Clinical Edge Journal Scan Commentary

Currently there are limited therapeutic options for myelodysplastic syndromes (MDS) after failure of standard therapy. Options for patients with lower risk MDS patients without presence of deletion 5q (del5q) or SF3B1 mutation are limited after growth factor support. Lenalidomide has been used as a single agent in patients with low risk non-del5q MDS refractory to erythropoietin stimulating agents (ESA) with limited erythroid response. A phase III US intergroup trial  compared erythroid response in low risk MDS non-del5q MDS patients after ESA to either combination of lenalidomide and epoetin alfa (EPO) versus lenalidomide alone. After four cycles of treatment, major erythroid response was higher in the combination group compared to lenalidomide alone (28.3% vs 11.5%, p=0.004). The response was durable, with median major erythroid response duration of 23.8 months compared to 13 months for lenalidomide alone. In patients with low risk MDS with del5q where lenalidomide is considered, lenalidomide should be considered in combination with epoetin alfa.

For higher risk MDS patients, standard upfront treatment is hypomethylating agents (HMA), either azacitidine or decitabine. Given increased PD-1 and PD-L1 expression in high risk MDS, pembrolizumab, a monoclonal antibody targeting PD-1, is currently being evaluated in MDS. Updated results of a phase II study evaluating combination of pembrolizumab and azacitidine in untreated higher risk MDS patients was reported in ASH 2020. Untreated MDS patients with intermediate-1 and high risk by IPSS were enrolled and treated with standard azacitidine in combination with pembrolizumab 200mg IV on day 1 every 21 days. Out of 17 patients, overall response rate was 80%, with 3 patients achieving complete remission (CR), 4 patients achieving marrow CR, 4 patients achieving marrow CR with hematologic improvement, and one patient demonstrating hematologic improvement of erythrocytes. Median overall survival was not reached with median follow up of 13.8 months. Pembrolizumab with azacitidine should be further investigated in MDS.

Poly(ADP-ribose) polymerase (PARP) inhibitors are utilized in a range of solid tumor cancers. There are emerging concerns of PARP inhibitors with increased risk of developing MDS and acute myeloid leukemia (AML). A meta-analysis of 28 randomized control trials (RCT) with PARP inhibitors was done to evaluate risk of developing MDS and AML. Based on 18 RCTs with placebo control, PARP inhibitors increased risk of MDS and AML compared to placebo (Peto OR 2.63, p=0.026).  There was increased incidence of MDS and AML in the PARP inhibitor group compared to placebo (0.73% vs 0.47%). The median treatment duration was 9.8 months and median latency period since first exposure to a PARP inhibitor was 17.8 months. Use of PARP inhibitors is associated with increased risk of development of MDS and AML, and patients should be monitored accordingly.

Currently there are limited therapeutic options for myelodysplastic syndromes (MDS) after failure of standard therapy. Options for patients with lower risk MDS patients without presence of deletion 5q (del5q) or SF3B1 mutation are limited after growth factor support. Lenalidomide has been used as a single agent in patients with low risk non-del5q MDS refractory to erythropoietin stimulating agents (ESA) with limited erythroid response. A phase III US intergroup trial  compared erythroid response in low risk MDS non-del5q MDS patients after ESA to either combination of lenalidomide and epoetin alfa (EPO) versus lenalidomide alone. After four cycles of treatment, major erythroid response was higher in the combination group compared to lenalidomide alone (28.3% vs 11.5%, p=0.004). The response was durable, with median major erythroid response duration of 23.8 months compared to 13 months for lenalidomide alone. In patients with low risk MDS with del5q where lenalidomide is considered, lenalidomide should be considered in combination with epoetin alfa.

For higher risk MDS patients, standard upfront treatment is hypomethylating agents (HMA), either azacitidine or decitabine. Given increased PD-1 and PD-L1 expression in high risk MDS, pembrolizumab, a monoclonal antibody targeting PD-1, is currently being evaluated in MDS. Updated results of a phase II study evaluating combination of pembrolizumab and azacitidine in untreated higher risk MDS patients was reported in ASH 2020. Untreated MDS patients with intermediate-1 and high risk by IPSS were enrolled and treated with standard azacitidine in combination with pembrolizumab 200mg IV on day 1 every 21 days. Out of 17 patients, overall response rate was 80%, with 3 patients achieving complete remission (CR), 4 patients achieving marrow CR, 4 patients achieving marrow CR with hematologic improvement, and one patient demonstrating hematologic improvement of erythrocytes. Median overall survival was not reached with median follow up of 13.8 months. Pembrolizumab with azacitidine should be further investigated in MDS.

Poly(ADP-ribose) polymerase (PARP) inhibitors are utilized in a range of solid tumor cancers. There are emerging concerns of PARP inhibitors with increased risk of developing MDS and acute myeloid leukemia (AML). A meta-analysis of 28 randomized control trials (RCT) with PARP inhibitors was done to evaluate risk of developing MDS and AML. Based on 18 RCTs with placebo control, PARP inhibitors increased risk of MDS and AML compared to placebo (Peto OR 2.63, p=0.026).  There was increased incidence of MDS and AML in the PARP inhibitor group compared to placebo (0.73% vs 0.47%). The median treatment duration was 9.8 months and median latency period since first exposure to a PARP inhibitor was 17.8 months. Use of PARP inhibitors is associated with increased risk of development of MDS and AML, and patients should be monitored accordingly.

