Clinical Edge Journal Scan Commentary

Multiple studies have emphasized the potential for severe COVID-19 outcomes in patients with rheumatic disease, including patients with rheumatoid arthritis (RA). Because these studies often group together patients with different diseases, medications, and manifestations, differences in outcomes between patients with these conditions may be difficult to tease out.

Figueroa-Parra and colleagues performed a retrospective cohort study comparing people with RA who developed COVID-19 to those who did not have RA to examine the effect of RA characteristics, such as interstitial lung disease (ILD), serostatus, and bone erosions, on COVID-19 outcomes. Patients with RA, particularly those with seropositive RA, bone erosions, and RA-associated ILD, had approximately twofold (or higher) risk for severe COVID-19 outcomes, such as mortality or mechanical ventilation, than did those without RA. However, there was no difference in outcomes seen between patients with RA who were seropositive compared with those who were seronegative, with or without bone erosions, or with or without ILD. The mechanism by which RA phenotypes and their treatment affect this risk remains unclear.

Li and colleagues also looked at COVID-19 outcomes in patients with RA according to vaccination status using a UK primary care database. Among unvaccinated patients, the risk for SARS-CoV-2 infection and hospitalization or mortality because of COVID-19 were modestly higher in people with RA. Among vaccinated patients, there was no increased risk for breakthrough infection, COVID-19 hospitalization, or mortality observed in patients with RA over 3 or 6 months of follow-up, with a slight increase over 9 months of follow-up. Overall, both studies support prior research suggesting a higher risk for more severe COVID-19 in patients with RA, as well as potential mitigation with vaccination.

Predictors of RA course and severity are of great interest in determining the optimal therapy to reduce joint damage and prevent RA progression while also minimizing the adverse effects of treatment. Early disease course has been shown to be important in several studies. Giollo and colleagues compared patients with "difficult-to-treat RA," ie, RA that is resistant to multiple biologic disease-modifying antirheumatic drugs (bDMARD) or targeted synthetic DMARD (tsDMARD), with those without in an inception cohort study and found that early difficult management as well as delay of methotrexate initiation was associated with persistent inflammatory symptoms. This finding does not show a causative relationship between methotrexate and protection from the development of refractory RA but does lend support for early aggressive treatment in patients with a high inflammatory burden.

Conversely, Parisi and colleagues performed a subanalysis of the STARTER study of patients with RA in clinical remission to evaluate the impact of different therapies. The STARTER study had shown an association between ultrasound detection of tenosynovitis and RA flares. Of the more than 250 patients completing the study, ultrasound evidence of tenosynovitis was better controlled in patients on combination bDMARD and conventional synthetic DMARD (csDMARD) therapy than in those on csDMARDs monotherapy, with a trend toward reduction in flares in patients on combination therapy. Given the relatively small effect, it is not clear that combination therapy is associated with deeper remission, but, as suggested in prior studies, ultrasound evidence of tenosynovitis may be worthwhile considering prior to tapering therapy.

Multiple studies have emphasized the potential for severe COVID-19 outcomes in patients with rheumatic disease, including patients with rheumatoid arthritis (RA). Because these studies often group together patients with different diseases, medications, and manifestations, differences in outcomes between patients with these conditions may be difficult to tease out.

Figueroa-Parra and colleagues performed a retrospective cohort study comparing people with RA who developed COVID-19 to those who did not have RA to examine the effect of RA characteristics, such as interstitial lung disease (ILD), serostatus, and bone erosions, on COVID-19 outcomes. Patients with RA, particularly those with seropositive RA, bone erosions, and RA-associated ILD, had approximately twofold (or higher) risk for severe COVID-19 outcomes, such as mortality or mechanical ventilation, than did those without RA. However, there was no difference in outcomes seen between patients with RA who were seropositive compared with those who were seronegative, with or without bone erosions, or with or without ILD. The mechanism by which RA phenotypes and their treatment affect this risk remains unclear.

Li and colleagues also looked at COVID-19 outcomes in patients with RA according to vaccination status using a UK primary care database. Among unvaccinated patients, the risk for SARS-CoV-2 infection and hospitalization or mortality because of COVID-19 were modestly higher in people with RA. Among vaccinated patients, there was no increased risk for breakthrough infection, COVID-19 hospitalization, or mortality observed in patients with RA over 3 or 6 months of follow-up, with a slight increase over 9 months of follow-up. Overall, both studies support prior research suggesting a higher risk for more severe COVID-19 in patients with RA, as well as potential mitigation with vaccination.

Predictors of RA course and severity are of great interest in determining the optimal therapy to reduce joint damage and prevent RA progression while also minimizing the adverse effects of treatment. Early disease course has been shown to be important in several studies. Giollo and colleagues compared patients with "difficult-to-treat RA," ie, RA that is resistant to multiple biologic disease-modifying antirheumatic drugs (bDMARD) or targeted synthetic DMARD (tsDMARD), with those without in an inception cohort study and found that early difficult management as well as delay of methotrexate initiation was associated with persistent inflammatory symptoms. This finding does not show a causative relationship between methotrexate and protection from the development of refractory RA but does lend support for early aggressive treatment in patients with a high inflammatory burden.

Conversely, Parisi and colleagues performed a subanalysis of the STARTER study of patients with RA in clinical remission to evaluate the impact of different therapies. The STARTER study had shown an association between ultrasound detection of tenosynovitis and RA flares. Of the more than 250 patients completing the study, ultrasound evidence of tenosynovitis was better controlled in patients on combination bDMARD and conventional synthetic DMARD (csDMARD) therapy than in those on csDMARDs monotherapy, with a trend toward reduction in flares in patients on combination therapy. Given the relatively small effect, it is not clear that combination therapy is associated with deeper remission, but, as suggested in prior studies, ultrasound evidence of tenosynovitis may be worthwhile considering prior to tapering therapy.

Multiple studies have emphasized the potential for severe COVID-19 outcomes in patients with rheumatic disease, including patients with rheumatoid arthritis (RA). Because these studies often group together patients with different diseases, medications, and manifestations, differences in outcomes between patients with these conditions may be difficult to tease out.

Figueroa-Parra and colleagues performed a retrospective cohort study comparing people with RA who developed COVID-19 to those who did not have RA to examine the effect of RA characteristics, such as interstitial lung disease (ILD), serostatus, and bone erosions, on COVID-19 outcomes. Patients with RA, particularly those with seropositive RA, bone erosions, and RA-associated ILD, had approximately twofold (or higher) risk for severe COVID-19 outcomes, such as mortality or mechanical ventilation, than did those without RA. However, there was no difference in outcomes seen between patients with RA who were seropositive compared with those who were seronegative, with or without bone erosions, or with or without ILD. The mechanism by which RA phenotypes and their treatment affect this risk remains unclear.

Li and colleagues also looked at COVID-19 outcomes in patients with RA according to vaccination status using a UK primary care database. Among unvaccinated patients, the risk for SARS-CoV-2 infection and hospitalization or mortality because of COVID-19 were modestly higher in people with RA. Among vaccinated patients, there was no increased risk for breakthrough infection, COVID-19 hospitalization, or mortality observed in patients with RA over 3 or 6 months of follow-up, with a slight increase over 9 months of follow-up. Overall, both studies support prior research suggesting a higher risk for more severe COVID-19 in patients with RA, as well as potential mitigation with vaccination.

Predictors of RA course and severity are of great interest in determining the optimal therapy to reduce joint damage and prevent RA progression while also minimizing the adverse effects of treatment. Early disease course has been shown to be important in several studies. Giollo and colleagues compared patients with "difficult-to-treat RA," ie, RA that is resistant to multiple biologic disease-modifying antirheumatic drugs (bDMARD) or targeted synthetic DMARD (tsDMARD), with those without in an inception cohort study and found that early difficult management as well as delay of methotrexate initiation was associated with persistent inflammatory symptoms. This finding does not show a causative relationship between methotrexate and protection from the development of refractory RA but does lend support for early aggressive treatment in patients with a high inflammatory burden.

Conversely, Parisi and colleagues performed a subanalysis of the STARTER study of patients with RA in clinical remission to evaluate the impact of different therapies. The STARTER study had shown an association between ultrasound detection of tenosynovitis and RA flares. Of the more than 250 patients completing the study, ultrasound evidence of tenosynovitis was better controlled in patients on combination bDMARD and conventional synthetic DMARD (csDMARD) therapy than in those on csDMARDs monotherapy, with a trend toward reduction in flares in patients on combination therapy. Given the relatively small effect, it is not clear that combination therapy is associated with deeper remission, but, as suggested in prior studies, ultrasound evidence of tenosynovitis may be worthwhile considering prior to tapering therapy.

