Some authors declared serving as consultants or members of data safety and monitoring boards or having ties with various sources.

Source: Whelan TJ et al for the LUMINA Study Investigators. Omitting radiotherapy after breast-conserving surgery in luminal A breast cancer. N Engl J Med. 2023;389(7):612-619 (Aug 17). doi: 10.1056/NEJMoa2302344

Key clinical point: The incidence rate of local recurrence was low even after omitting radiotherapy in women with luminal A breast cancer (BC) age ≥55 years who underwent breast-conserving surgery (BCS) followed by endocrine therapy.

Major finding: At 5 years, the cumulative incidence of local recurrence was low (2.3%; 95% CI 1.2%-4.1%), with 1.9% of patients (90% CI 1.1%-3.2%) reporting contralateral BC recurrences and 2.7% of patients (90% CI 1.6%-4.1%) reporting recurrences of any type.

Study details: This prospective cohort study included 500 women with T1N0 (tumor size < 2 cm and node negative) luminal A BC age ≥ 55 years who had undergone BCS followed by adjuvant endocrine therapy.

Disclosures: This study was supported by the Canadian Cancer Society and Canadian Breast Cancer Foundation. Some authors declared serving as consultants or members of data safety and monitoring boards or having ties with various sources.

Source: Whelan TJ et al for the LUMINA Study Investigators. Omitting radiotherapy after breast-conserving surgery in luminal A breast cancer. N Engl J Med. 2023;389(7):612-619 (Aug 17). doi: 10.1056/NEJMoa2302344

The calcitonin gene-related peptide (CGRP) antagonist class of medications has changed the face of migraine treatment — and there are now both acute and preventive options that are available in oral and injectable formulations. The gepant subclass of CGRP antagonists are small-molecule medications, in contrast to the CGRP monoclonal antibodies. Atogepant was developed as the first oral migraine-specific preventive medication, and the initial trials allowed for an initial approval by the US Food and Drug Administration for episodic migraine alone. The study by Pozo-Rosich and colleagues extended the patient population to patients with chronic migraine.

This was an international, multicenter, randomized controlled study of two dosages of atogepant (30 mg twice daily and 60 mg daily) compared with placebo over 12 weeks. The primary endpoint was change in mean monthly migraine days. There was a safety population as well that received a single dose of medication. Nearly 800 participants were enrolled equally into these three groups, and the authors used a modified intention-to-treat format that included all participants with at least 1 month of e-diary data and took at least one dose of the study medication.

The baseline number of mean monthly migraine days in this chronic migraine population was 18.6 days per month. After 12 weeks, the three groups showed decreases of 7.5, 6.1, and 5.1 days per month, which was statistically significant for the two intervention groups. The most common side effects were constipation and nausea, with up to 10% of the study population experiencing some gastrointestinal symptoms. Weight loss of 7% of body weight was also noticed in the two intervention groups.

This study describes the benefit of atogepant extending beyond the indication of episodic migraine. This chronic migraine population showed significant benefit in the decrease of mean monthly migraine days per month after 12 weeks. One additional benefit is weight loss even after 12 weeks. Compared with the monoclonal antibody class of CGRP antagonist, this medication appears to be approximately equally effective, with the additional benefit of weight loss. Because many preventive medications for migraine may be associated with weight gain — particularly the antidepressant and potentially the antihypertensive classes of medications — this can be a differentiating factor when choosing an appropriate preventive medication for your patients with chronic migraine.

CGRP is a known inflammatory modulator that also plays a significant role in the propagation of migraine. CGRP blockade has been associated, in some studies, with upper respiratory tract infection symptoms, raising the question of whether blocking CGRP chronically may increase the risk for infection. A prior study revealed that CGRP levels were decreased in patients with severe COVID-19, and another study did not find significant differences in COVID-19 disease, progression, or severity among migraine patients on CGRP antagonists. Wang and colleagues specifically sought to determine any potential association or risk between the use of CGRP antagonist medications and COVID.

This retrospective cohort study was performed in the US Veterans Affairs (VA) hospital system. It analyzed the electronic medical records of veterans diagnosed with migraine between January and May 2022. The participants' exposure to CGRP medications and the 30-day odds of hospitalization, as well as use of mechanical ventilation, were calculated. CGRP prescriptions were identified using outpatient pharmacy records for erenumab, fremanezumab (225 mg/1.5 mL), and galcanezumab (120 mg/mL), which were the only CGRP medications available at that point in the VA system. The primary outcome was cumulative incidence of SARS-CoV-2 infection; occurrences of SARS-CoV-2 infection were obtained from the VA COVID-19 Shared Data Resource. Secondary analysis of the clinical outcomes was performed among patients with a positive SARS-CoV-2 test result.

This analysis revealed that CGRP monoclonal antibody use was not associated with risk for COVID-19, and among participants who tested positive for COVID-19, there were no significant differences in hospitalization, oxygen supplementation, mechanical ventilation, or COVID-19–related death between those who were receiving CGRP medications and those who were not. Although another prior study implied that CGRP blockade may decrease the risk for severe disease related to a cytokine storm, those results were only in vitro, and no results from human or animal trials have replicated these data. There is, therefore, no contraindication to using CGRP antagonist medications in people at high risk for development of COVID-19.

