Jaime Rosenberg

As the promise of gene-specific therapies continues to unfold for neurological disorders, such as 

 (SMA), a group of researchers reviewed the latest 

Approaches to such therapy typically span 3 classes—RNA interference by antisense oligonucleotides (ASOs) or small interfering RNAs, splice modification by small molecules, and gene (transfer) therapy.

There are several treatments that have made their mark in the SMA space, including the ASO nusinersen, and small molecule risdiplam, which both entered the market and specifically mediate the inclusion of exon 7 into the mature 

While nusinersen is administered intrathecally every 4 months following a 1-year dosing phase, risdiplam is given orally and, according to researchers, could in principle reach all tissues of the body. Fornusinersen, approval for all forms of SMA is expected soon.

Meanwhile, the investigational small molecule branaplam is currently being studied in a phase 1/2 trial.

Although these therapies continue to revolutionize the treatment landscape for SMA, they are not without shortcomings or challenges, researchers yielded. “Although optimism regarding gene-specific therapies is justified, we may not forget that they are still in their infancy and must be considerably improved in many aspects,” they wrote.

For example, most ASOs currently need to be administered intrathecally, which the researchers note presents stress for the patient and creates an infrastructural and financial burden. As a result, the researchers say the success of these therapies relies on the development of suitable vector platforms and conjugate substances capable of penetrating brain or muscle tissue following systemic administration.

Among the most notable approvals for SMA is 

onasemnogene abeparvovec-xioi (Zolgensma)

, the first gene therapy approved by the FDA for this population. While the treatment is approved for use in patients with SMA type 1 who are under age 2 without end-stage weakness, a study assessing intrathecal administration of a single dose of the gene therapy was halted by the FDA based on a preclinical study showing dorsal root ganglia mononuclear cell inflammation in non-human primates.

The advent of gene therapies also brings questions regarding genetic testing along with the dilemma of who should be screened.

“While it is unquestionable that newborns should be screened for treatable infantile onset genetic diseases (such as SMA), many questions related to genetic testing of adult-onset genetic diseases for which gene-specific therapies exist remain unresolved,” researchers wrote. “Who shall be tested – only members of families with a known genetic disease or also sporadic patients without a family history? Who shall be treated?”

Brenner D, Ludolph AC, and Weishaupt JH. Gene specific therapies – the next therapeutic milestone in neurology. 

. 2020;2:25. doi:10.1186/s42466-020-00075-z

Articles

While these therapies continue to revolutionize the treatment landscape of SMA, treatments are not without shortcomings or challenges. 

Emergence of Gene-Specific Therapies for SMA Brings Promise, Questions

With emerging evidence suggesting that the impact of survival motor neuron (SMN) deficiency extends past motor neurons in patients with 

 on metabolic and nutritional issues associated with the condition.

Documented issues include lipid metabolic abnormalities, glucose metabolic abnormalities, and altered vitamin levels.

“Active nutrition support and metabolism surveillance are crucial for patients with SMA, and a comprehensive nutritional assessment could guide individualized nutrition therapy for this vulnerable population,” commented the researchers. “With the emergence of new gene-targeted and disease-modifying therapies, which may affect the metabolism of SMA patients, personalized nutritional optimization may become particularly important.”

The most commonly studied nutritional issue in SMA is dysregulated lipid metabolism, with abnormal levels of fatty acid oxidation metabolites—particularly dicarboxylic aciduria and esterified carnitine—detailed in several studies of patients with severe SMA type. Since these first reports, subsequent research has indicated that the condition likely causes metabolic defects involving fatty acid metabolism.

According to the researchers, there have been several serum fatty acids and lipids identified as correlated to motor function in SMA, which may have the potential to be leveraged as biomarkers in the condition.

Additional findings on altered lipid metabolism include:

Increased urine dicarboxylic acids in both fed and fasting states, especially in the longer-chain (C10 and C22) 3-hydroxydicarboxylic acids, in a 9-month-old patient with SMA type 1

Abnormal excretion of ethylmalonic acid from urine organic acids, reduced carnitine levels in serum, and increased excretion of urinary acylcarnitines across 14 patients with SMA type 2

Reductions in muscle mass, physical stress, and defects in fatty acid metabolism may cause hypoglycemia and non-diabetic ketoacidosis, according to a case report of a patient with SMA type 2

Several case studies and cross-sectional studies also highlighted an altered glucose metabolism in patients with SMA. Hypoglycemia was found across patients, explained in some cases by “reduced muscle protein, leading to lower availability of amino acids (alanine) as substrates for gluconeogenesis in the liver.”