The three PPH articles examine the use of preventive B-Lynch suture, risk factors for failure of intrauterine tamponade, and trend changes in risk factors for PPH. Kuwabara and colleagues looked at the effectiveness of preventative B-Lynch sutures in patients at high risk for PPH. Their retrospective observational study included 38 of 663 patients who underwent cesarean section (CS) who received the B-Lynch procedure at their tertiary perinatal medical center in Gifu, Japan, between January 2019 and May 2021. Overall, 92% of patients who received the B-Lynch suture showed no apparent postoperative bleeding within 2 hours after the CS. A total of 24 patients required blood transfusion, none required hysterectomy, and only one patient with a twin pregnancy required additional treatment because of secondary PPH 5 days after the CS. This suggests that earlier use of B-Lynch sutures could be considered in patients at high risk for atony.

Gibier and colleagues examined risk factors for uterine tamponade failure in women with PPH. This was a population-based retrospective cohort study of 1761 women with deliveries complicated by PPH who underwent intrauterine tamponade within 24 hours of PPH to manage persistent bleeding. They noted that the intrauterine tamponade failure rate was 11.1%. Risk for intrauterine tamponade failure was higher in women with CS (adjusted odds ratio [aOR] 4.2; 95% CI 2.9-6.0), preeclampsia (aOR 2.3; 95% CI 1.3-3.9), and uterine rupture (aOR 14.1; 95% CI 2.4-83.0). They concluded that CS, preeclampsia, and uterine rupture were significant risk factors for failures in this procedure.

Sade and colleagues examined trend changes in the individual contribution of risk factors for PPH over more than two decades. Their population-based, retrospective, nested, case-control study included 285,992 pregnancies and suggested that, in their hospital setting in Israel, risks from perineal or vaginal tears were increasing while large-for-gestational-age fetuses decreased and other risk factors remained stable.

Finally, Wu and colleagues examined incidence and outcomes of AHRCP diseases during pregnancy and the puerperium. This observational analysis examined 41,174,101 patients hospitalized for pregnancy and during the puerperium in the National Inpatient Sample (NIS) database from January 1, 2008, to December 31, 2017. The study noted that 40,285 patients were diagnosed with AHRCP diseases during this period. The NIS is the largest publicly available all-payer database in the United States. The investigators found that the incidence of AHRCP diseases increased significantly between 2002 and 2017, especially pulmonary embolism in the puerperium. Although mortality showed a downward trend, it is still at a high level. They suggested that we should strengthen monitoring and management of AHRCP in pregnancy and puerperium, especially for Black women, those in the lowest-income households, and parturients over 35 years of age.

The three PPH articles examine the use of preventive B-Lynch suture, risk factors for failure of intrauterine tamponade, and trend changes in risk factors for PPH. Kuwabara and colleagues looked at the effectiveness of preventative B-Lynch sutures in patients at high risk for PPH. Their retrospective observational study included 38 of 663 patients who underwent cesarean section (CS) who received the B-Lynch procedure at their tertiary perinatal medical center in Gifu, Japan, between January 2019 and May 2021. Overall, 92% of patients who received the B-Lynch suture showed no apparent postoperative bleeding within 2 hours after the CS. A total of 24 patients required blood transfusion, none required hysterectomy, and only one patient with a twin pregnancy required additional treatment because of secondary PPH 5 days after the CS. This suggests that earlier use of B-Lynch sutures could be considered in patients at high risk for atony.

Gibier and colleagues examined risk factors for uterine tamponade failure in women with PPH. This was a population-based retrospective cohort study of 1761 women with deliveries complicated by PPH who underwent intrauterine tamponade within 24 hours of PPH to manage persistent bleeding. They noted that the intrauterine tamponade failure rate was 11.1%. Risk for intrauterine tamponade failure was higher in women with CS (adjusted odds ratio [aOR] 4.2; 95% CI 2.9-6.0), preeclampsia (aOR 2.3; 95% CI 1.3-3.9), and uterine rupture (aOR 14.1; 95% CI 2.4-83.0). They concluded that CS, preeclampsia, and uterine rupture were significant risk factors for failures in this procedure.

Sade and colleagues examined trend changes in the individual contribution of risk factors for PPH over more than two decades. Their population-based, retrospective, nested, case-control study included 285,992 pregnancies and suggested that, in their hospital setting in Israel, risks from perineal or vaginal tears were increasing while large-for-gestational-age fetuses decreased and other risk factors remained stable.

Finally, Wu and colleagues examined incidence and outcomes of AHRCP diseases during pregnancy and the puerperium. This observational analysis examined 41,174,101 patients hospitalized for pregnancy and during the puerperium in the National Inpatient Sample (NIS) database from January 1, 2008, to December 31, 2017. The study noted that 40,285 patients were diagnosed with AHRCP diseases during this period. The NIS is the largest publicly available all-payer database in the United States. The investigators found that the incidence of AHRCP diseases increased significantly between 2002 and 2017, especially pulmonary embolism in the puerperium. Although mortality showed a downward trend, it is still at a high level. They suggested that we should strengthen monitoring and management of AHRCP in pregnancy and puerperium, especially for Black women, those in the lowest-income households, and parturients over 35 years of age.

The three PPH articles examine the use of preventive B-Lynch suture, risk factors for failure of intrauterine tamponade, and trend changes in risk factors for PPH. Kuwabara and colleagues looked at the effectiveness of preventative B-Lynch sutures in patients at high risk for PPH. Their retrospective observational study included 38 of 663 patients who underwent cesarean section (CS) who received the B-Lynch procedure at their tertiary perinatal medical center in Gifu, Japan, between January 2019 and May 2021. Overall, 92% of patients who received the B-Lynch suture showed no apparent postoperative bleeding within 2 hours after the CS. A total of 24 patients required blood transfusion, none required hysterectomy, and only one patient with a twin pregnancy required additional treatment because of secondary PPH 5 days after the CS. This suggests that earlier use of B-Lynch sutures could be considered in patients at high risk for atony.

Gibier and colleagues examined risk factors for uterine tamponade failure in women with PPH. This was a population-based retrospective cohort study of 1761 women with deliveries complicated by PPH who underwent intrauterine tamponade within 24 hours of PPH to manage persistent bleeding. They noted that the intrauterine tamponade failure rate was 11.1%. Risk for intrauterine tamponade failure was higher in women with CS (adjusted odds ratio [aOR] 4.2; 95% CI 2.9-6.0), preeclampsia (aOR 2.3; 95% CI 1.3-3.9), and uterine rupture (aOR 14.1; 95% CI 2.4-83.0). They concluded that CS, preeclampsia, and uterine rupture were significant risk factors for failures in this procedure.

Sade and colleagues examined trend changes in the individual contribution of risk factors for PPH over more than two decades. Their population-based, retrospective, nested, case-control study included 285,992 pregnancies and suggested that, in their hospital setting in Israel, risks from perineal or vaginal tears were increasing while large-for-gestational-age fetuses decreased and other risk factors remained stable.

Finally, Wu and colleagues examined incidence and outcomes of AHRCP diseases during pregnancy and the puerperium. This observational analysis examined 41,174,101 patients hospitalized for pregnancy and during the puerperium in the National Inpatient Sample (NIS) database from January 1, 2008, to December 31, 2017. The study noted that 40,285 patients were diagnosed with AHRCP diseases during this period. The NIS is the largest publicly available all-payer database in the United States. The investigators found that the incidence of AHRCP diseases increased significantly between 2002 and 2017, especially pulmonary embolism in the puerperium. Although mortality showed a downward trend, it is still at a high level. They suggested that we should strengthen monitoring and management of AHRCP in pregnancy and puerperium, especially for Black women, those in the lowest-income households, and parturients over 35 years of age.

Immune checkpoint inhibitors in combination with chemotherapy are part of standard treatment for patients with advanced gastroesophageal adenocarcinoma. However, not all patients benefit from immunotherapy addition. Programmed death-ligand 1 (PD-L1) expression has emerged as a useful, yet imperfect, biomarker for identifying patients who are most likely to benefit from the addition of immunotherapy. There is a need to better identify patients with higher chances of responding to these therapies, as well as a need to augment the activity that we are seeing with current approaches. Tumor mutational burden (TMB) has been previously identified as a predictive biomarker of response to immunotherapy. It is not widely used in clinical practice when treating patients with upper gastrointestinal cancers though, and it has not been extensively evaluated in this disease.

