2020 SABCS: Topics in Precision Oncology

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.

A Focus on PD-L1

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.¹

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%).²

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.³ 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,⁴ 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.⁵

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.

Other Novel Marker Concepts Gain Steam

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.^6,7

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.

References

1. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. New Engl J Med. 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. Lancet. 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). Ann Oncol. 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. J Clin Oncol. 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. Lancet Oncol. 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. JAMA Oncol. 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 BRCA1, 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.¹ Research also supports population-based screening among those diagnosed with the disease, while other research has urged caution for such an approach.

Making the case for testing all patients

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.² Robson noted that in the study, the criteria were relatively comprehensive for BRCA1/2 PVs, but less so once the criteria expanded out beyond the BRCA PVs.

“So, why is diagnostic yield important?” queried Robson, who then offered several answers. “Certainly for BRCA1/2, we know that there is a substantial risk of contralateral breast cancer (CBC)—greater for BRCA1 than BRCA2 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 BRCA1/2 carriers can identify those with metastatic disease who are eligible for poly (ADP-ribose) polymerase (PARP) inhibitor therapy, which was demonstrated in both the OlympiAD³ and EMBRACA⁴ trials.

This benefit might extend beyond BRCA1/2, 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 PALB2 mutations.⁵

Diagnostic yield may also be leveraged as an opportunity to identify index patients with BRCA 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 JAMA Oncology⁶ 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.

Emphasis on risk stratification

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 study⁷ presented at last year’s SABCS meeting found that 5% of patients with breast cancer had PVs, approximately half of which were BRCA1/2/PALB2 compared with 1.63% of unaffected women, 0.47% of which had BRCA1/2/PALB2 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 BRCA1/2/PALB2 PV specifically (5.19% vs 1.96%).

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 BRCA1/2/PALB2 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,⁸ patients who were over the age of 65 were found to have approximately a 1% risk of having a BRCA1/2 mutation.

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.

References

1. Caffrey M. Breast surgeons seek genetic testing for all patients with breast cancer. American Journal of Managed Care. 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? J Clin Oncol. 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 BRCA mutation. N Engl J Med. 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 BRCA mutation. New Engl J Med. 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. J Clin Oncol. 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. JAMA Oncol. 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. JAMA. 2020;323(10):995-997. doi:10.1001/jama.2020.0229