Breast Cancer ICYMI

Key clinical point: Pretreatment levels of testosterone and follicle-stimulating hormone (FSH) independently predicted pathological complete response (pCR) in premenopausal and postmenopausal women with breast cancer (BC) who received neoadjuvant chemotherapy (NAC).

Major finding: The likelihood of achieving pCR was higher in premenopausal women with lower vs. higher testosterone levels (odds ratio [OR] 0.996; P = .026) and in postmenopausal women with higher vs. lower FSH levels (OR 1.045; P = .005).

Study details: This was a retrospective study of 196 premenopausal and 137 postmenopausal women with invasive BC who received NAC.

Disclosures: This study was funded by National Natural Science Foundation of China. The authors declared no conflicts of interest.

Source: Lan A et al. Pre-treatment circulating reproductive hormones levels predict pathological and survival outcomes in breast cancer submitted to neoadjuvant chemotherapy. Int J Clin Oncol. 2022 (Mar 3). Doi: 10.1007/s10147-022-02141-9

Key clinical point: Pretreatment levels of testosterone and follicle-stimulating hormone (FSH) independently predicted pathological complete response (pCR) in premenopausal and postmenopausal women with breast cancer (BC) who received neoadjuvant chemotherapy (NAC).

Major finding: The likelihood of achieving pCR was higher in premenopausal women with lower vs. higher testosterone levels (odds ratio [OR] 0.996; P = .026) and in postmenopausal women with higher vs. lower FSH levels (OR 1.045; P = .005).

Study details: This was a retrospective study of 196 premenopausal and 137 postmenopausal women with invasive BC who received NAC.

Disclosures: This study was funded by National Natural Science Foundation of China. The authors declared no conflicts of interest.

Source: Lan A et al. Pre-treatment circulating reproductive hormones levels predict pathological and survival outcomes in breast cancer submitted to neoadjuvant chemotherapy. Int J Clin Oncol. 2022 (Mar 3). Doi: 10.1007/s10147-022-02141-9

Key clinical point: Pretreatment levels of testosterone and follicle-stimulating hormone (FSH) independently predicted pathological complete response (pCR) in premenopausal and postmenopausal women with breast cancer (BC) who received neoadjuvant chemotherapy (NAC).

Major finding: The likelihood of achieving pCR was higher in premenopausal women with lower vs. higher testosterone levels (odds ratio [OR] 0.996; P = .026) and in postmenopausal women with higher vs. lower FSH levels (OR 1.045; P = .005).

Study details: This was a retrospective study of 196 premenopausal and 137 postmenopausal women with invasive BC who received NAC.

Disclosures: This study was funded by National Natural Science Foundation of China. The authors declared no conflicts of interest.

Source: Lan A et al. Pre-treatment circulating reproductive hormones levels predict pathological and survival outcomes in breast cancer submitted to neoadjuvant chemotherapy. Int J Clin Oncol. 2022 (Mar 3). Doi: 10.1007/s10147-022-02141-9

Key clinical point: An anthracycline-containing chemotherapy (AC-T) regimen was not associated with a survival benefit compared with 6 cycles of docetaxel/cyclophosphamide (TC6) in an overall cohort of patients with human epidermal growth factor receptor 2 (HER2)-negative, high-risk, early breast cancer (BC); however, patients with lobular tumor and ≥3 affected lymph nodes may benefit.

Major finding: Although disease-free survival (DFS) was similar between AC-T and TC6 treatment arms in the overall cohort (P = .57), the subgroup of patients with lobular tumor and ≥3 affected lymph nodes showed improved DFS with AC-T vs. TC6 (hazard ratio 3.521; P = .003). The frequency of grade 3/4 adverse events was significantly higher in AC-T vs. TC6 treatment arm (P < .001).

Study details: Findings are from the pooled analysis of two phase 3 studies, SUCCESS-C and PlanB, including 5,924 patients with high-risk HER2-negative invasive early BC who were randomly assigned to receive TC6 or AC-T.

Disclosures: The study did not receive any funding. Some authors declared receiving financial and nonfinancial support from several sources.