The study by Lee and colleagues evaluated the association between TMB and pembrolizumab response in patients treated in the phase 3 KEYNOTE-62 study. This was a prespecified exploratory analysis, which included 306 of 763 patients, based on TMB data availability. Although there was association between high TMB (cut-off defined as 10 mut/Mb), the benefit from pembrolizumab was most pronounced in patients with microsatellite-unstable tumors. When the analysis was limited to microsatellite-stable tumors with high TMB, the signal was attenuated and was only detected when immunotherapy was combined with chemotherapy.

Ultimately, although TMB is a predictive biomarker of response to immunotherapy, it is unlikely to significantly alter our approach to treatment of upper gastrointestinal cancers, especially when PD-L1 testing and microsatellite testing are more readily available and do not require more time- and resource-consuming next-generation sequencing when selecting first-line treatments.

Perioperative chemotherapy plays a critical role in the management of patients with early-stage gastric cancer. In the United States, perioperative FLOT (5-fluorouracil, oxaliplatin, and docetaxel) chemotherapy is the standard approach to this disease, with four cycles administered before and four cycles administered after resection.

In Korea, adjuvant chemotherapy is typically used, with 1 year of S-1 chemotherapy or 6 months of CAPOX (capecitabine/oxaliplatin) chemotherapy used most frequently. Kim and colleagues analyzed whether a shorter duration of chemotherapy (either S-1 or CAPOX) had similar outcomes. In a retrospective analysis of 20,552 patients, which included 13,614 patients who received S-1 and 6938 patients who received CAPOX, overall survival was worse in those patients who received a shorter duration of adjuvant treatment. Although this study is not directly applicable to how we approach treatment of early-stage gastric cancer in the United States, it does suggest that any modification in the duration of perioperative chemotherapy should be evaluated in prospective clinical trials, similarly to recent investigations regarding the duration on adjuvant chemotherapy in colon cancer.

Immune checkpoint inhibitors in combination with chemotherapy are part of standard treatment for patients with advanced gastroesophageal adenocarcinoma. However, not all patients benefit from immunotherapy addition. Programmed death-ligand 1 (PD-L1) expression has emerged as a useful, yet imperfect, biomarker for identifying patients who are most likely to benefit from the addition of immunotherapy. There is a need to better identify patients with higher chances of responding to these therapies, as well as a need to augment the activity that we are seeing with current approaches. Tumor mutational burden (TMB) has been previously identified as a predictive biomarker of response to immunotherapy. It is not widely used in clinical practice when treating patients with upper gastrointestinal cancers though, and it has not been extensively evaluated in this disease.

The study by Lee and colleagues evaluated the association between TMB and pembrolizumab response in patients treated in the phase 3 KEYNOTE-62 study. This was a prespecified exploratory analysis, which included 306 of 763 patients, based on TMB data availability. Although there was association between high TMB (cut-off defined as 10 mut/Mb), the benefit from pembrolizumab was most pronounced in patients with microsatellite-unstable tumors. When the analysis was limited to microsatellite-stable tumors with high TMB, the signal was attenuated and was only detected when immunotherapy was combined with chemotherapy.

Ultimately, although TMB is a predictive biomarker of response to immunotherapy, it is unlikely to significantly alter our approach to treatment of upper gastrointestinal cancers, especially when PD-L1 testing and microsatellite testing are more readily available and do not require more time- and resource-consuming next-generation sequencing when selecting first-line treatments.

Perioperative chemotherapy plays a critical role in the management of patients with early-stage gastric cancer. In the United States, perioperative FLOT (5-fluorouracil, oxaliplatin, and docetaxel) chemotherapy is the standard approach to this disease, with four cycles administered before and four cycles administered after resection.

In Korea, adjuvant chemotherapy is typically used, with 1 year of S-1 chemotherapy or 6 months of CAPOX (capecitabine/oxaliplatin) chemotherapy used most frequently. Kim and colleagues analyzed whether a shorter duration of chemotherapy (either S-1 or CAPOX) had similar outcomes. In a retrospective analysis of 20,552 patients, which included 13,614 patients who received S-1 and 6938 patients who received CAPOX, overall survival was worse in those patients who received a shorter duration of adjuvant treatment. Although this study is not directly applicable to how we approach treatment of early-stage gastric cancer in the United States, it does suggest that any modification in the duration of perioperative chemotherapy should be evaluated in prospective clinical trials, similarly to recent investigations regarding the duration on adjuvant chemotherapy in colon cancer.

Immune checkpoint inhibitors in combination with chemotherapy are part of standard treatment for patients with advanced gastroesophageal adenocarcinoma. However, not all patients benefit from immunotherapy addition. Programmed death-ligand 1 (PD-L1) expression has emerged as a useful, yet imperfect, biomarker for identifying patients who are most likely to benefit from the addition of immunotherapy. There is a need to better identify patients with higher chances of responding to these therapies, as well as a need to augment the activity that we are seeing with current approaches. Tumor mutational burden (TMB) has been previously identified as a predictive biomarker of response to immunotherapy. It is not widely used in clinical practice when treating patients with upper gastrointestinal cancers though, and it has not been extensively evaluated in this disease.

The study by Lee and colleagues evaluated the association between TMB and pembrolizumab response in patients treated in the phase 3 KEYNOTE-62 study. This was a prespecified exploratory analysis, which included 306 of 763 patients, based on TMB data availability. Although there was association between high TMB (cut-off defined as 10 mut/Mb), the benefit from pembrolizumab was most pronounced in patients with microsatellite-unstable tumors. When the analysis was limited to microsatellite-stable tumors with high TMB, the signal was attenuated and was only detected when immunotherapy was combined with chemotherapy.

Ultimately, although TMB is a predictive biomarker of response to immunotherapy, it is unlikely to significantly alter our approach to treatment of upper gastrointestinal cancers, especially when PD-L1 testing and microsatellite testing are more readily available and do not require more time- and resource-consuming next-generation sequencing when selecting first-line treatments.

Perioperative chemotherapy plays a critical role in the management of patients with early-stage gastric cancer. In the United States, perioperative FLOT (5-fluorouracil, oxaliplatin, and docetaxel) chemotherapy is the standard approach to this disease, with four cycles administered before and four cycles administered after resection.

In Korea, adjuvant chemotherapy is typically used, with 1 year of S-1 chemotherapy or 6 months of CAPOX (capecitabine/oxaliplatin) chemotherapy used most frequently. Kim and colleagues analyzed whether a shorter duration of chemotherapy (either S-1 or CAPOX) had similar outcomes. In a retrospective analysis of 20,552 patients, which included 13,614 patients who received S-1 and 6938 patients who received CAPOX, overall survival was worse in those patients who received a shorter duration of adjuvant treatment. Although this study is not directly applicable to how we approach treatment of early-stage gastric cancer in the United States, it does suggest that any modification in the duration of perioperative chemotherapy should be evaluated in prospective clinical trials, similarly to recent investigations regarding the duration on adjuvant chemotherapy in colon cancer.

Research on psoriatic arthritis (PsA) published over the past month has highlighted the effect of disease on patients and provided insights into clinical management. Because of the heterogeneous nature of PsA, assessing disease activity is difficult. A blood biomarker for disease activity would be useful. C-reactive protein (CRP) is a commonly used and well-established marker of inflammation in general. However, CRP does not reflect PsA disease activity itself. In a cross-sectional study, Gialouri and colleagues evaluated the association between CRP and PsA disease activity. CRP status (CRP  ≤  0.5 mg/dL [normal] and CRP > 0.5  mg/dL [increased]) was not associated with any of the clinical disease activity (clinical Disease Activity Index for Psoriatic Arthritis [cDAPSA] or minimal disease activity [MDA]) or patient-reported outcomes measures (Patient Global, Patient Pain, Health Assessment Questionnaire-Disability Index [HAQ-DI] or EuroQol [EQ-5D]). Among patients with normal CRP levels, a substantial proportion (45.9%) were not in MDA (thus, an indicator of active disease) while 76.7% of patients with elevated CRP were not in MDA. Therefore, an elevated CRP may indicate active PsA, but a normal CRP is not a reliable indicator of disease state in PsA.