Many patients with migraine are recommended specific treatments for the prevention of migraine attacks and for the acute treatment of their attacks. Very few studies have investigated specific combinations of acute and preventive treatments. Although logically, there should be no contraindication to most treatment combinations, there may be some additional synergistic benefit to the combination of specific classes of medications. We have previously discussed a synergy between the CGRP antagonist class and onabotulinumtoxinA (Botox) for the prevention of chronic migraine; Manack Adams and colleagues sought to quantify the efficacy of ubrogepant when the patients were also administered botulinum toxin.

The joint American Academy of Neurology/American Headache Society consensus statement recommends starting preventive medication for anyone with migraine who experiences > 4-5 days of headache per month. It also recommends a migraine-specific acute treatment for anyone who experiences migraine attacks. Botulinum toxin is approved by the US Food and Drug Administration for the prevention of chronic migraine at a dose of 155 units injected every 3 months; ubrogepant is a CGRP oral small-molecule antagonist that is approved for the acute treatment of migraine.

This study investigated the effectiveness of ubrogepant, with a primary endpoint of meaningful pain relief and return to normal function 2 and 4 hours after an initial dose of 50 or 100 mg. Meaningful pain relief was defined as answering "yes" to a question about whether the patient experienced meaningful pain relief. This has been a pre-reported endpoint in other acute migraine treatment trials. Return to normal function was defined as the time point where the patient could perform their daily activities on the basis of a functional disability scale. Achieving normal function was classified as either remaining free of disability or by reporting functional disability before taking ubrogepant and then indicating a return to normal function at 2 and 4 hours post-dose.

A total of 134 patients were enrolled, taking both ubrogepant and botulinum toxin; patients were included if they were treated with ubrogepant at least once. Meaningful pain relief was achieved in 53.3% of patients at 2 hours and in 76.2% of patients at 4 hours post-dose. Return to normal function was achieved by 30.1% of patients at 2 hours and by 52.1% of patients at 4 hours post-dose. Both meaningful pain relief and return to normal function were seen to be statistically significant and stable across up to 10 attacks per person.

Headache treatment providers typically need to consider different classes of medications for prevention and acute treatment. A growing body of evidence describes a synergy between the CGRP class of medications and botulinum toxin. This appears to be true both when CGRP antagonists are used preventively and, in this case, when they are used for acute events. This certainly would be a safe and effective choice in many instances for many patients.

The calcitonin gene-related peptide (CGRP) antagonist class of medications has changed the face of migraine treatment — and there are now both acute and preventive options that are available in oral and injectable formulations. The gepant subclass of CGRP antagonists are small-molecule medications, in contrast to the CGRP monoclonal antibodies. Atogepant was developed as the first oral migraine-specific preventive medication, and the initial trials allowed for an initial approval by the US Food and Drug Administration for episodic migraine alone. The study by Pozo-Rosich and colleagues extended the patient population to patients with chronic migraine.

This was an international, multicenter, randomized controlled study of two dosages of atogepant (30 mg twice daily and 60 mg daily) compared with placebo over 12 weeks. The primary endpoint was change in mean monthly migraine days. There was a safety population as well that received a single dose of medication. Nearly 800 participants were enrolled equally into these three groups, and the authors used a modified intention-to-treat format that included all participants with at least 1 month of e-diary data and took at least one dose of the study medication.

The baseline number of mean monthly migraine days in this chronic migraine population was 18.6 days per month. After 12 weeks, the three groups showed decreases of 7.5, 6.1, and 5.1 days per month, which was statistically significant for the two intervention groups. The most common side effects were constipation and nausea, with up to 10% of the study population experiencing some gastrointestinal symptoms. Weight loss of 7% of body weight was also noticed in the two intervention groups.

This study describes the benefit of atogepant extending beyond the indication of episodic migraine. This chronic migraine population showed significant benefit in the decrease of mean monthly migraine days per month after 12 weeks. One additional benefit is weight loss even after 12 weeks. Compared with the monoclonal antibody class of CGRP antagonist, this medication appears to be approximately equally effective, with the additional benefit of weight loss. Because many preventive medications for migraine may be associated with weight gain — particularly the antidepressant and potentially the antihypertensive classes of medications — this can be a differentiating factor when choosing an appropriate preventive medication for your patients with chronic migraine.

CGRP is a known inflammatory modulator that also plays a significant role in the propagation of migraine. CGRP blockade has been associated, in some studies, with upper respiratory tract infection symptoms, raising the question of whether blocking CGRP chronically may increase the risk for infection. A prior study revealed that CGRP levels were decreased in patients with severe COVID-19, and another study did not find significant differences in COVID-19 disease, progression, or severity among migraine patients on CGRP antagonists. Wang and colleagues specifically sought to determine any potential association or risk between the use of CGRP antagonist medications and COVID.

This retrospective cohort study was performed in the US Veterans Affairs (VA) hospital system. It analyzed the electronic medical records of veterans diagnosed with migraine between January and May 2022. The participants' exposure to CGRP medications and the 30-day odds of hospitalization, as well as use of mechanical ventilation, were calculated. CGRP prescriptions were identified using outpatient pharmacy records for erenumab, fremanezumab (225 mg/1.5 mL), and galcanezumab (120 mg/mL), which were the only CGRP medications available at that point in the VA system. The primary outcome was cumulative incidence of SARS-CoV-2 infection; occurrences of SARS-CoV-2 infection were obtained from the VA COVID-19 Shared Data Resource. Secondary analysis of the clinical outcomes was performed among patients with a positive SARS-CoV-2 test result.