Source: Gregorio AD et al. The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer—a pooled analysis of the randomised clinical trials PlanB and SUCCESS C. Br J Cancer. 2022 (Feb 22). Doi: 10.1038/s41416-021-01690-6

Key clinical point: An anthracycline-containing chemotherapy (AC-T) regimen was not associated with a survival benefit compared with 6 cycles of docetaxel/cyclophosphamide (TC6) in an overall cohort of patients with human epidermal growth factor receptor 2 (HER2)-negative, high-risk, early breast cancer (BC); however, patients with lobular tumor and ≥3 affected lymph nodes may benefit.

Major finding: Although disease-free survival (DFS) was similar between AC-T and TC6 treatment arms in the overall cohort (P = .57), the subgroup of patients with lobular tumor and ≥3 affected lymph nodes showed improved DFS with AC-T vs. TC6 (hazard ratio 3.521; P = .003). The frequency of grade 3/4 adverse events was significantly higher in AC-T vs. TC6 treatment arm (P < .001).

Study details: Findings are from the pooled analysis of two phase 3 studies, SUCCESS-C and PlanB, including 5,924 patients with high-risk HER2-negative invasive early BC who were randomly assigned to receive TC6 or AC-T.

Disclosures: The study did not receive any funding. Some authors declared receiving financial and nonfinancial support from several sources.

Source: Gregorio AD et al. The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer—a pooled analysis of the randomised clinical trials PlanB and SUCCESS C. Br J Cancer. 2022 (Feb 22). Doi: 10.1038/s41416-021-01690-6

Key clinical point: An anthracycline-containing chemotherapy (AC-T) regimen was not associated with a survival benefit compared with 6 cycles of docetaxel/cyclophosphamide (TC6) in an overall cohort of patients with human epidermal growth factor receptor 2 (HER2)-negative, high-risk, early breast cancer (BC); however, patients with lobular tumor and ≥3 affected lymph nodes may benefit.

Major finding: Although disease-free survival (DFS) was similar between AC-T and TC6 treatment arms in the overall cohort (P = .57), the subgroup of patients with lobular tumor and ≥3 affected lymph nodes showed improved DFS with AC-T vs. TC6 (hazard ratio 3.521; P = .003). The frequency of grade 3/4 adverse events was significantly higher in AC-T vs. TC6 treatment arm (P < .001).

Study details: Findings are from the pooled analysis of two phase 3 studies, SUCCESS-C and PlanB, including 5,924 patients with high-risk HER2-negative invasive early BC who were randomly assigned to receive TC6 or AC-T.

Disclosures: The study did not receive any funding. Some authors declared receiving financial and nonfinancial support from several sources.

Source: Gregorio AD et al. The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer—a pooled analysis of the randomised clinical trials PlanB and SUCCESS C. Br J Cancer. 2022 (Feb 22). Doi: 10.1038/s41416-021-01690-6

Key clinical point: Ribociclib plus letrozole was safe and effective in male patients with hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (BC) who did not receive prior endocrine therapy (ET).

Major finding: Male patients vs. overall population experienced fewer treatment-related adverse events (AE), especially neutropenia (all grade 53.8% vs. 74.5%; grade ≥3 41.0% vs. 57.2%). After a median follow-up of 25.4 months, median time to progression was 27.1 months for the overall cohort vs. not reached in males.

Study details: Findings are from an exploratory analysis of the phase 3b CompLEEment-1 trial including 39 males with HR-positive HER2-negative advanced BC who received ribociclib+letrozole but not prior ET for the advanced disease.

Disclosures: The study was supported by Novartis Pharmaceuticals. The authors declared serving as members of speakers’ bureau or receiving honoraria, advisory/consulting fees, expert testimony fees, research grants, or travel and accommodation expenses from several sources, including Novartis. Two authors declared being employees or shareholders of Novartis.

Source: Campone M et al. Ribociclib plus letrozole in male patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: subgroup analysis of the phase IIIb CompLEEment-1 trial. Breast Cancer Res Treat. 2022 (Feb 25). Doi: 10.1007/s10549-022-06543-1

Key clinical point: Ribociclib plus letrozole was safe and effective in male patients with hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (BC) who did not receive prior endocrine therapy (ET).

Major finding: Male patients vs. overall population experienced fewer treatment-related adverse events (AE), especially neutropenia (all grade 53.8% vs. 74.5%; grade ≥3 41.0% vs. 57.2%). After a median follow-up of 25.4 months, median time to progression was 27.1 months for the overall cohort vs. not reached in males.