Gender differences in PsA are increasingly being recognized as important. In a real-world survey of 2270 PsA patients (1047 women) from Europe and the United States, Gossec and colleagues demonstrated that, despite similar disease duration, disease presentation, and biologic use, women had worse quality-of-life, disability, and physical functioning scores, a greater degree of work activity impairment, and higher pain and fatigue scores compared with men. Thus, it is increasingly clear that PsA affects women differently from men. Interventions for the holistic management of PsA should be tailored according to the patient's gender for optimal outcomes.

Despite major advances in the treatment of adult PsA, the treatment options for children with PsA (juvenile PsA [JPsA]) are limited. Anti–tumor necrosis factor (TNF) agents are the only currently approved advanced therapy. Brunner and colleagues conducted a treatment-withdrawal, phase 3 study including 86 biologic-naive patients with active enthesitis-related arthritis (n = 52) or JPsA (n = 34) who were randomly assigned to receive secukinumab or placebo.

This study demonstrated that, compared with placebo, secukinumab was associated with a significant delay in disease flare and a higher proportion of patients achieving juvenile idiopathic arthritis American College of Rheumatology 30 response at week 104. This study provides evidence that secukinumab, a safe and effective therapy used in adult psoriatic disease, may provide similar benefits in JPsA, especially in patients who either have not responded to or have contraindications to treatment with anti-TNF agents.

Finally, because skin disease predates joint disease in almost 90% of PsA patients, identifying predictors for the development of joint disease is of considerable interest. It is hoped that identifying such predictors will help dermatologists and primary care physicians stratify management such that those at higher risk are carefully followed up for early diagnosis or even preventive therapy.

To identify such predictors, Ogdie and colleagues conducted a prospective study of 1489 patients with psoriasis and no prior diagnosis of PsA from the CorEvitas Psoriasis registry. They demonstrated that 10% of patients with psoriasis developed PsA after 2 years. Psoriasis Epidemiology Screening Tool (PEST, a brief screening questionnaire for PsA) and body mass index (BMI) were important factors predicting the development of PsA. Although the incidence of PsA in this cohort is higher than that reported from other studies, the study indicates that PEST and BMI should be important factors that predict PsA and should be variables in any prediction model.

Research on psoriatic arthritis (PsA) published over the past month has highlighted the effect of disease on patients and provided insights into clinical management. Because of the heterogeneous nature of PsA, assessing disease activity is difficult. A blood biomarker for disease activity would be useful. C-reactive protein (CRP) is a commonly used and well-established marker of inflammation in general. However, CRP does not reflect PsA disease activity itself. In a cross-sectional study, Gialouri and colleagues evaluated the association between CRP and PsA disease activity. CRP status (CRP  ≤  0.5 mg/dL [normal] and CRP > 0.5  mg/dL [increased]) was not associated with any of the clinical disease activity (clinical Disease Activity Index for Psoriatic Arthritis [cDAPSA] or minimal disease activity [MDA]) or patient-reported outcomes measures (Patient Global, Patient Pain, Health Assessment Questionnaire-Disability Index [HAQ-DI] or EuroQol [EQ-5D]). Among patients with normal CRP levels, a substantial proportion (45.9%) were not in MDA (thus, an indicator of active disease) while 76.7% of patients with elevated CRP were not in MDA. Therefore, an elevated CRP may indicate active PsA, but a normal CRP is not a reliable indicator of disease state in PsA.

Gender differences in PsA are increasingly being recognized as important. In a real-world survey of 2270 PsA patients (1047 women) from Europe and the United States, Gossec and colleagues demonstrated that, despite similar disease duration, disease presentation, and biologic use, women had worse quality-of-life, disability, and physical functioning scores, a greater degree of work activity impairment, and higher pain and fatigue scores compared with men. Thus, it is increasingly clear that PsA affects women differently from men. Interventions for the holistic management of PsA should be tailored according to the patient's gender for optimal outcomes.

Despite major advances in the treatment of adult PsA, the treatment options for children with PsA (juvenile PsA [JPsA]) are limited. Anti–tumor necrosis factor (TNF) agents are the only currently approved advanced therapy. Brunner and colleagues conducted a treatment-withdrawal, phase 3 study including 86 biologic-naive patients with active enthesitis-related arthritis (n = 52) or JPsA (n = 34) who were randomly assigned to receive secukinumab or placebo.

This study demonstrated that, compared with placebo, secukinumab was associated with a significant delay in disease flare and a higher proportion of patients achieving juvenile idiopathic arthritis American College of Rheumatology 30 response at week 104. This study provides evidence that secukinumab, a safe and effective therapy used in adult psoriatic disease, may provide similar benefits in JPsA, especially in patients who either have not responded to or have contraindications to treatment with anti-TNF agents.

Finally, because skin disease predates joint disease in almost 90% of PsA patients, identifying predictors for the development of joint disease is of considerable interest. It is hoped that identifying such predictors will help dermatologists and primary care physicians stratify management such that those at higher risk are carefully followed up for early diagnosis or even preventive therapy.

To identify such predictors, Ogdie and colleagues conducted a prospective study of 1489 patients with psoriasis and no prior diagnosis of PsA from the CorEvitas Psoriasis registry. They demonstrated that 10% of patients with psoriasis developed PsA after 2 years. Psoriasis Epidemiology Screening Tool (PEST, a brief screening questionnaire for PsA) and body mass index (BMI) were important factors predicting the development of PsA. Although the incidence of PsA in this cohort is higher than that reported from other studies, the study indicates that PEST and BMI should be important factors that predict PsA and should be variables in any prediction model.

Research on psoriatic arthritis (PsA) published over the past month has highlighted the effect of disease on patients and provided insights into clinical management. Because of the heterogeneous nature of PsA, assessing disease activity is difficult. A blood biomarker for disease activity would be useful. C-reactive protein (CRP) is a commonly used and well-established marker of inflammation in general. However, CRP does not reflect PsA disease activity itself. In a cross-sectional study, Gialouri and colleagues evaluated the association between CRP and PsA disease activity. CRP status (CRP  ≤  0.5 mg/dL [normal] and CRP > 0.5  mg/dL [increased]) was not associated with any of the clinical disease activity (clinical Disease Activity Index for Psoriatic Arthritis [cDAPSA] or minimal disease activity [MDA]) or patient-reported outcomes measures (Patient Global, Patient Pain, Health Assessment Questionnaire-Disability Index [HAQ-DI] or EuroQol [EQ-5D]). Among patients with normal CRP levels, a substantial proportion (45.9%) were not in MDA (thus, an indicator of active disease) while 76.7% of patients with elevated CRP were not in MDA. Therefore, an elevated CRP may indicate active PsA, but a normal CRP is not a reliable indicator of disease state in PsA.

Gender differences in PsA are increasingly being recognized as important. In a real-world survey of 2270 PsA patients (1047 women) from Europe and the United States, Gossec and colleagues demonstrated that, despite similar disease duration, disease presentation, and biologic use, women had worse quality-of-life, disability, and physical functioning scores, a greater degree of work activity impairment, and higher pain and fatigue scores compared with men. Thus, it is increasingly clear that PsA affects women differently from men. Interventions for the holistic management of PsA should be tailored according to the patient's gender for optimal outcomes.

Despite major advances in the treatment of adult PsA, the treatment options for children with PsA (juvenile PsA [JPsA]) are limited. Anti–tumor necrosis factor (TNF) agents are the only currently approved advanced therapy. Brunner and colleagues conducted a treatment-withdrawal, phase 3 study including 86 biologic-naive patients with active enthesitis-related arthritis (n = 52) or JPsA (n = 34) who were randomly assigned to receive secukinumab or placebo.

This study demonstrated that, compared with placebo, secukinumab was associated with a significant delay in disease flare and a higher proportion of patients achieving juvenile idiopathic arthritis American College of Rheumatology 30 response at week 104. This study provides evidence that secukinumab, a safe and effective therapy used in adult psoriatic disease, may provide similar benefits in JPsA, especially in patients who either have not responded to or have contraindications to treatment with anti-TNF agents.

Finally, because skin disease predates joint disease in almost 90% of PsA patients, identifying predictors for the development of joint disease is of considerable interest. It is hoped that identifying such predictors will help dermatologists and primary care physicians stratify management such that those at higher risk are carefully followed up for early diagnosis or even preventive therapy.

To identify such predictors, Ogdie and colleagues conducted a prospective study of 1489 patients with psoriasis and no prior diagnosis of PsA from the CorEvitas Psoriasis registry. They demonstrated that 10% of patients with psoriasis developed PsA after 2 years. Psoriasis Epidemiology Screening Tool (PEST, a brief screening questionnaire for PsA) and body mass index (BMI) were important factors predicting the development of PsA. Although the incidence of PsA in this cohort is higher than that reported from other studies, the study indicates that PEST and BMI should be important factors that predict PsA and should be variables in any prediction model.