Currently there are limited therapeutic options for myelodysplastic syndromes (MDS) after failure of standard therapy. Options for patients with lower risk MDS patients without presence of deletion 5q (del5q) or SF3B1 mutation are limited after growth factor support. Lenalidomide has been used as a single agent in patients with low risk non-del5q MDS refractory to erythropoietin stimulating agents (ESA) with limited erythroid response. A phase III US intergroup trial  compared erythroid response in low risk MDS non-del5q MDS patients after ESA to either combination of lenalidomide and epoetin alfa (EPO) versus lenalidomide alone. After four cycles of treatment, major erythroid response was higher in the combination group compared to lenalidomide alone (28.3% vs 11.5%, p=0.004). The response was durable, with median major erythroid response duration of 23.8 months compared to 13 months for lenalidomide alone. In patients with low risk MDS with del5q where lenalidomide is considered, lenalidomide should be considered in combination with epoetin alfa.

For higher risk MDS patients, standard upfront treatment is hypomethylating agents (HMA), either azacitidine or decitabine. Given increased PD-1 and PD-L1 expression in high risk MDS, pembrolizumab, a monoclonal antibody targeting PD-1, is currently being evaluated in MDS. Updated results of a phase II study evaluating combination of pembrolizumab and azacitidine in untreated higher risk MDS patients was reported in ASH 2020. Untreated MDS patients with intermediate-1 and high risk by IPSS were enrolled and treated with standard azacitidine in combination with pembrolizumab 200mg IV on day 1 every 21 days. Out of 17 patients, overall response rate was 80%, with 3 patients achieving complete remission (CR), 4 patients achieving marrow CR, 4 patients achieving marrow CR with hematologic improvement, and one patient demonstrating hematologic improvement of erythrocytes. Median overall survival was not reached with median follow up of 13.8 months. Pembrolizumab with azacitidine should be further investigated in MDS.

Poly(ADP-ribose) polymerase (PARP) inhibitors are utilized in a range of solid tumor cancers. There are emerging concerns of PARP inhibitors with increased risk of developing MDS and acute myeloid leukemia (AML). A meta-analysis of 28 randomized control trials (RCT) with PARP inhibitors was done to evaluate risk of developing MDS and AML. Based on 18 RCTs with placebo control, PARP inhibitors increased risk of MDS and AML compared to placebo (Peto OR 2.63, p=0.026).  There was increased incidence of MDS and AML in the PARP inhibitor group compared to placebo (0.73% vs 0.47%). The median treatment duration was 9.8 months and median latency period since first exposure to a PARP inhibitor was 17.8 months. Use of PARP inhibitors is associated with increased risk of development of MDS and AML, and patients should be monitored accordingly.

Li et al looked at risk of thromboembolic disease in patients with RA within the first 5 years of diagnosis compared to those without RA. Using a population database in British Columbia, Canada, 39,142 RA patients were matched to 78,078 non-RA patients and those with prior venous thromboembolism (VTE) were excluded. Incidence rates of VTE, pulmonary embolism (PE), and deep venous thrombosis (DVT) were higher among the RA cohort than the non-RA cohort; this observation held true after adjusting for age, sex, glucocorticoid, and contraceptive use. It would be interesting to know if the increased risk holds true after control of inflammation (i.e. in patients with established RA in low vs. high disease activity states). In the absence of information about BMI and tobacco use, more studies are necessary to provide further support for this finding.

As noted above, RA is associated with cardiovascular disease (CVD), along with risk of death from cardiovascular complications. Because CVD is itself a risk factor for dementia, Sattui et al examined the potential for systemic inflammation and CVD to increase risk of developing dementia in RA patients. Using CMS claims data from 2006 to 2014, they studied 56,000 RA patients age 65 or older and looked at risk of dementia according to CVD status (no CVD or risk factors, CVD risk factors without disease, and CVD). Incidence rates for dementia were higher among RA patients with CVD risk factors than those without, and highest among RA patients with CVD. This effect was age-dependent, with a more significant risk among RA patients age 65-74, perhaps because of a general increase in dementia in older adults. As RA disease activity was not obtainable in this study, the effects of systemic inflammation are difficult to attribute. In addition, there may be some misclassification of data regarding coding of dementia subtypes (i.e. vascular and Alzheimer dementia). However, as there are limited studies in this area, this study provides credible evidence for an increase in dementia in RA patients with CVD, which should be further investigated.

Finally, hydroxychloroquine (HCQ) has come under increased scrutiny in the past year in terms of its potential use outside of treatment of lupus and RA as well as potential side effects. Cardiac toxicity related to HCQ is thought to be rare; Sorour et al looked at the association between chronic HCQ use in patients with RA and the development of heart failure (HF) using a retrospective study comparing patients who developed HF after RA diagnosis to those who did not develop HF. HCQ use was similar in both groups and a higher cumulative HCQ dose was not associated with increased risk of HF. As it is small and retrospective, larger prospective studies would be helpful, but this remains reassuring as to the safety of HCQ in RA patients.