Study details: Findings are from an exploratory analysis of the phase 3b CompLEEment-1 trial including 39 males with HR-positive HER2-negative advanced BC who received ribociclib+letrozole but not prior ET for the advanced disease.

Disclosures: The study was supported by Novartis Pharmaceuticals. The authors declared serving as members of speakers’ bureau or receiving honoraria, advisory/consulting fees, expert testimony fees, research grants, or travel and accommodation expenses from several sources, including Novartis. Two authors declared being employees or shareholders of Novartis.

Source: Campone M et al. Ribociclib plus letrozole in male patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: subgroup analysis of the phase IIIb CompLEEment-1 trial. Breast Cancer Res Treat. 2022 (Feb 25). Doi: 10.1007/s10549-022-06543-1

Key clinical point: Ribociclib plus letrozole was safe and effective in male patients with hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (BC) who did not receive prior endocrine therapy (ET).

Major finding: Male patients vs. overall population experienced fewer treatment-related adverse events (AE), especially neutropenia (all grade 53.8% vs. 74.5%; grade ≥3 41.0% vs. 57.2%). After a median follow-up of 25.4 months, median time to progression was 27.1 months for the overall cohort vs. not reached in males.

Study details: Findings are from an exploratory analysis of the phase 3b CompLEEment-1 trial including 39 males with HR-positive HER2-negative advanced BC who received ribociclib+letrozole but not prior ET for the advanced disease.

Disclosures: The study was supported by Novartis Pharmaceuticals. The authors declared serving as members of speakers’ bureau or receiving honoraria, advisory/consulting fees, expert testimony fees, research grants, or travel and accommodation expenses from several sources, including Novartis. Two authors declared being employees or shareholders of Novartis.

Source: Campone M et al. Ribociclib plus letrozole in male patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: subgroup analysis of the phase IIIb CompLEEment-1 trial. Breast Cancer Res Treat. 2022 (Feb 25). Doi: 10.1007/s10549-022-06543-1

Key clinical point: A family history of breast cancer (FHBC) was positively associated with mammographic breast density in premenopausal women, highlighting the role of heredity and the need for initiating early annual screening in women with an FHBC.

Major finding: The volumetric percent density was 25% higher among premenopausal women with vs. without FHBC (odds ratio [OR] 1.25; 95% CI 1.12-1.41) in the discovery cohort, and the odds of having a dense breast was 30% higher in premenopausal women with vs. without FHBC in the validation cohort (OR 1.30; 95% CI 1.17-1.45).

Study details: This study evaluated two retrospective cohorts, a discovery set of 375 premenopausal women and a validation set of 14,040 premenopausal women without any history of cancer, including breast cancer, or breast augmentation/reduction.

Disclosures: This study was supported by US National Institutes of Health (NIH)/National Cancer Institute and the National Institute on Minority Health and Health Disparities of the NIH. The authors declared no conflicts of interest.

Source: Han Y et al. Family history of breast cancer and mammographic breast density in premenopausal women. JAMA Netw Open. 2022;5(2):e2148983 (Feb 17). Doi: 10.1001/jamanetworkopen.2021.48983

Key clinical point: A family history of breast cancer (FHBC) was positively associated with mammographic breast density in premenopausal women, highlighting the role of heredity and the need for initiating early annual screening in women with an FHBC.

Major finding: The volumetric percent density was 25% higher among premenopausal women with vs. without FHBC (odds ratio [OR] 1.25; 95% CI 1.12-1.41) in the discovery cohort, and the odds of having a dense breast was 30% higher in premenopausal women with vs. without FHBC in the validation cohort (OR 1.30; 95% CI 1.17-1.45).

Study details: This study evaluated two retrospective cohorts, a discovery set of 375 premenopausal women and a validation set of 14,040 premenopausal women without any history of cancer, including breast cancer, or breast augmentation/reduction.

Disclosures: This study was supported by US National Institutes of Health (NIH)/National Cancer Institute and the National Institute on Minority Health and Health Disparities of the NIH. The authors declared no conflicts of interest.