As always, several provocative publications on colorectal cancer (CRC) have found their way into the medical literature. I will be discussing two of these in my Clinical Edge Journal Scan commentary for the month of October.

The first article, by Kennecke and colleagues, examines the role of neoadjuvant chemotherapy for early rectal cancer. We have been inundated with data showing that organ preservation is achievable in cases of node-positive rectal cancer with neoadjuvant chemoradiotherapy and chemotherapy (total neoadjuvant treatment [TNT] approach). As such, it stands to reason that organ preservation should also be achievable in cases of early, node-negative rectal cancer.

NEO was a single-arm, phase 2 trial examining the role of neoadjuvant chemotherapy only in early rectal cancer. In it, 58 patients with clinical T1-T3ab N0 low-to-mid rectal adenocarcinoma (proficient mismatch repair status) eligible for endoscopic resection were treated with 3 months of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin). Those with evidence of tumor regression proceeded to transanal resection.

The primary endpoint was a protocol-specified organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1 N0/X and who avoided radical surgery. Thirty-three (33) of the 58 patients were successfully downstaged, resulting in a protocol-specified organ preservation rate of 57% (90% CI 45-68). Of note, this treatment had no radiation at all and only used chemotherapy. Of the remaining 23 patients, 13 declined total mesorectal excision (TME) and went into observation. Of the 10 patients who underwent TME, seven had no histopathologic evidence of residual disease. The 1- and 2-year locoregional relapse-free survival rates were 98% (95% CI 86-100) and 90% (95% CI 58-98), respectively, and there were no metastatic recurrences or deaths. Although this is a small study, the results are enormously encouraging, suggesting that organ preservation not only can be achieved in early-stage rectal cancer, but also can be accomplished using only chemotherapy, further reducing morbidity to patients.

The second study I want to discuss was conducted by Ciardiello and colleagues and concerns the KRAS^G12C mutation in colorectal cancer. This mutation is targetable in lung cancer and has led to the approval of sotorasib for the treatment of advanced KRAS^G12C non–small-cell lung cancer . Unfortunately, previous studies of these inhibitors in advanced KRAS^G12C colorectal cancer have yielded disappointing results.

This study looked retrospectively at 6952 cases of metastatic colorectal cancer across Italy. A total of 256 cases (3.7%) demonstrated the KRAS^G12C mutation. Of those, 111 met inclusion criteria and were included in the analysis. Of note, this mutation was associated with a poor response to first-line chemotherapy (38.7%), with a median progression-free survival of 9 months (95% CI 7.5-10.5 months). Median overall survival was 21 months (95% CI 17.4-24.6 months). There was little difference between first-line oxaliplatin-containing regimens compared with those containing irinotecan. Triplet therapy (folinic acid, fluorouracil, oxaliplatin, and irinotecan; FOLFOXIRI) was associated with an objective response rate of 56.3% with a progression-free survival of 13 months and median overall survival of 32 months, suggesting that triplet therapy might be a better approach for these patients when they are identified. This study is important because it corroborates and builds upon data reported in smaller studies demonstrating the general resistance of KRAS^G12C metastatic colorectal cancer to chemotherapeutic treatments.

As always, several provocative publications on colorectal cancer (CRC) have found their way into the medical literature. I will be discussing two of these in my Clinical Edge Journal Scan commentary for the month of October.

The first article, by Kennecke and colleagues, examines the role of neoadjuvant chemotherapy for early rectal cancer. We have been inundated with data showing that organ preservation is achievable in cases of node-positive rectal cancer with neoadjuvant chemoradiotherapy and chemotherapy (total neoadjuvant treatment [TNT] approach). As such, it stands to reason that organ preservation should also be achievable in cases of early, node-negative rectal cancer.

NEO was a single-arm, phase 2 trial examining the role of neoadjuvant chemotherapy only in early rectal cancer. In it, 58 patients with clinical T1-T3ab N0 low-to-mid rectal adenocarcinoma (proficient mismatch repair status) eligible for endoscopic resection were treated with 3 months of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin). Those with evidence of tumor regression proceeded to transanal resection.

The primary endpoint was a protocol-specified organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1 N0/X and who avoided radical surgery. Thirty-three (33) of the 58 patients were successfully downstaged, resulting in a protocol-specified organ preservation rate of 57% (90% CI 45-68). Of note, this treatment had no radiation at all and only used chemotherapy. Of the remaining 23 patients, 13 declined total mesorectal excision (TME) and went into observation. Of the 10 patients who underwent TME, seven had no histopathologic evidence of residual disease. The 1- and 2-year locoregional relapse-free survival rates were 98% (95% CI 86-100) and 90% (95% CI 58-98), respectively, and there were no metastatic recurrences or deaths. Although this is a small study, the results are enormously encouraging, suggesting that organ preservation not only can be achieved in early-stage rectal cancer, but also can be accomplished using only chemotherapy, further reducing morbidity to patients.

The second study I want to discuss was conducted by Ciardiello and colleagues and concerns the KRAS^G12C mutation in colorectal cancer. This mutation is targetable in lung cancer and has led to the approval of sotorasib for the treatment of advanced KRAS^G12C non–small-cell lung cancer . Unfortunately, previous studies of these inhibitors in advanced KRAS^G12C colorectal cancer have yielded disappointing results.

This study looked retrospectively at 6952 cases of metastatic colorectal cancer across Italy. A total of 256 cases (3.7%) demonstrated the KRAS^G12C mutation. Of those, 111 met inclusion criteria and were included in the analysis. Of note, this mutation was associated with a poor response to first-line chemotherapy (38.7%), with a median progression-free survival of 9 months (95% CI 7.5-10.5 months). Median overall survival was 21 months (95% CI 17.4-24.6 months). There was little difference between first-line oxaliplatin-containing regimens compared with those containing irinotecan. Triplet therapy (folinic acid, fluorouracil, oxaliplatin, and irinotecan; FOLFOXIRI) was associated with an objective response rate of 56.3% with a progression-free survival of 13 months and median overall survival of 32 months, suggesting that triplet therapy might be a better approach for these patients when they are identified. This study is important because it corroborates and builds upon data reported in smaller studies demonstrating the general resistance of KRAS^G12C metastatic colorectal cancer to chemotherapeutic treatments.

As always, several provocative publications on colorectal cancer (CRC) have found their way into the medical literature. I will be discussing two of these in my Clinical Edge Journal Scan commentary for the month of October.

The first article, by Kennecke and colleagues, examines the role of neoadjuvant chemotherapy for early rectal cancer. We have been inundated with data showing that organ preservation is achievable in cases of node-positive rectal cancer with neoadjuvant chemoradiotherapy and chemotherapy (total neoadjuvant treatment [TNT] approach). As such, it stands to reason that organ preservation should also be achievable in cases of early, node-negative rectal cancer.

NEO was a single-arm, phase 2 trial examining the role of neoadjuvant chemotherapy only in early rectal cancer. In it, 58 patients with clinical T1-T3ab N0 low-to-mid rectal adenocarcinoma (proficient mismatch repair status) eligible for endoscopic resection were treated with 3 months of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin). Those with evidence of tumor regression proceeded to transanal resection.

The primary endpoint was a protocol-specified organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1 N0/X and who avoided radical surgery. Thirty-three (33) of the 58 patients were successfully downstaged, resulting in a protocol-specified organ preservation rate of 57% (90% CI 45-68). Of note, this treatment had no radiation at all and only used chemotherapy. Of the remaining 23 patients, 13 declined total mesorectal excision (TME) and went into observation. Of the 10 patients who underwent TME, seven had no histopathologic evidence of residual disease. The 1- and 2-year locoregional relapse-free survival rates were 98% (95% CI 86-100) and 90% (95% CI 58-98), respectively, and there were no metastatic recurrences or deaths. Although this is a small study, the results are enormously encouraging, suggesting that organ preservation not only can be achieved in early-stage rectal cancer, but also can be accomplished using only chemotherapy, further reducing morbidity to patients.

The second study I want to discuss was conducted by Ciardiello and colleagues and concerns the KRAS^G12C mutation in colorectal cancer. This mutation is targetable in lung cancer and has led to the approval of sotorasib for the treatment of advanced KRAS^G12C non–small-cell lung cancer . Unfortunately, previous studies of these inhibitors in advanced KRAS^G12C colorectal cancer have yielded disappointing results.