Li et al looked at risk of thromboembolic disease in patients with RA within the first 5 years of diagnosis compared to those without RA. Using a population database in British Columbia, Canada, 39,142 RA patients were matched to 78,078 non-RA patients and those with prior venous thromboembolism (VTE) were excluded. Incidence rates of VTE, pulmonary embolism (PE), and deep venous thrombosis (DVT) were higher among the RA cohort than the non-RA cohort; this observation held true after adjusting for age, sex, glucocorticoid, and contraceptive use. It would be interesting to know if the increased risk holds true after control of inflammation (i.e. in patients with established RA in low vs. high disease activity states). In the absence of information about BMI and tobacco use, more studies are necessary to provide further support for this finding.

As noted above, RA is associated with cardiovascular disease (CVD), along with risk of death from cardiovascular complications. Because CVD is itself a risk factor for dementia, Sattui et al examined the potential for systemic inflammation and CVD to increase risk of developing dementia in RA patients. Using CMS claims data from 2006 to 2014, they studied 56,000 RA patients age 65 or older and looked at risk of dementia according to CVD status (no CVD or risk factors, CVD risk factors without disease, and CVD). Incidence rates for dementia were higher among RA patients with CVD risk factors than those without, and highest among RA patients with CVD. This effect was age-dependent, with a more significant risk among RA patients age 65-74, perhaps because of a general increase in dementia in older adults. As RA disease activity was not obtainable in this study, the effects of systemic inflammation are difficult to attribute. In addition, there may be some misclassification of data regarding coding of dementia subtypes (i.e. vascular and Alzheimer dementia). However, as there are limited studies in this area, this study provides credible evidence for an increase in dementia in RA patients with CVD, which should be further investigated.

Finally, hydroxychloroquine (HCQ) has come under increased scrutiny in the past year in terms of its potential use outside of treatment of lupus and RA as well as potential side effects. Cardiac toxicity related to HCQ is thought to be rare; Sorour et al looked at the association between chronic HCQ use in patients with RA and the development of heart failure (HF) using a retrospective study comparing patients who developed HF after RA diagnosis to those who did not develop HF. HCQ use was similar in both groups and a higher cumulative HCQ dose was not associated with increased risk of HF. As it is small and retrospective, larger prospective studies would be helpful, but this remains reassuring as to the safety of HCQ in RA patients.

Li et al looked at risk of thromboembolic disease in patients with RA within the first 5 years of diagnosis compared to those without RA. Using a population database in British Columbia, Canada, 39,142 RA patients were matched to 78,078 non-RA patients and those with prior venous thromboembolism (VTE) were excluded. Incidence rates of VTE, pulmonary embolism (PE), and deep venous thrombosis (DVT) were higher among the RA cohort than the non-RA cohort; this observation held true after adjusting for age, sex, glucocorticoid, and contraceptive use. It would be interesting to know if the increased risk holds true after control of inflammation (i.e. in patients with established RA in low vs. high disease activity states). In the absence of information about BMI and tobacco use, more studies are necessary to provide further support for this finding.

As noted above, RA is associated with cardiovascular disease (CVD), along with risk of death from cardiovascular complications. Because CVD is itself a risk factor for dementia, Sattui et al examined the potential for systemic inflammation and CVD to increase risk of developing dementia in RA patients. Using CMS claims data from 2006 to 2014, they studied 56,000 RA patients age 65 or older and looked at risk of dementia according to CVD status (no CVD or risk factors, CVD risk factors without disease, and CVD). Incidence rates for dementia were higher among RA patients with CVD risk factors than those without, and highest among RA patients with CVD. This effect was age-dependent, with a more significant risk among RA patients age 65-74, perhaps because of a general increase in dementia in older adults. As RA disease activity was not obtainable in this study, the effects of systemic inflammation are difficult to attribute. In addition, there may be some misclassification of data regarding coding of dementia subtypes (i.e. vascular and Alzheimer dementia). However, as there are limited studies in this area, this study provides credible evidence for an increase in dementia in RA patients with CVD, which should be further investigated.

Finally, hydroxychloroquine (HCQ) has come under increased scrutiny in the past year in terms of its potential use outside of treatment of lupus and RA as well as potential side effects. Cardiac toxicity related to HCQ is thought to be rare; Sorour et al looked at the association between chronic HCQ use in patients with RA and the development of heart failure (HF) using a retrospective study comparing patients who developed HF after RA diagnosis to those who did not develop HF. HCQ use was similar in both groups and a higher cumulative HCQ dose was not associated with increased risk of HF. As it is small and retrospective, larger prospective studies would be helpful, but this remains reassuring as to the safety of HCQ in RA patients.