Source: Han Y et al. Family history of breast cancer and mammographic breast density in premenopausal women. JAMA Netw Open. 2022;5(2):e2148983 (Feb 17). Doi: 10.1001/jamanetworkopen.2021.48983

Key clinical point: A family history of breast cancer (FHBC) was positively associated with mammographic breast density in premenopausal women, highlighting the role of heredity and the need for initiating early annual screening in women with an FHBC.

Major finding: The volumetric percent density was 25% higher among premenopausal women with vs. without FHBC (odds ratio [OR] 1.25; 95% CI 1.12-1.41) in the discovery cohort, and the odds of having a dense breast was 30% higher in premenopausal women with vs. without FHBC in the validation cohort (OR 1.30; 95% CI 1.17-1.45).

Study details: This study evaluated two retrospective cohorts, a discovery set of 375 premenopausal women and a validation set of 14,040 premenopausal women without any history of cancer, including breast cancer, or breast augmentation/reduction.

Disclosures: This study was supported by US National Institutes of Health (NIH)/National Cancer Institute and the National Institute on Minority Health and Health Disparities of the NIH. The authors declared no conflicts of interest.

Source: Han Y et al. Family history of breast cancer and mammographic breast density in premenopausal women. JAMA Netw Open. 2022;5(2):e2148983 (Feb 17). Doi: 10.1001/jamanetworkopen.2021.48983

Key clinical point: In the real-world setting, adding pertuzumab to trastuzumab+chemotherapy improved overall survival (OS) in a large cohort of patients with metastatic breast cancer (BC).

Major finding: Median OS was higher with pertuzumab+trastuzumab+chemotherapy (40.2 months; 95% CI 35.6-47.8 months) vs. trastuzumab+chemotherapy (25.3 months; 95% CI 22.8-27.6 months), with pertuzumab associated with significantly reduced mortality (hazard ratio 0.66; 95% CI 0.57-0.79). The 1-year cumulative incidence of a direct hospital visit was lower in the pertuzumab+trastuzumab+chemotherapy vs. trastuzumab+chemotherapy group (P < .001).

Study details: Findings are from a population-based retrospective study including 1,158 patients with metastatic BC who received first-line treatment with pertuzumab+trastuzumab+chemotherapy (n = 579) or trastuzumab+chemotherapy (n = 579).

Disclosures: This study was supported by the Canadian Institutes of Health Research. Dr. Liu declared being an employee of ICES, which is funded by the Ontario Ministry of Health and Long-Term Care.

Source: Dai WF et al. Comparative effectiveness and safety of pertuzumab and trastuzumab plus chemotherapy vs trastuzumab plus chemotherapy for treatment of metastatic breast cancer. JAMA Netw Open. 2022;5(2):e2145460 (Feb 28). Doi: 10.1001/jamanetworkopen.2021.45460

Key clinical point: In the real-world setting, adding pertuzumab to trastuzumab+chemotherapy improved overall survival (OS) in a large cohort of patients with metastatic breast cancer (BC).

Major finding: Median OS was higher with pertuzumab+trastuzumab+chemotherapy (40.2 months; 95% CI 35.6-47.8 months) vs. trastuzumab+chemotherapy (25.3 months; 95% CI 22.8-27.6 months), with pertuzumab associated with significantly reduced mortality (hazard ratio 0.66; 95% CI 0.57-0.79). The 1-year cumulative incidence of a direct hospital visit was lower in the pertuzumab+trastuzumab+chemotherapy vs. trastuzumab+chemotherapy group (P < .001).

Study details: Findings are from a population-based retrospective study including 1,158 patients with metastatic BC who received first-line treatment with pertuzumab+trastuzumab+chemotherapy (n = 579) or trastuzumab+chemotherapy (n = 579).

Disclosures: This study was supported by the Canadian Institutes of Health Research. Dr. Liu declared being an employee of ICES, which is funded by the Ontario Ministry of Health and Long-Term Care.

Source: Dai WF et al. Comparative effectiveness and safety of pertuzumab and trastuzumab plus chemotherapy vs trastuzumab plus chemotherapy for treatment of metastatic breast cancer. JAMA Netw Open. 2022;5(2):e2145460 (Feb 28). Doi: 10.1001/jamanetworkopen.2021.45460

Key clinical point: In the real-world setting, adding pertuzumab to trastuzumab+chemotherapy improved overall survival (OS) in a large cohort of patients with metastatic breast cancer (BC).