This analysis revealed that CGRP monoclonal antibody use was not associated with risk for COVID-19, and among participants who tested positive for COVID-19, there were no significant differences in hospitalization, oxygen supplementation, mechanical ventilation, or COVID-19–related death between those who were receiving CGRP medications and those who were not. Although another prior study implied that CGRP blockade may decrease the risk for severe disease related to a cytokine storm, those results were only in vitro, and no results from human or animal trials have replicated these data. There is, therefore, no contraindication to using CGRP antagonist medications in people at high risk for development of COVID-19.

Many patients with migraine are recommended specific treatments for the prevention of migraine attacks and for the acute treatment of their attacks. Very few studies have investigated specific combinations of acute and preventive treatments. Although logically, there should be no contraindication to most treatment combinations, there may be some additional synergistic benefit to the combination of specific classes of medications. We have previously discussed a synergy between the CGRP antagonist class and onabotulinumtoxinA (Botox) for the prevention of chronic migraine; Manack Adams and colleagues sought to quantify the efficacy of ubrogepant when the patients were also administered botulinum toxin.

The joint American Academy of Neurology/American Headache Society consensus statement recommends starting preventive medication for anyone with migraine who experiences > 4-5 days of headache per month. It also recommends a migraine-specific acute treatment for anyone who experiences migraine attacks. Botulinum toxin is approved by the US Food and Drug Administration for the prevention of chronic migraine at a dose of 155 units injected every 3 months; ubrogepant is a CGRP oral small-molecule antagonist that is approved for the acute treatment of migraine.

This study investigated the effectiveness of ubrogepant, with a primary endpoint of meaningful pain relief and return to normal function 2 and 4 hours after an initial dose of 50 or 100 mg. Meaningful pain relief was defined as answering "yes" to a question about whether the patient experienced meaningful pain relief. This has been a pre-reported endpoint in other acute migraine treatment trials. Return to normal function was defined as the time point where the patient could perform their daily activities on the basis of a functional disability scale. Achieving normal function was classified as either remaining free of disability or by reporting functional disability before taking ubrogepant and then indicating a return to normal function at 2 and 4 hours post-dose.

A total of 134 patients were enrolled, taking both ubrogepant and botulinum toxin; patients were included if they were treated with ubrogepant at least once. Meaningful pain relief was achieved in 53.3% of patients at 2 hours and in 76.2% of patients at 4 hours post-dose. Return to normal function was achieved by 30.1% of patients at 2 hours and by 52.1% of patients at 4 hours post-dose. Both meaningful pain relief and return to normal function were seen to be statistically significant and stable across up to 10 attacks per person.

Headache treatment providers typically need to consider different classes of medications for prevention and acute treatment. A growing body of evidence describes a synergy between the CGRP class of medications and botulinum toxin. This appears to be true both when CGRP antagonists are used preventively and, in this case, when they are used for acute events. This certainly would be a safe and effective choice in many instances for many patients.

The calcitonin gene-related peptide (CGRP) antagonist class of medications has changed the face of migraine treatment — and there are now both acute and preventive options that are available in oral and injectable formulations. The gepant subclass of CGRP antagonists are small-molecule medications, in contrast to the CGRP monoclonal antibodies. Atogepant was developed as the first oral migraine-specific preventive medication, and the initial trials allowed for an initial approval by the US Food and Drug Administration for episodic migraine alone. The study by Pozo-Rosich and colleagues extended the patient population to patients with chronic migraine.

This was an international, multicenter, randomized controlled study of two dosages of atogepant (30 mg twice daily and 60 mg daily) compared with placebo over 12 weeks. The primary endpoint was change in mean monthly migraine days. There was a safety population as well that received a single dose of medication. Nearly 800 participants were enrolled equally into these three groups, and the authors used a modified intention-to-treat format that included all participants with at least 1 month of e-diary data and took at least one dose of the study medication.

The baseline number of mean monthly migraine days in this chronic migraine population was 18.6 days per month. After 12 weeks, the three groups showed decreases of 7.5, 6.1, and 5.1 days per month, which was statistically significant for the two intervention groups. The most common side effects were constipation and nausea, with up to 10% of the study population experiencing some gastrointestinal symptoms. Weight loss of 7% of body weight was also noticed in the two intervention groups.

This study describes the benefit of atogepant extending beyond the indication of episodic migraine. This chronic migraine population showed significant benefit in the decrease of mean monthly migraine days per month after 12 weeks. One additional benefit is weight loss even after 12 weeks. Compared with the monoclonal antibody class of CGRP antagonist, this medication appears to be approximately equally effective, with the additional benefit of weight loss. Because many preventive medications for migraine may be associated with weight gain — particularly the antidepressant and potentially the antihypertensive classes of medications — this can be a differentiating factor when choosing an appropriate preventive medication for your patients with chronic migraine.

CGRP is a known inflammatory modulator that also plays a significant role in the propagation of migraine. CGRP blockade has been associated, in some studies, with upper respiratory tract infection symptoms, raising the question of whether blocking CGRP chronically may increase the risk for infection. A prior study revealed that CGRP levels were decreased in patients with severe COVID-19, and another study did not find significant differences in COVID-19 disease, progression, or severity among migraine patients on CGRP antagonists. Wang and colleagues specifically sought to determine any potential association or risk between the use of CGRP antagonist medications and COVID.