Breast cancer patients treated with curative intent do not often experience symptoms related to the cancer itself, and treatment toxicities may impact adherence and subsequently prognosis. Mittendorf et al reported on patient reported outcomes (PROs) from the phase 3 IMpassion031 trial which showed pCR improvement with atezolizumab/chemotherapy compared to placebo/chemotherapy for neoadjuvant early-stage TNBC. Health-related quality of life items and treatment-related symptoms worsened similarly in both arms during neoadjuvant therapy, and recovered/stabilized in the adjuvant setting. Further exploration of immunotherapy PROs is warranted, as clinical benefit is seen with these agents and they do not appear to negatively impact functioning and patient experience with treatment long-term. Side effect profiles of immunotherapy and standard chemotherapy are different, and design of immunotherapy-specific PROs are desired.

The PRIME 2 10 year results evaluating the role of whole breast irradiation in women ≥65 years with early-stage HR-positive breast cancer receiving hormonal therapy showed RT reduced risk of local recurrence from 9.8% to 0.9% at 10 years (p=0.0008). Patients with low ER tumors had higher 10 year local recurrence rate compared to high ER tumors (18.8% versus 9.2% (p0.007)). Rates of overall survival (80.4% in no RT group vs 81.0% in RT group) and metastasis free survival were similar. A shared decision making approach is key, carefully weighing benefits and risks, considering pathologic features, patient preferences and co-morbidities that may influence endocrine therapy adherence. The impact of molecular subtypes and genomic assays is also being explored to help assess radiation benefit and guide treatment recommendations.

Breast cancer in young women presents unique challenges considering the lifetime period during which diagnosis occurs. Previous studies have supported the safety of pregnancy after breast cancer and guidelines recommend oncofertility counseling in young patients. Blondeaux et al found that breast cancer patients had a 60% lower chance of pregnancy after treatment and were more likely to have complications including low birth weight, small for gestational age, preterm delivery and cesarean section. Although increased risk of congenital abnormalities did not appear to be statistically significant, the HR was 1.63. Importantly, pregnancy after breast cancer did not negatively impact maternal outcomes. This study further supports the safety of pregnancy after breast cancer, highlights the need for close monitoring of pregnancies in these women, and emphasizes the importance of fertility and family planning discussion, which is most optimally provided in a multidisciplinary fashion.

References:

Dent R, Oliveira AM, Isakoff SJ, Im SA, Espié M, Blau S, Saura C, Wongchenko MJ, Xu N, Bradley D, Reilly SJ, Mani A, Kim SB. Final results of the double-blind placebo (PBO)-controlled randomised phase II LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for inoperable locally advanced/metastatic triple-negative breast cancer (mTNBC). Presented during 2020 ESMO breast cancer virtual meeting; May 23-24, 2020. Abstract 139O.

Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, Baird RD, Park YH, Hall PS, Perren T, Stein RC, Mangel L, Ferrero JM, Phillips M, Conibear J, Cortes J, Foxley A, de Bruin EC, McEwen R, Stetson D, Dougherty B, Sarker SJ, Prendergast A, McLaughlin-Callan M, Burgess M, Lawrence C, Cartwright H, Mousa K, Turner NC. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol. 2020;38:423-433.

Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396:1090-1100.

King-Kallimanis BL, Howie LJ, Roydhouse JK, Singh H, Theoret MR, Blumenthal GM, Kluetz PG. Patient reported outcomes in anti-PD-1/PD-L1 inhibitor immunotherapy registration trials: FDA analysis of data submitted and future directions. Clin Trials. 2019;16:322-326.

Fodor A, Brombin C, Mangili P, Borroni F, Pasetti M, Tummineri R, Zerbetto F, Longobardi B, Perna L, Dell'Oca I, Deantoni CL, Deli AM, Chiara A, Broggi S, Castriconi R, Esposito PG, Slim N, Passoni P, Baroni S, Villa SL, Rancoita PMV, Fiorino C, Del Vecchio A, Bianchini G, Gentilini OD, Di Serio MS, Di Muzio NG. Impact of molecular subtype on 1325 early-stage breast cancer patients homogeneously treated with hypofractionated radiotherapy without boost: Should the indications for radiotherapy be more personalized? Breast. 2020;55:45-54.

Azim HA Jr, Santoro L, Pavlidis N, Gelber S, Kroman N, Azim H, Peccatori FA. Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies. Eur J Cancer. 2011;47:74-83.

Breast cancer patients treated with curative intent do not often experience symptoms related to the cancer itself, and treatment toxicities may impact adherence and subsequently prognosis. Mittendorf et al reported on patient reported outcomes (PROs) from the phase 3 IMpassion031 trial which showed pCR improvement with atezolizumab/chemotherapy compared to placebo/chemotherapy for neoadjuvant early-stage TNBC. Health-related quality of life items and treatment-related symptoms worsened similarly in both arms during neoadjuvant therapy, and recovered/stabilized in the adjuvant setting. Further exploration of immunotherapy PROs is warranted, as clinical benefit is seen with these agents and they do not appear to negatively impact functioning and patient experience with treatment long-term. Side effect profiles of immunotherapy and standard chemotherapy are different, and design of immunotherapy-specific PROs are desired.