Major finding: Median OS was higher with pertuzumab+trastuzumab+chemotherapy (40.2 months; 95% CI 35.6-47.8 months) vs. trastuzumab+chemotherapy (25.3 months; 95% CI 22.8-27.6 months), with pertuzumab associated with significantly reduced mortality (hazard ratio 0.66; 95% CI 0.57-0.79). The 1-year cumulative incidence of a direct hospital visit was lower in the pertuzumab+trastuzumab+chemotherapy vs. trastuzumab+chemotherapy group (P < .001).

Study details: Findings are from a population-based retrospective study including 1,158 patients with metastatic BC who received first-line treatment with pertuzumab+trastuzumab+chemotherapy (n = 579) or trastuzumab+chemotherapy (n = 579).

Disclosures: This study was supported by the Canadian Institutes of Health Research. Dr. Liu declared being an employee of ICES, which is funded by the Ontario Ministry of Health and Long-Term Care.

Source: Dai WF et al. Comparative effectiveness and safety of pertuzumab and trastuzumab plus chemotherapy vs trastuzumab plus chemotherapy for treatment of metastatic breast cancer. JAMA Netw Open. 2022;5(2):e2145460 (Feb 28). Doi: 10.1001/jamanetworkopen.2021.45460

Key clinical point: HD201, a trastuzumab biosimilar, and reference trastuzumab display equivalence in terms of efficacy (along with a similar safety profile) in patients with human epidermal growth factor receptor 2 (ERBB2)-positive early breast cancer (BC) treated in the neoadjuvant setting.

Major finding: At the time of surgery, the rate of total pathological complete response with HD201 vs. referent trastuzumab was 45% vs. 48.7%, respectively, with the difference between the groups within the predefined equivalence margin (−3.8%; 95% CI −12.8% to 5.4%). Treatment-emergent adverse events of special interest for trastuzumab were reported by 88% and 84.5% of patients receiving HD201 and trastuzumab, respectively.

Study details: Findings are from the phase 3 TROIKA study including 502 women with ERBB2-positive early BC who were randomly assigned to receive HD201 or trastuzumab in a neoadjuvant setting along with chemotherapy.

Disclosures: This study was funded by Prestige BioPharma Ltd. Some of the authors declared serving as unpaid advisors or receiving personal fees and grants from several sources, including Prestige BioPharma Ltd. Three authors declared being employees of DICE Ltd.

Source: Pivot X et al. Efficacy of HD201 vs referent trastuzumab in patients with ERBB2-positive breast cancer treated in the neoadjuvant setting: A multicenter phase 3 randomized clinical trial. JAMA Oncol. 2022 (Mar 3). Doi: 10.1001/jamaoncol.2021.8171

Key clinical point: HD201, a trastuzumab biosimilar, and reference trastuzumab display equivalence in terms of efficacy (along with a similar safety profile) in patients with human epidermal growth factor receptor 2 (ERBB2)-positive early breast cancer (BC) treated in the neoadjuvant setting.

Major finding: At the time of surgery, the rate of total pathological complete response with HD201 vs. referent trastuzumab was 45% vs. 48.7%, respectively, with the difference between the groups within the predefined equivalence margin (−3.8%; 95% CI −12.8% to 5.4%). Treatment-emergent adverse events of special interest for trastuzumab were reported by 88% and 84.5% of patients receiving HD201 and trastuzumab, respectively.

Study details: Findings are from the phase 3 TROIKA study including 502 women with ERBB2-positive early BC who were randomly assigned to receive HD201 or trastuzumab in a neoadjuvant setting along with chemotherapy.

Disclosures: This study was funded by Prestige BioPharma Ltd. Some of the authors declared serving as unpaid advisors or receiving personal fees and grants from several sources, including Prestige BioPharma Ltd. Three authors declared being employees of DICE Ltd.

Source: Pivot X et al. Efficacy of HD201 vs referent trastuzumab in patients with ERBB2-positive breast cancer treated in the neoadjuvant setting: A multicenter phase 3 randomized clinical trial. JAMA Oncol. 2022 (Mar 3). Doi: 10.1001/jamaoncol.2021.8171

Key clinical point: HD201, a trastuzumab biosimilar, and reference trastuzumab display equivalence in terms of efficacy (along with a similar safety profile) in patients with human epidermal growth factor receptor 2 (ERBB2)-positive early breast cancer (BC) treated in the neoadjuvant setting.