This study looked retrospectively at 6952 cases of metastatic colorectal cancer across Italy. A total of 256 cases (3.7%) demonstrated the KRAS^G12C mutation. Of those, 111 met inclusion criteria and were included in the analysis. Of note, this mutation was associated with a poor response to first-line chemotherapy (38.7%), with a median progression-free survival of 9 months (95% CI 7.5-10.5 months). Median overall survival was 21 months (95% CI 17.4-24.6 months). There was little difference between first-line oxaliplatin-containing regimens compared with those containing irinotecan. Triplet therapy (folinic acid, fluorouracil, oxaliplatin, and irinotecan; FOLFOXIRI) was associated with an objective response rate of 56.3% with a progression-free survival of 13 months and median overall survival of 32 months, suggesting that triplet therapy might be a better approach for these patients when they are identified. This study is important because it corroborates and builds upon data reported in smaller studies demonstrating the general resistance of KRAS^G12C metastatic colorectal cancer to chemotherapeutic treatments.

Interleukin (IL)–6 is known to be of great importance in the pathogenesis of rheumatoid arthritis (RA) owing to its role in the inflammatory response. Current IL-6-directed therapies in RA, namely sarilumab and tocilizumab, target the receptor. In a double-blind randomized controlled trial with both placebo and active comparators, Smolen and colleagues evaluated the efficacy of olokizumab, which directly binds and inhibits the activity of IL-6, in combination with methotrexate, in the treatment of people with RA. Patients were treated with methotrexate alone or in combination with adalimumab or olokizumab, and clinical outcomes were evaluated after 12 weeks, a relatively short time frame. Olokizumab was noninferior to adalimumab in terms of the proportion of patients achieving an American College of Rheumatology 20 response, with similar rates of serious adverse events, the most common of which was infection. Though this study included patients from across the globe, the percentage of Black and Asian patients was relatively low and thus may affect the generalizability of this study to a US population; the numbers of patients in each group was also relatively small. These results certainly warrant larger-scale and longer studies to evaluate olokizumab's efficacy.

For those patients with RA who achieve sustained disease remission, the question of medication tapering has been raised as a possible strategy for minimizing risks for therapy. Using insurance database information, Birkner and colleagues performed a prospective cohort study of over 400 patients in Germany. Using shared decision-making between patients and their rheumatologists, two groups of patients were followed: 237 people who elected to remain on therapy and 200 who decided to taper medication. Of note, similar proportions of patients in both groups were taking conventional and biologic disease-modifying antirheumatic drug (DMARD) monotherapy, but more patients in the tapering group were taking a combination therapy with both. Flares and loss of remission were more common in the continuation group, a difference that did not persist after adjusting for patient risk characteristics. Overall, results from this "real-world" study were consistent with prior studies and support the possibility of tapering with flare in a subset of patients. Although the authors address the potential for selection bias in terms of patients "assigned" to each group, this can also be viewed as part of the shared decision-making in determining the appropriateness of tapering therapy in individual patients.

Because people receiving rituximab have experienced more severe COVID-19, studies aimed at enhancing the protection of these patients are of current interest. Of note, in a follow-up to a prior observational study by van der Togt and colleagues on the response to COVID-19 vaccines in people with RA being treated with rituximab, they looked at responses to the third (booster) dose of the COVID-19 vaccine. Only about 20% of patients treated with rituximab developed a humoral response to a third vaccine dose, as defined by immunoglobulins (Ig; total, IgG, and IgM) against SARS-CoV-2. Patients treated with 200 mg rituximab had a higher response rate than did those treated with 500 mg or 1000 mg, though this difference was not statistically significant. The study lacked a control arm of people being treated with other DMARD and also did not measure B-cell counts, COVID-19, or outcomes. Reassuringly, those patients who did have a positive humoral response to the first two vaccine doses tended to maintain a humoral response to the third, regardless of rituximab dose or timing.

Interleukin (IL)–6 is known to be of great importance in the pathogenesis of rheumatoid arthritis (RA) owing to its role in the inflammatory response. Current IL-6-directed therapies in RA, namely sarilumab and tocilizumab, target the receptor. In a double-blind randomized controlled trial with both placebo and active comparators, Smolen and colleagues evaluated the efficacy of olokizumab, which directly binds and inhibits the activity of IL-6, in combination with methotrexate, in the treatment of people with RA. Patients were treated with methotrexate alone or in combination with adalimumab or olokizumab, and clinical outcomes were evaluated after 12 weeks, a relatively short time frame. Olokizumab was noninferior to adalimumab in terms of the proportion of patients achieving an American College of Rheumatology 20 response, with similar rates of serious adverse events, the most common of which was infection. Though this study included patients from across the globe, the percentage of Black and Asian patients was relatively low and thus may affect the generalizability of this study to a US population; the numbers of patients in each group was also relatively small. These results certainly warrant larger-scale and longer studies to evaluate olokizumab's efficacy.

For those patients with RA who achieve sustained disease remission, the question of medication tapering has been raised as a possible strategy for minimizing risks for therapy. Using insurance database information, Birkner and colleagues performed a prospective cohort study of over 400 patients in Germany. Using shared decision-making between patients and their rheumatologists, two groups of patients were followed: 237 people who elected to remain on therapy and 200 who decided to taper medication. Of note, similar proportions of patients in both groups were taking conventional and biologic disease-modifying antirheumatic drug (DMARD) monotherapy, but more patients in the tapering group were taking a combination therapy with both. Flares and loss of remission were more common in the continuation group, a difference that did not persist after adjusting for patient risk characteristics. Overall, results from this "real-world" study were consistent with prior studies and support the possibility of tapering with flare in a subset of patients. Although the authors address the potential for selection bias in terms of patients "assigned" to each group, this can also be viewed as part of the shared decision-making in determining the appropriateness of tapering therapy in individual patients.

Because people receiving rituximab have experienced more severe COVID-19, studies aimed at enhancing the protection of these patients are of current interest. Of note, in a follow-up to a prior observational study by van der Togt and colleagues on the response to COVID-19 vaccines in people with RA being treated with rituximab, they looked at responses to the third (booster) dose of the COVID-19 vaccine. Only about 20% of patients treated with rituximab developed a humoral response to a third vaccine dose, as defined by immunoglobulins (Ig; total, IgG, and IgM) against SARS-CoV-2. Patients treated with 200 mg rituximab had a higher response rate than did those treated with 500 mg or 1000 mg, though this difference was not statistically significant. The study lacked a control arm of people being treated with other DMARD and also did not measure B-cell counts, COVID-19, or outcomes. Reassuringly, those patients who did have a positive humoral response to the first two vaccine doses tended to maintain a humoral response to the third, regardless of rituximab dose or timing.

Interleukin (IL)–6 is known to be of great importance in the pathogenesis of rheumatoid arthritis (RA) owing to its role in the inflammatory response. Current IL-6-directed therapies in RA, namely sarilumab and tocilizumab, target the receptor. In a double-blind randomized controlled trial with both placebo and active comparators, Smolen and colleagues evaluated the efficacy of olokizumab, which directly binds and inhibits the activity of IL-6, in combination with methotrexate, in the treatment of people with RA. Patients were treated with methotrexate alone or in combination with adalimumab or olokizumab, and clinical outcomes were evaluated after 12 weeks, a relatively short time frame. Olokizumab was noninferior to adalimumab in terms of the proportion of patients achieving an American College of Rheumatology 20 response, with similar rates of serious adverse events, the most common of which was infection. Though this study included patients from across the globe, the percentage of Black and Asian patients was relatively low and thus may affect the generalizability of this study to a US population; the numbers of patients in each group was also relatively small. These results certainly warrant larger-scale and longer studies to evaluate olokizumab's efficacy.

For those patients with RA who achieve sustained disease remission, the question of medication tapering has been raised as a possible strategy for minimizing risks for therapy. Using insurance database information, Birkner and colleagues performed a prospective cohort study of over 400 patients in Germany. Using shared decision-making between patients and their rheumatologists, two groups of patients were followed: 237 people who elected to remain on therapy and 200 who decided to taper medication. Of note, similar proportions of patients in both groups were taking conventional and biologic disease-modifying antirheumatic drug (DMARD) monotherapy, but more patients in the tapering group were taking a combination therapy with both. Flares and loss of remission were more common in the continuation group, a difference that did not persist after adjusting for patient risk characteristics. Overall, results from this "real-world" study were consistent with prior studies and support the possibility of tapering with flare in a subset of patients. Although the authors address the potential for selection bias in terms of patients "assigned" to each group, this can also be viewed as part of the shared decision-making in determining the appropriateness of tapering therapy in individual patients.