This retrospective cohort study was performed in the US Veterans Affairs (VA) hospital system. It analyzed the electronic medical records of veterans diagnosed with migraine between January and May 2022. The participants' exposure to CGRP medications and the 30-day odds of hospitalization, as well as use of mechanical ventilation, were calculated. CGRP prescriptions were identified using outpatient pharmacy records for erenumab, fremanezumab (225 mg/1.5 mL), and galcanezumab (120 mg/mL), which were the only CGRP medications available at that point in the VA system. The primary outcome was cumulative incidence of SARS-CoV-2 infection; occurrences of SARS-CoV-2 infection were obtained from the VA COVID-19 Shared Data Resource. Secondary analysis of the clinical outcomes was performed among patients with a positive SARS-CoV-2 test result.

This analysis revealed that CGRP monoclonal antibody use was not associated with risk for COVID-19, and among participants who tested positive for COVID-19, there were no significant differences in hospitalization, oxygen supplementation, mechanical ventilation, or COVID-19–related death between those who were receiving CGRP medications and those who were not. Although another prior study implied that CGRP blockade may decrease the risk for severe disease related to a cytokine storm, those results were only in vitro, and no results from human or animal trials have replicated these data. There is, therefore, no contraindication to using CGRP antagonist medications in people at high risk for development of COVID-19.

Many patients with migraine are recommended specific treatments for the prevention of migraine attacks and for the acute treatment of their attacks. Very few studies have investigated specific combinations of acute and preventive treatments. Although logically, there should be no contraindication to most treatment combinations, there may be some additional synergistic benefit to the combination of specific classes of medications. We have previously discussed a synergy between the CGRP antagonist class and onabotulinumtoxinA (Botox) for the prevention of chronic migraine; Manack Adams and colleagues sought to quantify the efficacy of ubrogepant when the patients were also administered botulinum toxin.

The joint American Academy of Neurology/American Headache Society consensus statement recommends starting preventive medication for anyone with migraine who experiences > 4-5 days of headache per month. It also recommends a migraine-specific acute treatment for anyone who experiences migraine attacks. Botulinum toxin is approved by the US Food and Drug Administration for the prevention of chronic migraine at a dose of 155 units injected every 3 months; ubrogepant is a CGRP oral small-molecule antagonist that is approved for the acute treatment of migraine.

This study investigated the effectiveness of ubrogepant, with a primary endpoint of meaningful pain relief and return to normal function 2 and 4 hours after an initial dose of 50 or 100 mg. Meaningful pain relief was defined as answering "yes" to a question about whether the patient experienced meaningful pain relief. This has been a pre-reported endpoint in other acute migraine treatment trials. Return to normal function was defined as the time point where the patient could perform their daily activities on the basis of a functional disability scale. Achieving normal function was classified as either remaining free of disability or by reporting functional disability before taking ubrogepant and then indicating a return to normal function at 2 and 4 hours post-dose.

A total of 134 patients were enrolled, taking both ubrogepant and botulinum toxin; patients were included if they were treated with ubrogepant at least once. Meaningful pain relief was achieved in 53.3% of patients at 2 hours and in 76.2% of patients at 4 hours post-dose. Return to normal function was achieved by 30.1% of patients at 2 hours and by 52.1% of patients at 4 hours post-dose. Both meaningful pain relief and return to normal function were seen to be statistically significant and stable across up to 10 attacks per person.

Headache treatment providers typically need to consider different classes of medications for prevention and acute treatment. A growing body of evidence describes a synergy between the CGRP class of medications and botulinum toxin. This appears to be true both when CGRP antagonists are used preventively and, in this case, when they are used for acute events. This certainly would be a safe and effective choice in many instances for many patients.

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma that is characterized by t(11;14) and cyclin D1 overexpression. It is also known to be clinically heterogenous, with disease presentations ranging from indolent to aggressive. Baseline risk can be determined on the basis of a combination of clinical and pathologic features. A key prognostic tool, for example, is the Mantle Cell Lymphoma International Prognostic Index-Combined (MIPI-c), which integrates the standard MIPI clinical factors (age, performance status, lactate dehydrogenase, and leukocyte count) with estimates of proliferation (Ki-67).¹ Other features, including the presence of TP53 alterations, have also been associated with poor outcomes, even with intensive therapy.²

Recently, a study aimed to further refine prognostication in MCL in order to identify high-risk patients that may be more likely to benefit from novel treatment strategies (Scheubeck et al). This retrospective study included 684 patients with MCL from the MCL-Younger and MCL-Elderly trials with evaluable data for Ki-67 or p53 expression (a surrogate for TP53 alterations). Patients were classified as having high-risk disease on the basis of a high-risk MIPI-c or p53 expression > 50% or as having low-risk disease on the basis of low, low-intermediate, or high-intermediate MIPI-c and p53 expression ≤ 50%. Patients with high-risk disease had significantly shorter median failure-free survival (1.1 vs 5.6 years; P < .0001) and overall survival (2.2 vs 13.2 years; P < .0001) compared with those with low-risk disease. The differences were confirmed in two validation cohorts from the Italian MCL0208 and Nordic-MCL4 trials. These data highlight the poor outcomes of conventional therapy in patients with high-risk MCL. Evaluation of novel approaches should be considered in these patients.