The PRIME 2 10 year results evaluating the role of whole breast irradiation in women ≥65 years with early-stage HR-positive breast cancer receiving hormonal therapy showed RT reduced risk of local recurrence from 9.8% to 0.9% at 10 years (p=0.0008). Patients with low ER tumors had higher 10 year local recurrence rate compared to high ER tumors (18.8% versus 9.2% (p0.007)). Rates of overall survival (80.4% in no RT group vs 81.0% in RT group) and metastasis free survival were similar. A shared decision making approach is key, carefully weighing benefits and risks, considering pathologic features, patient preferences and co-morbidities that may influence endocrine therapy adherence. The impact of molecular subtypes and genomic assays is also being explored to help assess radiation benefit and guide treatment recommendations.

Breast cancer in young women presents unique challenges considering the lifetime period during which diagnosis occurs. Previous studies have supported the safety of pregnancy after breast cancer and guidelines recommend oncofertility counseling in young patients. Blondeaux et al found that breast cancer patients had a 60% lower chance of pregnancy after treatment and were more likely to have complications including low birth weight, small for gestational age, preterm delivery and cesarean section. Although increased risk of congenital abnormalities did not appear to be statistically significant, the HR was 1.63. Importantly, pregnancy after breast cancer did not negatively impact maternal outcomes. This study further supports the safety of pregnancy after breast cancer, highlights the need for close monitoring of pregnancies in these women, and emphasizes the importance of fertility and family planning discussion, which is most optimally provided in a multidisciplinary fashion.

References:

Dent R, Oliveira AM, Isakoff SJ, Im SA, Espié M, Blau S, Saura C, Wongchenko MJ, Xu N, Bradley D, Reilly SJ, Mani A, Kim SB. Final results of the double-blind placebo (PBO)-controlled randomised phase II LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for inoperable locally advanced/metastatic triple-negative breast cancer (mTNBC). Presented during 2020 ESMO breast cancer virtual meeting; May 23-24, 2020. Abstract 139O.

Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, Baird RD, Park YH, Hall PS, Perren T, Stein RC, Mangel L, Ferrero JM, Phillips M, Conibear J, Cortes J, Foxley A, de Bruin EC, McEwen R, Stetson D, Dougherty B, Sarker SJ, Prendergast A, McLaughlin-Callan M, Burgess M, Lawrence C, Cartwright H, Mousa K, Turner NC. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol. 2020;38:423-433.

Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396:1090-1100.

King-Kallimanis BL, Howie LJ, Roydhouse JK, Singh H, Theoret MR, Blumenthal GM, Kluetz PG. Patient reported outcomes in anti-PD-1/PD-L1 inhibitor immunotherapy registration trials: FDA analysis of data submitted and future directions. Clin Trials. 2019;16:322-326.

Fodor A, Brombin C, Mangili P, Borroni F, Pasetti M, Tummineri R, Zerbetto F, Longobardi B, Perna L, Dell'Oca I, Deantoni CL, Deli AM, Chiara A, Broggi S, Castriconi R, Esposito PG, Slim N, Passoni P, Baroni S, Villa SL, Rancoita PMV, Fiorino C, Del Vecchio A, Bianchini G, Gentilini OD, Di Serio MS, Di Muzio NG. Impact of molecular subtype on 1325 early-stage breast cancer patients homogeneously treated with hypofractionated radiotherapy without boost: Should the indications for radiotherapy be more personalized? Breast. 2020;55:45-54.

Azim HA Jr, Santoro L, Pavlidis N, Gelber S, Kroman N, Azim H, Peccatori FA. Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies. Eur J Cancer. 2011;47:74-83.

Breast cancer patients treated with curative intent do not often experience symptoms related to the cancer itself, and treatment toxicities may impact adherence and subsequently prognosis. Mittendorf et al reported on patient reported outcomes (PROs) from the phase 3 IMpassion031 trial which showed pCR improvement with atezolizumab/chemotherapy compared to placebo/chemotherapy for neoadjuvant early-stage TNBC. Health-related quality of life items and treatment-related symptoms worsened similarly in both arms during neoadjuvant therapy, and recovered/stabilized in the adjuvant setting. Further exploration of immunotherapy PROs is warranted, as clinical benefit is seen with these agents and they do not appear to negatively impact functioning and patient experience with treatment long-term. Side effect profiles of immunotherapy and standard chemotherapy are different, and design of immunotherapy-specific PROs are desired.

The PRIME 2 10 year results evaluating the role of whole breast irradiation in women ≥65 years with early-stage HR-positive breast cancer receiving hormonal therapy showed RT reduced risk of local recurrence from 9.8% to 0.9% at 10 years (p=0.0008). Patients with low ER tumors had higher 10 year local recurrence rate compared to high ER tumors (18.8% versus 9.2% (p0.007)). Rates of overall survival (80.4% in no RT group vs 81.0% in RT group) and metastasis free survival were similar. A shared decision making approach is key, carefully weighing benefits and risks, considering pathologic features, patient preferences and co-morbidities that may influence endocrine therapy adherence. The impact of molecular subtypes and genomic assays is also being explored to help assess radiation benefit and guide treatment recommendations.