Major finding: At the time of surgery, the rate of total pathological complete response with HD201 vs. referent trastuzumab was 45% vs. 48.7%, respectively, with the difference between the groups within the predefined equivalence margin (−3.8%; 95% CI −12.8% to 5.4%). Treatment-emergent adverse events of special interest for trastuzumab were reported by 88% and 84.5% of patients receiving HD201 and trastuzumab, respectively.

Study details: Findings are from the phase 3 TROIKA study including 502 women with ERBB2-positive early BC who were randomly assigned to receive HD201 or trastuzumab in a neoadjuvant setting along with chemotherapy.

Disclosures: This study was funded by Prestige BioPharma Ltd. Some of the authors declared serving as unpaid advisors or receiving personal fees and grants from several sources, including Prestige BioPharma Ltd. Three authors declared being employees of DICE Ltd.

Source: Pivot X et al. Efficacy of HD201 vs referent trastuzumab in patients with ERBB2-positive breast cancer treated in the neoadjuvant setting: A multicenter phase 3 randomized clinical trial. JAMA Oncol. 2022 (Mar 3). Doi: 10.1001/jamaoncol.2021.8171

Key clinical point: Patients with metastatic breast cancer (BC) with a lobular subtype may have worse outcomes compared with those with a ductal subtype.

Major finding: Invasive lobular carcinoma (ILC) vs. invasive ductal carcinoma (IDC) subtype was significantly associated with worse survival (hazard ratio [HR] 1.31; P < .0001) and progression-free survival (HR 1.15; P < .0001).

Study details: Findings are from a retrospective analysis of 13,111 patients with metastatic BC with ILC (13.8%) or IDC (86.2%) subtype from the UNICANCER Epidemiological Strategy and Medico Economics (ESME)-metastatic BC cohort.

Disclosures: ESME is supported by Roche, Pfizer, and other pharmaceutical companies. The authors declared no conflicts of interest.

Source: Dalenc F et al. Impact of lobular versus ductal histology on overall survival in metastatic breast cancer: a French retrospective multicentre cohort study. Eur J Cancer. 2022;164:70-79 (Feb 14). Doi: 10.1016/j.ejca.2021.12.031

Key clinical point: Patients with metastatic breast cancer (BC) with a lobular subtype may have worse outcomes compared with those with a ductal subtype.

Major finding: Invasive lobular carcinoma (ILC) vs. invasive ductal carcinoma (IDC) subtype was significantly associated with worse survival (hazard ratio [HR] 1.31; P < .0001) and progression-free survival (HR 1.15; P < .0001).

Study details: Findings are from a retrospective analysis of 13,111 patients with metastatic BC with ILC (13.8%) or IDC (86.2%) subtype from the UNICANCER Epidemiological Strategy and Medico Economics (ESME)-metastatic BC cohort.

Disclosures: ESME is supported by Roche, Pfizer, and other pharmaceutical companies. The authors declared no conflicts of interest.

Source: Dalenc F et al. Impact of lobular versus ductal histology on overall survival in metastatic breast cancer: a French retrospective multicentre cohort study. Eur J Cancer. 2022;164:70-79 (Feb 14). Doi: 10.1016/j.ejca.2021.12.031

Key clinical point: Patients with metastatic breast cancer (BC) with a lobular subtype may have worse outcomes compared with those with a ductal subtype.

Major finding: Invasive lobular carcinoma (ILC) vs. invasive ductal carcinoma (IDC) subtype was significantly associated with worse survival (hazard ratio [HR] 1.31; P < .0001) and progression-free survival (HR 1.15; P < .0001).

Study details: Findings are from a retrospective analysis of 13,111 patients with metastatic BC with ILC (13.8%) or IDC (86.2%) subtype from the UNICANCER Epidemiological Strategy and Medico Economics (ESME)-metastatic BC cohort.

Disclosures: ESME is supported by Roche, Pfizer, and other pharmaceutical companies. The authors declared no conflicts of interest.