Bruton tyrosine kinase (BTK) inhibitors have been promising options for patients with MCL, including those with high-risk features. Acalabrutinib is a second-generation covalent BTK inhibitor that is approved by the US Food and Drug Administration for patients who have received at least one prior line of therapy. The final results of the single-arm, phase 2 ACE-LY-004 study recently demonstrated long-term safety and efficacy in patients with relapsed/refractory MCL (Le Gouill et al). The overall and complete response rates were 81.5% (95% CI 73.5%-87.9%) and 47.6% (95% CI 38.5%-56.7%), respectively. After a 38.1-month median follow-up, the median duration of response and progression-free survival were 28.6 months (95% CI 17.5-39.1) and 22.0 months (95% CI 16.6-33.3), respectively. Responses were also seen in patients with high-risk features, including blastoid morphology, high-risk MIPI score, and high Ki-67. No new safety signals were observed. This study confirms the role of BTK inhibitors in MCL and providers longer-term estimates of response. Evaluation of BTK inhibitors in earlier lines of therapy and in combination with other agents are ongoing.

Although the majority of patients with MCL will have favorable responses to initial therapy, those with high-risk features, particularly TP53 aberrations, have poor outcomes with standard approaches. Despite a growing number of treatment options in the relapsed setting, such as targeted therapies and chimeric antigen receptor (CAR) T-cell therapy, relapses remain common. Allogenic stem cell transplantation can be associated with prolonged response for patients with relapsed MCL, though it has the potential for significant treatment-associated toxicity.

Recently, prolonged follow-up of a retrospective cohort of patients with MCL, including a subset with TP53 aberrations, was reported (Lew et al). Thirty-six patients with MCL were included, including 13 with TP53-mutated disease. A subset of patients (61%) received an allogeneic transplant in first remission. The estimated overall survival rates after allogenic transplant were 56% (95% CI 36%-72%) at 10 years for the overall cohort and 59% (95% CI 21%-75%) at 4 years for patients with TP53-mutated disease at median follow-ups of 10.8 and 4.2 years, respectively. No relapses were observed in the TP53-mutated subset beyond 6 months after transplantation. These data suggest a potentially curative option for patients with high-risk MCL. Given the availability of CAR T-cell therapy, the optimal timing of allogenic stem cell transplant has become less clear for patients with TP53-mutant disease. Although this study was small and retrospective, these data are encouraging for patients with high-risk disease.

Additional References

1.            Hoster E, Rosenwald A, Berger F, et al. Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: Results from randomized trials of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2016;34:1386-1394. doi: 10.1200/JCO.2015.63.8387

2.            Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017;130:1903-1910. doi: 10.1182/blood-2017-04-77973

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma that is characterized by t(11;14) and cyclin D1 overexpression. It is also known to be clinically heterogenous, with disease presentations ranging from indolent to aggressive. Baseline risk can be determined on the basis of a combination of clinical and pathologic features. A key prognostic tool, for example, is the Mantle Cell Lymphoma International Prognostic Index-Combined (MIPI-c), which integrates the standard MIPI clinical factors (age, performance status, lactate dehydrogenase, and leukocyte count) with estimates of proliferation (Ki-67).¹ Other features, including the presence of TP53 alterations, have also been associated with poor outcomes, even with intensive therapy.²

Recently, a study aimed to further refine prognostication in MCL in order to identify high-risk patients that may be more likely to benefit from novel treatment strategies (Scheubeck et al). This retrospective study included 684 patients with MCL from the MCL-Younger and MCL-Elderly trials with evaluable data for Ki-67 or p53 expression (a surrogate for TP53 alterations). Patients were classified as having high-risk disease on the basis of a high-risk MIPI-c or p53 expression > 50% or as having low-risk disease on the basis of low, low-intermediate, or high-intermediate MIPI-c and p53 expression ≤ 50%. Patients with high-risk disease had significantly shorter median failure-free survival (1.1 vs 5.6 years; P < .0001) and overall survival (2.2 vs 13.2 years; P < .0001) compared with those with low-risk disease. The differences were confirmed in two validation cohorts from the Italian MCL0208 and Nordic-MCL4 trials. These data highlight the poor outcomes of conventional therapy in patients with high-risk MCL. Evaluation of novel approaches should be considered in these patients.

Bruton tyrosine kinase (BTK) inhibitors have been promising options for patients with MCL, including those with high-risk features. Acalabrutinib is a second-generation covalent BTK inhibitor that is approved by the US Food and Drug Administration for patients who have received at least one prior line of therapy. The final results of the single-arm, phase 2 ACE-LY-004 study recently demonstrated long-term safety and efficacy in patients with relapsed/refractory MCL (Le Gouill et al). The overall and complete response rates were 81.5% (95% CI 73.5%-87.9%) and 47.6% (95% CI 38.5%-56.7%), respectively. After a 38.1-month median follow-up, the median duration of response and progression-free survival were 28.6 months (95% CI 17.5-39.1) and 22.0 months (95% CI 16.6-33.3), respectively. Responses were also seen in patients with high-risk features, including blastoid morphology, high-risk MIPI score, and high Ki-67. No new safety signals were observed. This study confirms the role of BTK inhibitors in MCL and providers longer-term estimates of response. Evaluation of BTK inhibitors in earlier lines of therapy and in combination with other agents are ongoing.