Because people receiving rituximab have experienced more severe COVID-19, studies aimed at enhancing the protection of these patients are of current interest. Of note, in a follow-up to a prior observational study by van der Togt and colleagues on the response to COVID-19 vaccines in people with RA being treated with rituximab, they looked at responses to the third (booster) dose of the COVID-19 vaccine. Only about 20% of patients treated with rituximab developed a humoral response to a third vaccine dose, as defined by immunoglobulins (Ig; total, IgG, and IgM) against SARS-CoV-2. Patients treated with 200 mg rituximab had a higher response rate than did those treated with 500 mg or 1000 mg, though this difference was not statistically significant. The study lacked a control arm of people being treated with other DMARD and also did not measure B-cell counts, COVID-19, or outcomes. Reassuringly, those patients who did have a positive humoral response to the first two vaccine doses tended to maintain a humoral response to the third, regardless of rituximab dose or timing.

Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.

Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.

Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.

Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.

Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.

Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.

Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.

Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.

Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.

Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.

Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.

Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.

Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.

Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.

Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.

Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.

Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.

Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.

Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.

Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.

Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.

Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.

Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.

Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.

The phase 3 NALA trial² demonstrated superior outcomes with the combination of neratinib plus capecitabine vs lapatinib plus capecitabine among patients with previously treated HER2+ metastatic breast cancer (hazard ratio 0.76; 1-year PFS 29% vs 15%). Findings from a single-center retrospective study including 72 patients with HER2+ advanced breast cancer who received either neratinib plus capecitabine or neratinib alone support efficacy and tolerability in the real-world setting (Cunningham et al). Among all patients, the median PFS was 5.9 months and median OS was 15.0 months; for those with brain metastases (n = 38), median PFS and median OS were 5.7 and 12.5 months, respectively. The gastrointestinal toxicity of neratinib can affect its clinical use, and a total of 64% of patients in this study reported diarrhea (10% reported grade 3) despite using antidiarrheal prophylaxis.

The treatment algorithm for HER2+ metastatic breast cancer has been evolving at a rapid pace, specifically for second-line and beyond. Neratinib remains a relevant therapy choice for these patients. The central nervous system activity of neratinib and other tyrosine kinase inhibitors, such as tucatinib, often make these the preferred treatment options for patients with brain metastases and stimulate the idea of prevention of brain metastases at an earlier time point.

Young women with breast cancer encounter unique challenges related to the stage of life during which they are diagnosed. It is essential to consider the effect of cancer treatment on fertility, including direct effects of chemotherapy and the duration of endocrine therapy (5-10 years) that can delay attempts at conceiving. Potential concerns surrounding fertility preservation (FP) include the theoretical risk of increased estradiol levels and treatment delay to allow these procedures to occur; however, various studies have supported the safety of FP.³

A prospective cohort study including 1257 women of reproductive age who were diagnosed with breast cancer and underwent FP treatment demonstrated similar disease-specific mortality in women who underwent hormonal FP (adjusted hazard ratio [aHR] 0.59; 95% CI 0.32-1.09), those who underwent nonhormonal FP (aHR 0.51, 95% CI 0.20-1.29), and women who did not pursue FP (Marklund et al). Furthermore, among 723 women with detailed information on relapse there was no significant difference in rate of relapse or death among those who underwent hormonal FP (aHR 0.81; 95% CI 0.49-1.37) vs those who underwent nonhormonal FP (aHR 0.75; 95% CI 0.35-1.62).

The growing body of evidence in this field highlights the importance of oncofertility awareness for both patients and providers. Young women diagnosed with breast cancer should be offered referrals to fertility specialists when interested and educated on the safety of these approaches as it relates to breast cancer outcomes.

A multicenter retrospective study compared the efficacy and safety of controlled ovarian hyperstimulation with letrozole (LetCOH) or without letrozole (cCOH) among 97 young women (≤ 40 years) diagnosed with early-stage breast cancer (Goldrat et al). The LetCOH group had lower peak estradiol levels (343 pg/mL vs 1009 pg/mL; P < .001) and higher oocyte maturation rates compared with the cCOH group, but a similar number of mature oocytes collected (P = .281). Disease recurrence occurred more frequently in the LetCOH group than in the cCOH group (17% vs 7.2%), and five patients in total had a distant recurrence (four undergoing LetCOH vs one undergoing cCOH).

The LetCOH group did have larger tumors and a higher number of HER2+ cancers. These findings suggest that a COH protocol using letrozole can yield FP outcomes similar to those of the conventional protocol while minimizing exposure to high levels of estradiol. Extended follow-up and future prospective studies will be essential to gain survival data and further define the roles of various FP procedures.

Additional References

1. Bardia A, Tolaney SM, Loirat D, et al. Sacituzumab govitecan (SG) versus treatment of physician's choice (TPC) in patients (pts) with previously treated, metastatic triple-negative breast cancer (mTNBC): final results from the phase 3 ASCENT study. J Clin Oncol. 2022;40(16 Suppl):107 Doi: 10.1200/JCO.2022.40.16_suppl.1071
2. Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol. 2020;38:3138-3149. Doi: 10.1200/JCO.20.00147
3. Moravek MB, Confino R, Lawson AK, et al. Predictors and outcomes in breast cancer patients who did or did not pursue fertility preservation. Breast Cancer Res Treat. 2021;186:429-437. Doi: 10.1007/s10549-020-06031-4

The phase 3 NALA trial² demonstrated superior outcomes with the combination of neratinib plus capecitabine vs lapatinib plus capecitabine among patients with previously treated HER2+ metastatic breast cancer (hazard ratio 0.76; 1-year PFS 29% vs 15%). Findings from a single-center retrospective study including 72 patients with HER2+ advanced breast cancer who received either neratinib plus capecitabine or neratinib alone support efficacy and tolerability in the real-world setting (Cunningham et al). Among all patients, the median PFS was 5.9 months and median OS was 15.0 months; for those with brain metastases (n = 38), median PFS and median OS were 5.7 and 12.5 months, respectively. The gastrointestinal toxicity of neratinib can affect its clinical use, and a total of 64% of patients in this study reported diarrhea (10% reported grade 3) despite using antidiarrheal prophylaxis.

The treatment algorithm for HER2+ metastatic breast cancer has been evolving at a rapid pace, specifically for second-line and beyond. Neratinib remains a relevant therapy choice for these patients. The central nervous system activity of neratinib and other tyrosine kinase inhibitors, such as tucatinib, often make these the preferred treatment options for patients with brain metastases and stimulate the idea of prevention of brain metastases at an earlier time point.

Young women with breast cancer encounter unique challenges related to the stage of life during which they are diagnosed. It is essential to consider the effect of cancer treatment on fertility, including direct effects of chemotherapy and the duration of endocrine therapy (5-10 years) that can delay attempts at conceiving. Potential concerns surrounding fertility preservation (FP) include the theoretical risk of increased estradiol levels and treatment delay to allow these procedures to occur; however, various studies have supported the safety of FP.³

A prospective cohort study including 1257 women of reproductive age who were diagnosed with breast cancer and underwent FP treatment demonstrated similar disease-specific mortality in women who underwent hormonal FP (adjusted hazard ratio [aHR] 0.59; 95% CI 0.32-1.09), those who underwent nonhormonal FP (aHR 0.51, 95% CI 0.20-1.29), and women who did not pursue FP (Marklund et al). Furthermore, among 723 women with detailed information on relapse there was no significant difference in rate of relapse or death among those who underwent hormonal FP (aHR 0.81; 95% CI 0.49-1.37) vs those who underwent nonhormonal FP (aHR 0.75; 95% CI 0.35-1.62).

The growing body of evidence in this field highlights the importance of oncofertility awareness for both patients and providers. Young women diagnosed with breast cancer should be offered referrals to fertility specialists when interested and educated on the safety of these approaches as it relates to breast cancer outcomes.

A multicenter retrospective study compared the efficacy and safety of controlled ovarian hyperstimulation with letrozole (LetCOH) or without letrozole (cCOH) among 97 young women (≤ 40 years) diagnosed with early-stage breast cancer (Goldrat et al). The LetCOH group had lower peak estradiol levels (343 pg/mL vs 1009 pg/mL; P < .001) and higher oocyte maturation rates compared with the cCOH group, but a similar number of mature oocytes collected (P = .281). Disease recurrence occurred more frequently in the LetCOH group than in the cCOH group (17% vs 7.2%), and five patients in total had a distant recurrence (four undergoing LetCOH vs one undergoing cCOH).