Breast cancer in young women presents unique challenges considering the lifetime period during which diagnosis occurs. Previous studies have supported the safety of pregnancy after breast cancer and guidelines recommend oncofertility counseling in young patients. Blondeaux et al found that breast cancer patients had a 60% lower chance of pregnancy after treatment and were more likely to have complications including low birth weight, small for gestational age, preterm delivery and cesarean section. Although increased risk of congenital abnormalities did not appear to be statistically significant, the HR was 1.63. Importantly, pregnancy after breast cancer did not negatively impact maternal outcomes. This study further supports the safety of pregnancy after breast cancer, highlights the need for close monitoring of pregnancies in these women, and emphasizes the importance of fertility and family planning discussion, which is most optimally provided in a multidisciplinary fashion.

References:

Dent R, Oliveira AM, Isakoff SJ, Im SA, Espié M, Blau S, Saura C, Wongchenko MJ, Xu N, Bradley D, Reilly SJ, Mani A, Kim SB. Final results of the double-blind placebo (PBO)-controlled randomised phase II LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for inoperable locally advanced/metastatic triple-negative breast cancer (mTNBC). Presented during 2020 ESMO breast cancer virtual meeting; May 23-24, 2020. Abstract 139O.

Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, Baird RD, Park YH, Hall PS, Perren T, Stein RC, Mangel L, Ferrero JM, Phillips M, Conibear J, Cortes J, Foxley A, de Bruin EC, McEwen R, Stetson D, Dougherty B, Sarker SJ, Prendergast A, McLaughlin-Callan M, Burgess M, Lawrence C, Cartwright H, Mousa K, Turner NC. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol. 2020;38:423-433.

Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396:1090-1100.

King-Kallimanis BL, Howie LJ, Roydhouse JK, Singh H, Theoret MR, Blumenthal GM, Kluetz PG. Patient reported outcomes in anti-PD-1/PD-L1 inhibitor immunotherapy registration trials: FDA analysis of data submitted and future directions. Clin Trials. 2019;16:322-326.

Fodor A, Brombin C, Mangili P, Borroni F, Pasetti M, Tummineri R, Zerbetto F, Longobardi B, Perna L, Dell'Oca I, Deantoni CL, Deli AM, Chiara A, Broggi S, Castriconi R, Esposito PG, Slim N, Passoni P, Baroni S, Villa SL, Rancoita PMV, Fiorino C, Del Vecchio A, Bianchini G, Gentilini OD, Di Serio MS, Di Muzio NG. Impact of molecular subtype on 1325 early-stage breast cancer patients homogeneously treated with hypofractionated radiotherapy without boost: Should the indications for radiotherapy be more personalized? Breast. 2020;55:45-54.

Azim HA Jr, Santoro L, Pavlidis N, Gelber S, Kroman N, Azim H, Peccatori FA. Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies. Eur J Cancer. 2011;47:74-83.

The availability of biologic DMARDs such as TNF-alpha inhibitors has expanded the therapies available to patient with RA. However, these agents have been associated with immunogenicity and the development of anti-drug antibodies that can in turn be associated with allergic reactions as well as secondary non-response to the medication. This observational study analyzes the potential relationship between the presence of anti-nuclear antibodies before and after administration of different TNF-alpha inhibitors (infliximab (IFX), adalimumab (ADA), and etanercept (ADA)) with the development of anti-drug antibodies, with the aim of predicting treatment failure. Interestingly, patients who were ANA negative (by immunofluorescence) prior to initiation of therapy did not develop antibodies to ADA or IFX (antibodies to ETN were not measured). How this is related to treatment efficacy is not clear; more patients who had anti-drug antibodies discontinued therapy within 52 weeks and were classified as non-responders to therapy, but whether there was a secondary non-response was not examined in this study. As many patients with RA are also ANA positive and have SSA antibodies, these findings could potentially greatly alter treatment algorithms if proven in longer-term randomized trials and should be examined in other biologic DMARDs as well.

The Leiden Early Arthritis Cohort (EAC) is an inception cohort that was established to study inflammatory arthritis early in the disease state, with a particular interest in RA. This cross-sectional study evaluates the frequency of intermetatarsal and submetatarsal bursitis (IMB and SMB) in early RA. The presence of these forefoot disorders on MRI was evaluated in 441 consecutive patients presenting to the EAC and in 193 healthy controls. IMB and SMB were found more frequently in RA than in other inflammatory arthritides or healthy controls, with a specificity of 70-97%. Sensitivity was higher for IMB than SMB. While the study was not designed to evaluate MRI of the forefoot as a predictive test for development of RA, these findings raise the possibility that this could be used as a diagnostic test in early arthritis and would be worthwhile studying prospectively.

Another question with regard to prediction of response of RA to therapy is that of the possibility of maintaining sustained DMARD-free remission (SDFR). Another study from the Leiden EAC examined 772 RA patients treated with synthetic and biologic DMARDs who had achieved clinical remission (DAS < 2.4) without synovitis. Taper and discontinuation of therapy was attempted, and patients were followed to evaluate whether absence of synovitis on exam was sustained on followup for at least 1 year. Of these patients, 149 achieved SDFR within 7 years of followup; 130 of these patients were seronegative for ACPA. Baseline DAS was similar between patients who did and did not achieve SDFR, but a better early DAS response (larger decrease between baseline and 4 months) was associated an increased chance of SDFR. As the study is observational without a control, it is hard to evaluate how SDFR may proceed in the natural course of the disease. Although the importance of treatment response at 4 months places a premium on early reduction of inflammation, achievement of SDFR in these patients may also be related to other baseline characteristics of the group, especially as ACPA-positive patients less frequently achieved SDFR.