Although the majority of patients with MCL will have favorable responses to initial therapy, those with high-risk features, particularly TP53 aberrations, have poor outcomes with standard approaches. Despite a growing number of treatment options in the relapsed setting, such as targeted therapies and chimeric antigen receptor (CAR) T-cell therapy, relapses remain common. Allogenic stem cell transplantation can be associated with prolonged response for patients with relapsed MCL, though it has the potential for significant treatment-associated toxicity.

Recently, prolonged follow-up of a retrospective cohort of patients with MCL, including a subset with TP53 aberrations, was reported (Lew et al). Thirty-six patients with MCL were included, including 13 with TP53-mutated disease. A subset of patients (61%) received an allogeneic transplant in first remission. The estimated overall survival rates after allogenic transplant were 56% (95% CI 36%-72%) at 10 years for the overall cohort and 59% (95% CI 21%-75%) at 4 years for patients with TP53-mutated disease at median follow-ups of 10.8 and 4.2 years, respectively. No relapses were observed in the TP53-mutated subset beyond 6 months after transplantation. These data suggest a potentially curative option for patients with high-risk MCL. Given the availability of CAR T-cell therapy, the optimal timing of allogenic stem cell transplant has become less clear for patients with TP53-mutant disease. Although this study was small and retrospective, these data are encouraging for patients with high-risk disease.

Additional References

1.            Hoster E, Rosenwald A, Berger F, et al. Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: Results from randomized trials of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2016;34:1386-1394. doi: 10.1200/JCO.2015.63.8387

2.            Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017;130:1903-1910. doi: 10.1182/blood-2017-04-77973

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma that is characterized by t(11;14) and cyclin D1 overexpression. It is also known to be clinically heterogenous, with disease presentations ranging from indolent to aggressive. Baseline risk can be determined on the basis of a combination of clinical and pathologic features. A key prognostic tool, for example, is the Mantle Cell Lymphoma International Prognostic Index-Combined (MIPI-c), which integrates the standard MIPI clinical factors (age, performance status, lactate dehydrogenase, and leukocyte count) with estimates of proliferation (Ki-67).¹ Other features, including the presence of TP53 alterations, have also been associated with poor outcomes, even with intensive therapy.²

Recently, a study aimed to further refine prognostication in MCL in order to identify high-risk patients that may be more likely to benefit from novel treatment strategies (Scheubeck et al). This retrospective study included 684 patients with MCL from the MCL-Younger and MCL-Elderly trials with evaluable data for Ki-67 or p53 expression (a surrogate for TP53 alterations). Patients were classified as having high-risk disease on the basis of a high-risk MIPI-c or p53 expression > 50% or as having low-risk disease on the basis of low, low-intermediate, or high-intermediate MIPI-c and p53 expression ≤ 50%. Patients with high-risk disease had significantly shorter median failure-free survival (1.1 vs 5.6 years; P < .0001) and overall survival (2.2 vs 13.2 years; P < .0001) compared with those with low-risk disease. The differences were confirmed in two validation cohorts from the Italian MCL0208 and Nordic-MCL4 trials. These data highlight the poor outcomes of conventional therapy in patients with high-risk MCL. Evaluation of novel approaches should be considered in these patients.

Bruton tyrosine kinase (BTK) inhibitors have been promising options for patients with MCL, including those with high-risk features. Acalabrutinib is a second-generation covalent BTK inhibitor that is approved by the US Food and Drug Administration for patients who have received at least one prior line of therapy. The final results of the single-arm, phase 2 ACE-LY-004 study recently demonstrated long-term safety and efficacy in patients with relapsed/refractory MCL (Le Gouill et al). The overall and complete response rates were 81.5% (95% CI 73.5%-87.9%) and 47.6% (95% CI 38.5%-56.7%), respectively. After a 38.1-month median follow-up, the median duration of response and progression-free survival were 28.6 months (95% CI 17.5-39.1) and 22.0 months (95% CI 16.6-33.3), respectively. Responses were also seen in patients with high-risk features, including blastoid morphology, high-risk MIPI score, and high Ki-67. No new safety signals were observed. This study confirms the role of BTK inhibitors in MCL and providers longer-term estimates of response. Evaluation of BTK inhibitors in earlier lines of therapy and in combination with other agents are ongoing.

Although the majority of patients with MCL will have favorable responses to initial therapy, those with high-risk features, particularly TP53 aberrations, have poor outcomes with standard approaches. Despite a growing number of treatment options in the relapsed setting, such as targeted therapies and chimeric antigen receptor (CAR) T-cell therapy, relapses remain common. Allogenic stem cell transplantation can be associated with prolonged response for patients with relapsed MCL, though it has the potential for significant treatment-associated toxicity.

Recently, prolonged follow-up of a retrospective cohort of patients with MCL, including a subset with TP53 aberrations, was reported (Lew et al). Thirty-six patients with MCL were included, including 13 with TP53-mutated disease. A subset of patients (61%) received an allogeneic transplant in first remission. The estimated overall survival rates after allogenic transplant were 56% (95% CI 36%-72%) at 10 years for the overall cohort and 59% (95% CI 21%-75%) at 4 years for patients with TP53-mutated disease at median follow-ups of 10.8 and 4.2 years, respectively. No relapses were observed in the TP53-mutated subset beyond 6 months after transplantation. These data suggest a potentially curative option for patients with high-risk MCL. Given the availability of CAR T-cell therapy, the optimal timing of allogenic stem cell transplant has become less clear for patients with TP53-mutant disease. Although this study was small and retrospective, these data are encouraging for patients with high-risk disease.