The researchers noted that there have been indications among patients receiving SMN restoration therapy that it may increase the risk of pancreatic and glucose metabolism defects, suggesting the need for close monitoring of glucose homeostasis in patients to better determine the role of SMN in glucose metabolism and pancreatic function.

SMA has also been reported to impact levels of vitamin E, vitamin K, folate intakes, vitamin D, and calcium.

“The SMN protein may play an active role in bone remodeling or uptake of vitamin D and calcium; therefore, patients with SMA are often accompanied by osteopenia and may contend with fractures due to minor injuries,” said the researchers, writing that suboptimal vitamin D intake is often observed in patients with SMA. 

“Compared with other neuromuscular disorders, reduced bone mineral density seems more significant in patients with SMA, especially in those losing ambulatory function.”

Li Y, Chen T, Wu Y, Tseng Y. Metabolic and nutritional issues associated with spinal muscular atrophy. 

. 2020;12(12):3842. doi:10.3390/nu12123842

Documented issues include lipid metabolic abnormalities, glucose metabolic abnormalities, and altered vitamin levels. 

SMA Associated With Metabolic, Nutritional Issues   

A Look at Established, Emerging Biomarkers for I-O Therapy in Breast Cancer

Research focused on leveraging immuno-oncology (I-O) in breast cancer has been rampant in recent years, with 17,000 related manuscripts having been published in the past 2 years alone, explained Lajos Pusztai, MD, DPhil, professor of medicine at Yale Cancer Center, during a session at the San Antonio Breast Cancer Symposium 2020.

Throughout the session, Pusztai provided an overview of newly established and emerging biomarkers in both the neoadjuvant and metastatic breast cancer settings.

Notable differences in the neoadjuvant treatment strategy versus therapy for metastatic disease can be highlighted from the use of PD-1/PD-L1 immune checkpoint inhibitors, explained Pusztai, noting that PD-L1 expression does not hold as much weight in the neoadjuvant setting as it does in the metastatic setting.

In the neoadjuvant treatment setting, Pusztai provided the examples of the KEYNOTE-522 and IMpassion031 trials, which both demonstrated benefit of (I-O) therapy in patients, regardless of PD-L1 expression. In the phase 3 KEYNOTE-522 study, which assessed pembrolizumab plus chemotherapy in patients with triple-negative breast cancer (TNBC), the combination was favorable to chemotherapy alone for both PD-L1 positive (68.9% vs 54.9%) and PD-L1 negative (45.3% vs 30.3%) patients.

In the IMpassion031 study of atezolizumab plus chemotherapy, the combination elicited improved complete response rates vs chemotherapy alone for both PD-L1 positive (69% vs 49%) and PD-L1 negative patients (48% vs 34%).

Meanwhile, when administered in the metastatic setting, PD-L1 expression is all but required for response to I-O treatment, said Pusztai. For example, in the KEYNOTE-119 trial, while pembrolizumab was not found to be superior to chemotherapy, the study did show a “remarkably close” correlation between benefit with pembrolizumab and PD-L1 expression.

 In fact, in the group with the highest PD-L1 expression (combined positive score [CPS] ≥20), response rates were 26.3% compared with 11.5% for chemotherapy alone. These patients accounted for 18% of the study population.

Similarly, the KEYNOTE-355 trial confirmed the benefit of adding pembrolizumab to chemotherapy in first-line treatment of patients with metastatic TNBC,

	leading to FDA approval of the immunotherapy for patients with CPS≥10.

Atezolizumab, the first FDA-approved immune checkpoint inhibitor in breast cancer, showed a benefit in PD-L1 expression in the IMpassion130 trial, in which the treatment in combination with nab-paclitaxel led to improved response rates compared with nab-paclitaxel alone in metastatic TNBC for the subset of patients who were PD-L1 positive.

Pusztai noted that in this study, it became evident that choice of PD-L1 immunohistochemistry assay matters. Using the threshold of CPS≥1, researchers found that the SP142 assay identified the fewest positive patients but had the highest accuracy, confirming the notion that high PD-L1 expression is needed for benefit of an I-O.

“It is clear that in the neoadjuvant treatment setting PD-L1 expression is not required for benefit from anti-PD1/PD-L1 therapy with chemo whereas in the metastatic setting, PD-L1 expression is required,” said Pusztai, who left the audience with a question of, “Why?”