The availability of biologic DMARDs such as TNF-alpha inhibitors has expanded the therapies available to patient with RA. However, these agents have been associated with immunogenicity and the development of anti-drug antibodies that can in turn be associated with allergic reactions as well as secondary non-response to the medication. This observational study analyzes the potential relationship between the presence of anti-nuclear antibodies before and after administration of different TNF-alpha inhibitors (infliximab (IFX), adalimumab (ADA), and etanercept (ADA)) with the development of anti-drug antibodies, with the aim of predicting treatment failure. Interestingly, patients who were ANA negative (by immunofluorescence) prior to initiation of therapy did not develop antibodies to ADA or IFX (antibodies to ETN were not measured). How this is related to treatment efficacy is not clear; more patients who had anti-drug antibodies discontinued therapy within 52 weeks and were classified as non-responders to therapy, but whether there was a secondary non-response was not examined in this study. As many patients with RA are also ANA positive and have SSA antibodies, these findings could potentially greatly alter treatment algorithms if proven in longer-term randomized trials and should be examined in other biologic DMARDs as well.

The Leiden Early Arthritis Cohort (EAC) is an inception cohort that was established to study inflammatory arthritis early in the disease state, with a particular interest in RA. This cross-sectional study evaluates the frequency of intermetatarsal and submetatarsal bursitis (IMB and SMB) in early RA. The presence of these forefoot disorders on MRI was evaluated in 441 consecutive patients presenting to the EAC and in 193 healthy controls. IMB and SMB were found more frequently in RA than in other inflammatory arthritides or healthy controls, with a specificity of 70-97%. Sensitivity was higher for IMB than SMB. While the study was not designed to evaluate MRI of the forefoot as a predictive test for development of RA, these findings raise the possibility that this could be used as a diagnostic test in early arthritis and would be worthwhile studying prospectively.

Another question with regard to prediction of response of RA to therapy is that of the possibility of maintaining sustained DMARD-free remission (SDFR). Another study from the Leiden EAC examined 772 RA patients treated with synthetic and biologic DMARDs who had achieved clinical remission (DAS < 2.4) without synovitis. Taper and discontinuation of therapy was attempted, and patients were followed to evaluate whether absence of synovitis on exam was sustained on followup for at least 1 year. Of these patients, 149 achieved SDFR within 7 years of followup; 130 of these patients were seronegative for ACPA. Baseline DAS was similar between patients who did and did not achieve SDFR, but a better early DAS response (larger decrease between baseline and 4 months) was associated an increased chance of SDFR. As the study is observational without a control, it is hard to evaluate how SDFR may proceed in the natural course of the disease. Although the importance of treatment response at 4 months places a premium on early reduction of inflammation, achievement of SDFR in these patients may also be related to other baseline characteristics of the group, especially as ACPA-positive patients less frequently achieved SDFR.

The availability of biologic DMARDs such as TNF-alpha inhibitors has expanded the therapies available to patient with RA. However, these agents have been associated with immunogenicity and the development of anti-drug antibodies that can in turn be associated with allergic reactions as well as secondary non-response to the medication. This observational study analyzes the potential relationship between the presence of anti-nuclear antibodies before and after administration of different TNF-alpha inhibitors (infliximab (IFX), adalimumab (ADA), and etanercept (ADA)) with the development of anti-drug antibodies, with the aim of predicting treatment failure. Interestingly, patients who were ANA negative (by immunofluorescence) prior to initiation of therapy did not develop antibodies to ADA or IFX (antibodies to ETN were not measured). How this is related to treatment efficacy is not clear; more patients who had anti-drug antibodies discontinued therapy within 52 weeks and were classified as non-responders to therapy, but whether there was a secondary non-response was not examined in this study. As many patients with RA are also ANA positive and have SSA antibodies, these findings could potentially greatly alter treatment algorithms if proven in longer-term randomized trials and should be examined in other biologic DMARDs as well.

The Leiden Early Arthritis Cohort (EAC) is an inception cohort that was established to study inflammatory arthritis early in the disease state, with a particular interest in RA. This cross-sectional study evaluates the frequency of intermetatarsal and submetatarsal bursitis (IMB and SMB) in early RA. The presence of these forefoot disorders on MRI was evaluated in 441 consecutive patients presenting to the EAC and in 193 healthy controls. IMB and SMB were found more frequently in RA than in other inflammatory arthritides or healthy controls, with a specificity of 70-97%. Sensitivity was higher for IMB than SMB. While the study was not designed to evaluate MRI of the forefoot as a predictive test for development of RA, these findings raise the possibility that this could be used as a diagnostic test in early arthritis and would be worthwhile studying prospectively.