Source: Dalenc F et al. Impact of lobular versus ductal histology on overall survival in metastatic breast cancer: a French retrospective multicentre cohort study. Eur J Cancer. 2022;164:70-79 (Feb 14). Doi: 10.1016/j.ejca.2021.12.031

Key clinical point: The addition of atezolizumab to chemotherapy with nanoparticle albumin-bound nab-paclitaxel and carboplatin failed to improve pathological complete response (pCR) rates compared with chemotherapy alone in early high-risk, locally advanced, triple-negative breast cancer (TNBC).

Major finding: The rate of pCR was not significantly different between atezolizumab and non-atezolizumab treatment arms (48.6% vs. 44.4%; odds ratio 1.18; P = .48). Serious adverse events and any grade liver transaminase abnormalities were higher in the atezolizumab vs. non-atezolizumab treatment arm (P = .001).

Study details: Findings are from the NeoTRIP study including 280 women with early high-risk, locally advanced TNBC who were randomly assigned to receive neoadjuvant carboplatin and nab-paclitaxel with or without atezolizumab.

Disclosures: This study was supported by Fondazione Michelangelo. The authors declared serving on advisory boards or receiving consulting fees, honoraria, grants, support for attending meetings, and other nonfinancial support from several sources.

Source: Gianni L et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study. Ann Oncol. 2022 (Feb 16). Doi: 10.1016/j.annonc.2022.02.004

Key clinical point: The addition of atezolizumab to chemotherapy with nanoparticle albumin-bound nab-paclitaxel and carboplatin failed to improve pathological complete response (pCR) rates compared with chemotherapy alone in early high-risk, locally advanced, triple-negative breast cancer (TNBC).

Major finding: The rate of pCR was not significantly different between atezolizumab and non-atezolizumab treatment arms (48.6% vs. 44.4%; odds ratio 1.18; P = .48). Serious adverse events and any grade liver transaminase abnormalities were higher in the atezolizumab vs. non-atezolizumab treatment arm (P = .001).

Study details: Findings are from the NeoTRIP study including 280 women with early high-risk, locally advanced TNBC who were randomly assigned to receive neoadjuvant carboplatin and nab-paclitaxel with or without atezolizumab.

Disclosures: This study was supported by Fondazione Michelangelo. The authors declared serving on advisory boards or receiving consulting fees, honoraria, grants, support for attending meetings, and other nonfinancial support from several sources.

Source: Gianni L et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study. Ann Oncol. 2022 (Feb 16). Doi: 10.1016/j.annonc.2022.02.004

Key clinical point: The addition of atezolizumab to chemotherapy with nanoparticle albumin-bound nab-paclitaxel and carboplatin failed to improve pathological complete response (pCR) rates compared with chemotherapy alone in early high-risk, locally advanced, triple-negative breast cancer (TNBC).

Major finding: The rate of pCR was not significantly different between atezolizumab and non-atezolizumab treatment arms (48.6% vs. 44.4%; odds ratio 1.18; P = .48). Serious adverse events and any grade liver transaminase abnormalities were higher in the atezolizumab vs. non-atezolizumab treatment arm (P = .001).

Study details: Findings are from the NeoTRIP study including 280 women with early high-risk, locally advanced TNBC who were randomly assigned to receive neoadjuvant carboplatin and nab-paclitaxel with or without atezolizumab.

Disclosures: This study was supported by Fondazione Michelangelo. The authors declared serving on advisory boards or receiving consulting fees, honoraria, grants, support for attending meetings, and other nonfinancial support from several sources.

Source: Gianni L et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study. Ann Oncol. 2022 (Feb 16). Doi: 10.1016/j.annonc.2022.02.004

Key clinical point: Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab postsurgery significantly prolonged event-free survival (EFS) compared with neoadjuvant chemotherapy alone in patients with early triple-negative breast cancer (TNBC).

Major finding: At 36 months, estimated EFS significantly improved in the pembrolizumab-chemotherapy vs. placebo-chemotherapy group (84.5% vs. 76.8%; hazard ratio for event or death, 0.63; P < .001). No new adverse events were reported.

Study details: Findings are from an interim analysis of the phase 3 KEYNOTE-522 study including 1,174 patients with early, previously untreated stage II/III TNBC who were randomly assigned to receive neoadjuvant therapy with pembrolizumab or placebo. In the adjuvant phase, patients received pembrolizumab or placebo after definitive surgery and radiotherapy, if indicated.