To answer just that, Pusztai and a group of researchers analyzed the microenvironment of primary and metastatic tissues. Their research compared a “fit” immune microenvironment of a primary tumor, with a few scattered immune cells that can ignite an immune response, with that of an immune attenuated metastatic lesion, where a massive immune presence is needed to mount effective immune response.

Pusztai explained that there are several immunophenotypic markers being explored. Certain research has focused on the potential use of imaging analysis techniques to query whether the proximity of tumor and immune cells or the semi-quantitative analysis of different immune cell types and their ratios could serve as response markers. For example, in the I-SPY trial consortium, researchers found several correlations including that greater T cell-to-tumor cell density is associated with a pathologic complete response (pCR), as is greater PD-1 tumor cell to PD-L1 immune cell proximity.

Another line of investigation has focused on what researchers can learn from exceptionally resistant breast cancer cases.

In ER+ early-stage disease, Pusztai says researchers may have found a way to identify which patients need an immune checkpoint inhibitor added to their neoadjuvant chemotherapy to maximize response rate. In the I-SPY 2 trial, both pembrolizumab and durvalumab plus olaparib increased pCR rates when combined with paclitaxel in ER+/HER2- patients.

Among those who are ER+, they compared different patients who received MammaPrint, a prognostic and predictive diagnostic test for breast cancer that assesses the risk that a tumor will metastasize to other parts of the body. Patients who were “MammaPrint ultra high,” or MP2, had increased pCR rates, while the MP1 group had the same pCR rate seen with chemotherapy alone.

Researchers looked further to see what molecular features characterized this MP2 subset, finding that a low sensitivity to endocrine therapy gene signature and high expression of proliferation genes are the hallmarks of the group.

Several other biomarkers are being explored for identifying patients with metastatic breast cancer that can benefit from immune checkpoint therapy. These biomarkers include microsatellite instability, high tumor mutation burden, and tumor PD-L1 gene copy number gain/amplification.

1. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. 

. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549

2. Mittendorf EA, Zhang H, Barrios CH, et al. 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. 

. 2020;396(10257):1090-1100. doi:10.1016/S0140-6736(20)31953-X

3. Cortes J, Lipatov O, Im SA, et al. KEYNOTE-119: Phase III study of pembrolizumab (pembro) versus single-agent chemotherapy (chemo) for metastatic triple negative breast cancer (mTNBC). 

. 2019;30(5):v859-v860. doi:10.1093/annonc/mdz394.010

4. Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. 

. 2020;38(15):1000. doi:10.1200/JCO.2020.38.15_suppl.1000

5. Schmid P, Rugo HS, Adams S, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. 

 2020;21(1):44-59. doi:10.1016/S1470-2045(19)30689-8

6. Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. 

 2020;6(5):676-684. doi:10.1001/jamaoncol.2019.6650

7. I-SPY2 TRIAL demonstrates significant improvement in pCR with durvalumab and olaparib with paclitaxel, (compared to chemotherapy alone) in women with stage II/III high-risk, HER2-negative breast cancer, in HR+ and TNBC subsets. News release. Quantum Leap Healthcare Collaborative. April 27, 2020. Accessed December 9, 2020. https://www.prnewswire.com/news-releases/i-spy2-trial-demonstrates-significant-improvement-in-pcr-with-durvalumab-and-olaparib-with-paclitaxel-compared-to-chemotherapy-alone-in-women-with-stage-iiiii-high-riskher2-negative-breast-cancer-in-hr-and-tnbc-subsets-301047042.html

Should All Patients With Breast Cancer Receive Genetic Testing?

In light of the 30th anniversary of Mary-Claire King, PhD, mapping 

, a session on the final day of the 2020 San Antonio Breast Cancer Symposium (SABCS) begged the question: Should all women with breast cancer receive genetic testing?

Recent years have seen calls for genetic testing for all patients with breast cancer, most notably from the American Society of Breast Surgeons, which issued guidelines in February 2019 urging genetic testing with a multigene panel for every person diagnosed with breast cancer.

Research also supports population-based screening among those diagnosed with the disease, while other research has urged caution for such an approach.

Mark Robson, MD, a medical oncologist and chief of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center, started the SABCS session off by outlining the benefits of testing all patients.

According to Robson, since criteria for genetic testing were first established, some assumptions previously used to assess risk have been debunked. One thing Robson says has become evident in recent years is that family history-related criteria are somewhat insensitive for detecting pathogenic variants (PVs).