Additional References

1.            Hoster E, Rosenwald A, Berger F, et al. Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: Results from randomized trials of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2016;34:1386-1394. doi: 10.1200/JCO.2015.63.8387

2.            Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017;130:1903-1910. doi: 10.1182/blood-2017-04-77973

Anti-drug antibody (ADA) testing for biologics, particularly anti–tumor necrosis factor (TNF) agents, has been commercially available for several years, though its clinical use in rheumatoid arthritis (RA) is not known owing to lack of prospective data. Bitoun and colleagues analyzed data from the European ABI-RA registry to evaluate the association between ADA and the anti–TNF monoclonal antibodies (mAb) etanercept, tocilizumab, and rituximab, and clinical response (as measured by disease activity scores, inflammatory markers, and European Alliance of Associations for Rheumatology [EULAR] response rate). Higher rates of ADA positivity were seen in patients treated with rituximab (50%), anti-TNF mAb (38%), and tocilizumab (20%) compared with etanercept (6%). Patients who had a positive ADA test were less likely to have a EULAR response. In addition, patients treated with methotrexate were less likely to have persistent ADA. Though the study was not powered enough to detect differences between the drug classes, the evidence presented is compelling and suggests a role for measuring ADA in patients with RA who do not respond to treatment.

RA is well-known to be associated with cardiovascular disease, particularly atherosclerotic disease and heart failure, but its association with valvular heart disease and its progression has not been well-explored in the literature. Johnson and colleagues performed a cohort study of over 73,000 patients with RA in the Veterans Health Administration (VHA) system compared with 640,000 patients without RA to evaluate the incidence of aortic stenosis, need for intervention, and risk for death. Though the overall incidence rate was low (about 3%), patients with RA had a higher risk for aortic stenosis, with a hazard ratio of 1.48 compared with those without RA, as well as a higher risk for aortic valve replacement and aortic stenosis–related death. The risk for aortic stenosis was associated with hypertension, stroke, and other cardiovascular disease, as well as a body mass index > 30 kg/m², although not with a history of smoking or diabetes. Because the study was performed using data from the VHA — that is, from predominantly male patients — this finding may not be generalizable. In addition, the diagnosis of aortic stenosis is generally reliant on echocardiography and may be detected while searching for other conditions not evaluated here (such as pericarditis). As such, these findings would not support routine screening in patients with RA without other reasons for suspicion of valvular heart disease.

In particular, the increase in cardiovascular risk associated with glucocorticoid therapy in patients with RA has received increased scrutiny, along with other side effects of systemic glucocorticoids. In a recent retrospective study, So and colleagues examined the clinical data of over 12,000 patients with RA treated in public hospitals in Hong Kong with a mean of 9 years of follow-up. Consistent with prior studies, systemic glucocorticoid use (prednisolone equivalent > 5 mg daily) was associated with an increased risk for adverse cardiovascular events, whereas lower doses did not increase cardiovascular risk. Because the data on some disease activity measures and traditional cardiovascular risk factors (such as smoking or obesity) were not available in the database, the study supports, but does not expand on, prior evidence regarding cardiovascular risk.

Almayali and colleagues also looked at glucocorticoid therapy in RA in a follow-up study to the previously published pragmatic randomized double-blinded placebo-controlled GLORIA study, which evaluated the effects of 5 mg/d prednisolone added to standard care for 2 years in patients with active RA who were age 65 years or older. In the current study, 191 patients out of the initial 451 were followed for 3 months and prednisolone tapered off. Patients who tapered off prednisolone had, as expected, an increased risk for flare but no evidence of adrenal insufficiency. Although, again, this is not likely to change practice, it does suggest that glucocorticoid tapering is a reasonable goal in RA therapeutic trials.

Anti-drug antibody (ADA) testing for biologics, particularly anti–tumor necrosis factor (TNF) agents, has been commercially available for several years, though its clinical use in rheumatoid arthritis (RA) is not known owing to lack of prospective data. Bitoun and colleagues analyzed data from the European ABI-RA registry to evaluate the association between ADA and the anti–TNF monoclonal antibodies (mAb) etanercept, tocilizumab, and rituximab, and clinical response (as measured by disease activity scores, inflammatory markers, and European Alliance of Associations for Rheumatology [EULAR] response rate). Higher rates of ADA positivity were seen in patients treated with rituximab (50%), anti-TNF mAb (38%), and tocilizumab (20%) compared with etanercept (6%). Patients who had a positive ADA test were less likely to have a EULAR response. In addition, patients treated with methotrexate were less likely to have persistent ADA. Though the study was not powered enough to detect differences between the drug classes, the evidence presented is compelling and suggests a role for measuring ADA in patients with RA who do not respond to treatment.