Disclosures: This study was supported by Merck Sharp and Dohme. The authors declared serving as consultants, advisory board members, or receiving research grants, contracts, and honoraria from several sources, including Merck/Merck Sharp and Dohme. Four authors declared being employees and stock/stock option owners of Merck/Merck Sharp and Dohme.

Source: Schmid P et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567 (Feb 10). Doi: 10.1056/NEJMoa2112651

Key clinical point: Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab postsurgery significantly prolonged event-free survival (EFS) compared with neoadjuvant chemotherapy alone in patients with early triple-negative breast cancer (TNBC).

Major finding: At 36 months, estimated EFS significantly improved in the pembrolizumab-chemotherapy vs. placebo-chemotherapy group (84.5% vs. 76.8%; hazard ratio for event or death, 0.63; P < .001). No new adverse events were reported.

Study details: Findings are from an interim analysis of the phase 3 KEYNOTE-522 study including 1,174 patients with early, previously untreated stage II/III TNBC who were randomly assigned to receive neoadjuvant therapy with pembrolizumab or placebo. In the adjuvant phase, patients received pembrolizumab or placebo after definitive surgery and radiotherapy, if indicated.

Disclosures: This study was supported by Merck Sharp and Dohme. The authors declared serving as consultants, advisory board members, or receiving research grants, contracts, and honoraria from several sources, including Merck/Merck Sharp and Dohme. Four authors declared being employees and stock/stock option owners of Merck/Merck Sharp and Dohme.

Source: Schmid P et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567 (Feb 10). Doi: 10.1056/NEJMoa2112651

Key clinical point: Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab postsurgery significantly prolonged event-free survival (EFS) compared with neoadjuvant chemotherapy alone in patients with early triple-negative breast cancer (TNBC).

Major finding: At 36 months, estimated EFS significantly improved in the pembrolizumab-chemotherapy vs. placebo-chemotherapy group (84.5% vs. 76.8%; hazard ratio for event or death, 0.63; P < .001). No new adverse events were reported.

Study details: Findings are from an interim analysis of the phase 3 KEYNOTE-522 study including 1,174 patients with early, previously untreated stage II/III TNBC who were randomly assigned to receive neoadjuvant therapy with pembrolizumab or placebo. In the adjuvant phase, patients received pembrolizumab or placebo after definitive surgery and radiotherapy, if indicated.

Disclosures: This study was supported by Merck Sharp and Dohme. The authors declared serving as consultants, advisory board members, or receiving research grants, contracts, and honoraria from several sources, including Merck/Merck Sharp and Dohme. Four authors declared being employees and stock/stock option owners of Merck/Merck Sharp and Dohme.

Source: Schmid P et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567 (Feb 10). Doi: 10.1056/NEJMoa2112651

WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.

Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the annual Gut Microbiota for Health World Summit.

Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “The answer now is totally yes.”
 

New approaches for CDI

“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), he said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”

Several of the microbiome-based therapies under investigation – including two poised for phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.

The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.

Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”

The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.

One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.

The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.

Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.

Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroidia and Clostridia.

And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”

Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”

In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.

Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with UC who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”

Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.

The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.
 

Gut microbiome manipulation for cancer

Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.

Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.

Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.

Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.

“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.

Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vendata, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.

WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.

Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the annual Gut Microbiota for Health World Summit.

Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “The answer now is totally yes.”
 

New approaches for CDI

“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), he said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”

Several of the microbiome-based therapies under investigation – including two poised for phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.

The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.

Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”

The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.

One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.

The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.

Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.

Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroidia and Clostridia.

And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”

Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”

In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.

Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with UC who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”

Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.

The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.
 

Gut microbiome manipulation for cancer

Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.

Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.

Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.

Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.

“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.

Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vendata, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.

WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.

Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the annual Gut Microbiota for Health World Summit.

Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “The answer now is totally yes.”
 

New approaches for CDI

“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), he said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”

Several of the microbiome-based therapies under investigation – including two poised for phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.

The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.

Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”

The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.

One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.

The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.

Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.

Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroidia and Clostridia.

And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”

Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”

In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.

Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with UC who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”

Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.

The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.
 

Gut microbiome manipulation for cancer

Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.

Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.

Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.

Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.

“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.

Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vendata, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.