For example, a 2018 study of nearly 1000 women with breast cancer found that National Comprehensive Cancer Network criteria were not sensitive enough to catch all cancers; nearly half of patients with PV that would be caught by a guideline under development are missed by current guidelines.

 Robson noted that in the study, the criteria were relatively comprehensive for 

 PVs, but less so once the criteria expanded out beyond the 

“So, why is diagnostic yield important?” queried Robson, who then offered several answers. “Certainly for 

, we know that there is a substantial risk of contralateral breast cancer (CBC)—greater for 

and probably greater for younger women than for older women, but nonetheless the risks are high enough that a woman would very much want to consider bilateral mastectomy as her local treatment even if she were otherwise eligible for breast conservation to mitigate this risk.”

And while this decision is made from a personal utility perspective, there is some research showing that contralateral prophylactic mastectomy might improve survival, said Robson.

Another factor that highlights the importance of diagnostic yield is that selection of 

carriers can identify those with metastatic disease who are eligible for poly (ADP-ribose) polymerase (PARP) inhibitor therapy, which was demonstrated in both the OlympiAD

, according to Robson, highlighting TBCRC 048, a phase 2 study looking at patients with breast cancer treated with olaparib who had PVs in other susceptible genes. This study showed a dramatic benefit in patients who had 

Diagnostic yield may also be leveraged as an opportunity to identify index patients with 

 mutations or PVs in other genes and use them as an entry point for cascade testing throughout the family, which “can more rapidly identify unaffected PV carriers, which is the greatest opportunity for reduction in risk of morbidity and mortality from inherited susceptibility,” said Robson.

Such testing may also help reduce racial and socioeconomic inequities in access to genetic testing, as research has shown that Black patients and those from higher-poverty census are currently less likely to be tested.

Outside of a clinical perspective, research has suggested that testing all patients may actually be cost-effective. A 2019 study published in 

 found that testing all patients at diagnosis was extremely cost-effective compared with testing based on clinical criteria or family history at the usual willingness-to-pay threshold of $100,000 (incremental cost-effectiveness ratio $65,661/quality-adjusted life year [QALY] from the payer perspective or $61,618/QALY from the societal perspective). This cost effectiveness remained for up to $2432 per test from a payer perspective and for up to $2679 from a societal perspective.

According to Susan Domchek, MD, director of the MacDonald Women’s Cancer Risk Evaluation Center, executive director of the Basser Center for BRCA, and Basser Professor in Oncology at Penn Medicine, evidence also supports the use of risk stratification through factors like family history and phenotype rather than testing all patients.

For example, data from the CARRIERS study

 presented at last year’s SABCS meeting found that 5% of patients with breast cancer had PVs, approximately half of which were 

compared with 1.63% of unaffected women, 0.47% of which had 

 PVs. Looking deeper into the cohorts, the researchers saw that having a first-degree relative, such as a parent or sibling, with breast cancer carried a significantly higher risk of having a PV (8.29% vs 4.18%) and of having a 

Phenotype was also shown to matter, with patients with ER+ disease having a much lower risk of a PV compared with those that had ER- disease or triple-negative breast cancer (4.23% vs 8.18% vs 10.05%, respectively) and for having a 

 PV specifically (1.85% vs 6.26% vs 8.13%, respectively).

Looking at age, the study also showed that younger age was associated with a higher risk of having a PV. In a JAMA 2019 study,

 patients who were over the age of 65 were found to have approximately a 1% risk of having a 

According to Domchek, a recent finding has been made that suggests all women under the age of 60 should be tested and then should be risk-stratified from there.

1. Caffrey M. Breast surgeons seek genetic testing for all patients with breast cancer. 

 February 18, 2019. Accessed December 11, 2020. https://www.ajmc.com/view/breast-surgeons-seek-genetic-testing-for-all-patients-with-breast-cancer

2. Beitsch PD, Whitworth PW, Hughes K, et al. Underdiagnosis of hereditary breast cancer: Are genetic testing guidelines a tool or an obstacle? 

. 2018;37(6):453-460. doi:10.1200/JCO.18.01631

3. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline 

. 2017; 377(6):523-533. doi:10.1056/NEJMoa1706450

4. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline 

. 2018; 379(8):753-763. doi:10.1056/NEJMoa1802905

5. Tung NM, Robson ME, Vents S, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. 

. Published online October 29, 2020. doi:10.1200/JCO.20.02151

6. Sun L, Brentnall A, Patel S, et al. A cost-effectiveness analysis of multigene testing for all patients with breast cancer. 