The LetCOH group did have larger tumors and a higher number of HER2+ cancers. These findings suggest that a COH protocol using letrozole can yield FP outcomes similar to those of the conventional protocol while minimizing exposure to high levels of estradiol. Extended follow-up and future prospective studies will be essential to gain survival data and further define the roles of various FP procedures.

Additional References

1. Bardia A, Tolaney SM, Loirat D, et al. Sacituzumab govitecan (SG) versus treatment of physician's choice (TPC) in patients (pts) with previously treated, metastatic triple-negative breast cancer (mTNBC): final results from the phase 3 ASCENT study. J Clin Oncol. 2022;40(16 Suppl):107 Doi: 10.1200/JCO.2022.40.16_suppl.1071
2. Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol. 2020;38:3138-3149. Doi: 10.1200/JCO.20.00147
3. Moravek MB, Confino R, Lawson AK, et al. Predictors and outcomes in breast cancer patients who did or did not pursue fertility preservation. Breast Cancer Res Treat. 2021;186:429-437. Doi: 10.1007/s10549-020-06031-4

The phase 3 NALA trial² demonstrated superior outcomes with the combination of neratinib plus capecitabine vs lapatinib plus capecitabine among patients with previously treated HER2+ metastatic breast cancer (hazard ratio 0.76; 1-year PFS 29% vs 15%). Findings from a single-center retrospective study including 72 patients with HER2+ advanced breast cancer who received either neratinib plus capecitabine or neratinib alone support efficacy and tolerability in the real-world setting (Cunningham et al). Among all patients, the median PFS was 5.9 months and median OS was 15.0 months; for those with brain metastases (n = 38), median PFS and median OS were 5.7 and 12.5 months, respectively. The gastrointestinal toxicity of neratinib can affect its clinical use, and a total of 64% of patients in this study reported diarrhea (10% reported grade 3) despite using antidiarrheal prophylaxis.

The treatment algorithm for HER2+ metastatic breast cancer has been evolving at a rapid pace, specifically for second-line and beyond. Neratinib remains a relevant therapy choice for these patients. The central nervous system activity of neratinib and other tyrosine kinase inhibitors, such as tucatinib, often make these the preferred treatment options for patients with brain metastases and stimulate the idea of prevention of brain metastases at an earlier time point.

Young women with breast cancer encounter unique challenges related to the stage of life during which they are diagnosed. It is essential to consider the effect of cancer treatment on fertility, including direct effects of chemotherapy and the duration of endocrine therapy (5-10 years) that can delay attempts at conceiving. Potential concerns surrounding fertility preservation (FP) include the theoretical risk of increased estradiol levels and treatment delay to allow these procedures to occur; however, various studies have supported the safety of FP.³

A prospective cohort study including 1257 women of reproductive age who were diagnosed with breast cancer and underwent FP treatment demonstrated similar disease-specific mortality in women who underwent hormonal FP (adjusted hazard ratio [aHR] 0.59; 95% CI 0.32-1.09), those who underwent nonhormonal FP (aHR 0.51, 95% CI 0.20-1.29), and women who did not pursue FP (Marklund et al). Furthermore, among 723 women with detailed information on relapse there was no significant difference in rate of relapse or death among those who underwent hormonal FP (aHR 0.81; 95% CI 0.49-1.37) vs those who underwent nonhormonal FP (aHR 0.75; 95% CI 0.35-1.62).

The growing body of evidence in this field highlights the importance of oncofertility awareness for both patients and providers. Young women diagnosed with breast cancer should be offered referrals to fertility specialists when interested and educated on the safety of these approaches as it relates to breast cancer outcomes.

A multicenter retrospective study compared the efficacy and safety of controlled ovarian hyperstimulation with letrozole (LetCOH) or without letrozole (cCOH) among 97 young women (≤ 40 years) diagnosed with early-stage breast cancer (Goldrat et al). The LetCOH group had lower peak estradiol levels (343 pg/mL vs 1009 pg/mL; P < .001) and higher oocyte maturation rates compared with the cCOH group, but a similar number of mature oocytes collected (P = .281). Disease recurrence occurred more frequently in the LetCOH group than in the cCOH group (17% vs 7.2%), and five patients in total had a distant recurrence (four undergoing LetCOH vs one undergoing cCOH).

The LetCOH group did have larger tumors and a higher number of HER2+ cancers. These findings suggest that a COH protocol using letrozole can yield FP outcomes similar to those of the conventional protocol while minimizing exposure to high levels of estradiol. Extended follow-up and future prospective studies will be essential to gain survival data and further define the roles of various FP procedures.

Additional References

1. Bardia A, Tolaney SM, Loirat D, et al. Sacituzumab govitecan (SG) versus treatment of physician's choice (TPC) in patients (pts) with previously treated, metastatic triple-negative breast cancer (mTNBC): final results from the phase 3 ASCENT study. J Clin Oncol. 2022;40(16 Suppl):107 Doi: 10.1200/JCO.2022.40.16_suppl.1071
2. Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol. 2020;38:3138-3149. Doi: 10.1200/JCO.20.00147
3. Moravek MB, Confino R, Lawson AK, et al. Predictors and outcomes in breast cancer patients who did or did not pursue fertility preservation. Breast Cancer Res Treat. 2021;186:429-437. Doi: 10.1007/s10549-020-06031-4

• Fairbrass et al: Natural history and impact of IBS-type symptoms in inflammatory bowel disease during 6 years of longitudinal follow-up
• Nabi et al: Endometriosis and IBS — a systematic review and meta-analyses
• Wang et al: Factors related to IBS and differences among subtypes — a cross-sectional study in the UK Biobank

Combined diseases can make assessment and treatment very difficult for clinicians. Having a thorough understanding of the pathophysiology and phenotype of each of these diseases is imperative to ensuring that they are managed to the standard of care. When these diseases are in remission and abdominal symptoms persist, it begs the question what is the cause? IBS should always be in the differential diagnosis. The dynamic relationship between the varying presentations of IBS and co-occurring conditions can greatly affect the patient's quality of life and experience with the healthcare system. Thus, it is vital to implement an interdisciplinary approach in order to comprehensively care for the patient and build a therapeutic relationship with the patient. Establishing short-term and long-term goals through shared decision-making will create a foundation of trust and allow for improved patient experience.

• Fairbrass et al: Natural history and impact of IBS-type symptoms in inflammatory bowel disease during 6 years of longitudinal follow-up
• Nabi et al: Endometriosis and IBS — a systematic review and meta-analyses
• Wang et al: Factors related to IBS and differences among subtypes — a cross-sectional study in the UK Biobank

Combined diseases can make assessment and treatment very difficult for clinicians. Having a thorough understanding of the pathophysiology and phenotype of each of these diseases is imperative to ensuring that they are managed to the standard of care. When these diseases are in remission and abdominal symptoms persist, it begs the question what is the cause? IBS should always be in the differential diagnosis. The dynamic relationship between the varying presentations of IBS and co-occurring conditions can greatly affect the patient's quality of life and experience with the healthcare system. Thus, it is vital to implement an interdisciplinary approach in order to comprehensively care for the patient and build a therapeutic relationship with the patient. Establishing short-term and long-term goals through shared decision-making will create a foundation of trust and allow for improved patient experience.

• Fairbrass et al: Natural history and impact of IBS-type symptoms in inflammatory bowel disease during 6 years of longitudinal follow-up
• Nabi et al: Endometriosis and IBS — a systematic review and meta-analyses
• Wang et al: Factors related to IBS and differences among subtypes — a cross-sectional study in the UK Biobank

Combined diseases can make assessment and treatment very difficult for clinicians. Having a thorough understanding of the pathophysiology and phenotype of each of these diseases is imperative to ensuring that they are managed to the standard of care. When these diseases are in remission and abdominal symptoms persist, it begs the question what is the cause? IBS should always be in the differential diagnosis. The dynamic relationship between the varying presentations of IBS and co-occurring conditions can greatly affect the patient's quality of life and experience with the healthcare system. Thus, it is vital to implement an interdisciplinary approach in order to comprehensively care for the patient and build a therapeutic relationship with the patient. Establishing short-term and long-term goals through shared decision-making will create a foundation of trust and allow for improved patient experience.