Another question with regard to prediction of response of RA to therapy is that of the possibility of maintaining sustained DMARD-free remission (SDFR). Another study from the Leiden EAC examined 772 RA patients treated with synthetic and biologic DMARDs who had achieved clinical remission (DAS < 2.4) without synovitis. Taper and discontinuation of therapy was attempted, and patients were followed to evaluate whether absence of synovitis on exam was sustained on followup for at least 1 year. Of these patients, 149 achieved SDFR within 7 years of followup; 130 of these patients were seronegative for ACPA. Baseline DAS was similar between patients who did and did not achieve SDFR, but a better early DAS response (larger decrease between baseline and 4 months) was associated an increased chance of SDFR. As the study is observational without a control, it is hard to evaluate how SDFR may proceed in the natural course of the disease. Although the importance of treatment response at 4 months places a premium on early reduction of inflammation, achievement of SDFR in these patients may also be related to other baseline characteristics of the group, especially as ACPA-positive patients less frequently achieved SDFR.

Higher expression of Wilms’ tumor 1 (WT-1) has been associated with poor survival in MDS. To further characterize the prognostic value of WT-1 expression level, peripheral WT-1 mRNA expression level at baseline was measured in MDS patients undergoing treatment with azacitidine. Lower WT-1 mRNA level was associated with higher overall response, as defined by CR, marrow CR, partial response, or HI (p=0.03), although WT-1 mRNA level did not show difference in overall survival. This was a small retrospective, single center study; role of WT-1 mRNA level as a biomarker for response to azacitidine should be further investigated.

Results of a multi-center trial comparing reduced intensity allogeneic stem cell transplant (SCT) to hypomethylating agents or best supportive care in higher risk MDS patients aged 50-75 was reported in the annual meeting of the American Society of Hematology in 2020. Patients with intermediate-2 or higher risk by IPSS were assigned based on SCT or no SCT arm based on donor status, and patients who had donor proceeded to reduced intensity SCT within 6 months of enrolment. In an intent-to-treat analysis, the study showed different in 3-year overall survival, which was the primary endpoint between SCT vs non-SCT arms (47.9% vs 26.6%, p=0.0001). Leukemia-free survival at 3 years was also greater for the SCT arm (35.8% vs 20.6%, p=0.003). Allogenic stem cell transplant is currently offered to patients with higher risk MDS given this is the only potential curable approach for MDS patients. This study further supports allogeneic stem cell transplant for older patients with higher risk MDS.

Higher expression of Wilms’ tumor 1 (WT-1) has been associated with poor survival in MDS. To further characterize the prognostic value of WT-1 expression level, peripheral WT-1 mRNA expression level at baseline was measured in MDS patients undergoing treatment with azacitidine. Lower WT-1 mRNA level was associated with higher overall response, as defined by CR, marrow CR, partial response, or HI (p=0.03), although WT-1 mRNA level did not show difference in overall survival. This was a small retrospective, single center study; role of WT-1 mRNA level as a biomarker for response to azacitidine should be further investigated.

Results of a multi-center trial comparing reduced intensity allogeneic stem cell transplant (SCT) to hypomethylating agents or best supportive care in higher risk MDS patients aged 50-75 was reported in the annual meeting of the American Society of Hematology in 2020. Patients with intermediate-2 or higher risk by IPSS were assigned based on SCT or no SCT arm based on donor status, and patients who had donor proceeded to reduced intensity SCT within 6 months of enrolment. In an intent-to-treat analysis, the study showed different in 3-year overall survival, which was the primary endpoint between SCT vs non-SCT arms (47.9% vs 26.6%, p=0.0001). Leukemia-free survival at 3 years was also greater for the SCT arm (35.8% vs 20.6%, p=0.003). Allogenic stem cell transplant is currently offered to patients with higher risk MDS given this is the only potential curable approach for MDS patients. This study further supports allogeneic stem cell transplant for older patients with higher risk MDS.

Higher expression of Wilms’ tumor 1 (WT-1) has been associated with poor survival in MDS. To further characterize the prognostic value of WT-1 expression level, peripheral WT-1 mRNA expression level at baseline was measured in MDS patients undergoing treatment with azacitidine. Lower WT-1 mRNA level was associated with higher overall response, as defined by CR, marrow CR, partial response, or HI (p=0.03), although WT-1 mRNA level did not show difference in overall survival. This was a small retrospective, single center study; role of WT-1 mRNA level as a biomarker for response to azacitidine should be further investigated.

Results of a multi-center trial comparing reduced intensity allogeneic stem cell transplant (SCT) to hypomethylating agents or best supportive care in higher risk MDS patients aged 50-75 was reported in the annual meeting of the American Society of Hematology in 2020. Patients with intermediate-2 or higher risk by IPSS were assigned based on SCT or no SCT arm based on donor status, and patients who had donor proceeded to reduced intensity SCT within 6 months of enrolment. In an intent-to-treat analysis, the study showed different in 3-year overall survival, which was the primary endpoint between SCT vs non-SCT arms (47.9% vs 26.6%, p=0.0001). Leukemia-free survival at 3 years was also greater for the SCT arm (35.8% vs 20.6%, p=0.003). Allogenic stem cell transplant is currently offered to patients with higher risk MDS given this is the only potential curable approach for MDS patients. This study further supports allogeneic stem cell transplant for older patients with higher risk MDS.