. 2019;5(12):1718-1730. doi:10.1001/jamaoncol.2019.3323

7. Couch FJ, Hu C, Hart SN, et al. Age-related breast cancer risk estimates for the general population based on sequencing of cancer predisposition genes in 19,228 breast cancer patients and 20,211 matched unaffected controls from US based cohorts in the CARRIERS study. Proceedings of the San Antonio Breast Cancer Symposium. doi: 10.1158/1538-7445. SABCS18-GS2-01

8. Kurian AW, Bernhisel R, Larson, et al. Prevalence of pathogenic variants in cancer susceptibility genes among women with postmenopausal breast cancer. 

 2020;323(10):995-997. doi:10.1001/jama.2020.0229

Biomarkers and genetic testing were topics of interest in precision medicine at the virtual 2020 San Antonio Breast Cancer Symposium.

2020 SABCS: Topics in Precision Oncology

An open-label extension of the phase 3 ASCERTAIN trial is providing insight into the impact of switching from intravenous (IV) to subcutaneous (SC) interleukin-6 (IL-6) receptor inhibitor therapy for patients with 

 (RA), confirming the feasibility of the switch.

, which show no new safety issues, can ease concerns that physicians or patients may have when weighing the decision to switch route of administration for RA treatment.

“There is a trend for increasing use of SC over IV administration in RA, and evidence that both physicians and patients prefer SC therapy over IV,” wrote the researchers. “The convenience of home treatment, faster treatment time, lower costs, reduced travel time, and fewer visits to clinics or hospitals were all cited as advantages of SC treatment versus IV, though some patients preferred IV treatment because it meant administration by a medical professional and interaction with other patients during treatment.”

With this shift in treatment preference in mind, the extension study included patients originally receiving IV tocilizumab plus SC placebo in the ASCERTAIN trial who then switched over to receiving SC sarilumab. The cohort totaled 168 patients, including those who switched from 150- to 200-mg sarilumab and patients who continued the 200-mg dose.

Notably, the 5-year follow-up did not unearth any new safety signals among the patients who switched between the 2 treatments. There were also no new safety signals for those who continued on sarilumab treatment and therefore had long-term data on the treatment’s safety.

By the end of the study period, there was a cumulative sarilumab exposure of over 270 patient-years, throughout which 38 (23%) patients discontinued before 96 weeks, with 22 of those patients discontinuing due to an adverse event (AE).

The most common AEs per 100 patient-years were neutropenia (19.4) and urinary tract infections (6.6), while the most common AEs of special interest per 100 patient-years were infections (59.9), injection-site reactions (42.4), and leukopenia (23.7). There were no reported cases of grade 4 neutropenia.

Sustained efficacy was also observed, with continued responses seen over 96 weeks of follow-up when either switching to or continuing on sarilumab.

“There have been concerns that unblinding patients following commencement of open-label treatment may introduce bias due to altered perceptions in patient self-reporting or changes in placebo effects,” wrote the researchers. “These issues do not seem to have had an effect on the outcomes in the present study, in which clinical assessment scores remained stable in the sarilumab continuation groups after switching to open-label sarilumab.”

There were a small number of patients who did not achieve low disease activity at the end of the ASCERTAIN study who did go on to achieve the marker in the extension study. The researchers note that this could be a result of late response to IL-6 inhibitor therapy, positive effects of switching treatment, or unknown mechanistic differences between the 2 treatments.

Emery P, Hoogstraten H, Thangavelu K, Mangan E, John E, Verschueren P. Subcutaneous sarilumab in patients with rheumatoid arthritis who previously received subcutaneous sarilumab or intravenous tocilizumab: an open-label extension of a randomized controlled trial. 

. 2020;2(11): 672-680. doi:10.1002/acr2.11188

The researchers say their new results can ease the concerns physicians or patients have when weighing the decision to switch route of administration for rheumatoid arthritis treatment.

Jaime Rosenberg

Articles

Emergence of Gene-Specific Therapies for SMA Brings Promise, Questions

SMA Associated With Metabolic, Nutritional Issues

2020 SABCS: Topics in Precision Oncology

Switching From IV to SC IL-6 Receptor Inhibitor Therapy Shows No New Safety Signals