RA is well-known to be associated with cardiovascular disease, particularly atherosclerotic disease and heart failure, but its association with valvular heart disease and its progression has not been well-explored in the literature. Johnson and colleagues performed a cohort study of over 73,000 patients with RA in the Veterans Health Administration (VHA) system compared with 640,000 patients without RA to evaluate the incidence of aortic stenosis, need for intervention, and risk for death. Though the overall incidence rate was low (about 3%), patients with RA had a higher risk for aortic stenosis, with a hazard ratio of 1.48 compared with those without RA, as well as a higher risk for aortic valve replacement and aortic stenosis–related death. The risk for aortic stenosis was associated with hypertension, stroke, and other cardiovascular disease, as well as a body mass index > 30 kg/m², although not with a history of smoking or diabetes. Because the study was performed using data from the VHA — that is, from predominantly male patients — this finding may not be generalizable. In addition, the diagnosis of aortic stenosis is generally reliant on echocardiography and may be detected while searching for other conditions not evaluated here (such as pericarditis). As such, these findings would not support routine screening in patients with RA without other reasons for suspicion of valvular heart disease.

In particular, the increase in cardiovascular risk associated with glucocorticoid therapy in patients with RA has received increased scrutiny, along with other side effects of systemic glucocorticoids. In a recent retrospective study, So and colleagues examined the clinical data of over 12,000 patients with RA treated in public hospitals in Hong Kong with a mean of 9 years of follow-up. Consistent with prior studies, systemic glucocorticoid use (prednisolone equivalent > 5 mg daily) was associated with an increased risk for adverse cardiovascular events, whereas lower doses did not increase cardiovascular risk. Because the data on some disease activity measures and traditional cardiovascular risk factors (such as smoking or obesity) were not available in the database, the study supports, but does not expand on, prior evidence regarding cardiovascular risk.

Almayali and colleagues also looked at glucocorticoid therapy in RA in a follow-up study to the previously published pragmatic randomized double-blinded placebo-controlled GLORIA study, which evaluated the effects of 5 mg/d prednisolone added to standard care for 2 years in patients with active RA who were age 65 years or older. In the current study, 191 patients out of the initial 451 were followed for 3 months and prednisolone tapered off. Patients who tapered off prednisolone had, as expected, an increased risk for flare but no evidence of adrenal insufficiency. Although, again, this is not likely to change practice, it does suggest that glucocorticoid tapering is a reasonable goal in RA therapeutic trials.

Anti-drug antibody (ADA) testing for biologics, particularly anti–tumor necrosis factor (TNF) agents, has been commercially available for several years, though its clinical use in rheumatoid arthritis (RA) is not known owing to lack of prospective data. Bitoun and colleagues analyzed data from the European ABI-RA registry to evaluate the association between ADA and the anti–TNF monoclonal antibodies (mAb) etanercept, tocilizumab, and rituximab, and clinical response (as measured by disease activity scores, inflammatory markers, and European Alliance of Associations for Rheumatology [EULAR] response rate). Higher rates of ADA positivity were seen in patients treated with rituximab (50%), anti-TNF mAb (38%), and tocilizumab (20%) compared with etanercept (6%). Patients who had a positive ADA test were less likely to have a EULAR response. In addition, patients treated with methotrexate were less likely to have persistent ADA. Though the study was not powered enough to detect differences between the drug classes, the evidence presented is compelling and suggests a role for measuring ADA in patients with RA who do not respond to treatment.

RA is well-known to be associated with cardiovascular disease, particularly atherosclerotic disease and heart failure, but its association with valvular heart disease and its progression has not been well-explored in the literature. Johnson and colleagues performed a cohort study of over 73,000 patients with RA in the Veterans Health Administration (VHA) system compared with 640,000 patients without RA to evaluate the incidence of aortic stenosis, need for intervention, and risk for death. Though the overall incidence rate was low (about 3%), patients with RA had a higher risk for aortic stenosis, with a hazard ratio of 1.48 compared with those without RA, as well as a higher risk for aortic valve replacement and aortic stenosis–related death. The risk for aortic stenosis was associated with hypertension, stroke, and other cardiovascular disease, as well as a body mass index > 30 kg/m², although not with a history of smoking or diabetes. Because the study was performed using data from the VHA — that is, from predominantly male patients — this finding may not be generalizable. In addition, the diagnosis of aortic stenosis is generally reliant on echocardiography and may be detected while searching for other conditions not evaluated here (such as pericarditis). As such, these findings would not support routine screening in patients with RA without other reasons for suspicion of valvular heart disease.

In particular, the increase in cardiovascular risk associated with glucocorticoid therapy in patients with RA has received increased scrutiny, along with other side effects of systemic glucocorticoids. In a recent retrospective study, So and colleagues examined the clinical data of over 12,000 patients with RA treated in public hospitals in Hong Kong with a mean of 9 years of follow-up. Consistent with prior studies, systemic glucocorticoid use (prednisolone equivalent > 5 mg daily) was associated with an increased risk for adverse cardiovascular events, whereas lower doses did not increase cardiovascular risk. Because the data on some disease activity measures and traditional cardiovascular risk factors (such as smoking or obesity) were not available in the database, the study supports, but does not expand on, prior evidence regarding cardiovascular risk.

Almayali and colleagues also looked at glucocorticoid therapy in RA in a follow-up study to the previously published pragmatic randomized double-blinded placebo-controlled GLORIA study, which evaluated the effects of 5 mg/d prednisolone added to standard care for 2 years in patients with active RA who were age 65 years or older. In the current study, 191 patients out of the initial 451 were followed for 3 months and prednisolone tapered off. Patients who tapered off prednisolone had, as expected, an increased risk for flare but no evidence of adrenal insufficiency. Although, again, this is not likely to change practice, it does suggest that glucocorticoid tapering is a reasonable goal in RA therapeutic trials.