Should Every Metastatic Breast Cancer Patient Undergo Next-Generation Sequencing?

Kate M. O'Rourke


July 30, 2018

Should all patients with metastatic breast cancer (MBC) undergo next-generation sequencing (NGS)?

"It is only worth doing a test if it will change patient care," said Funda Meric-Bernstam, MD, Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, addressing this question with other experts at the 2017 San Antonio Breast Cancer Symposium (SABCS). "In this context, patient care is routine care with approved agents, as well as providing patients with clinical trial options, locally and elsewhere."

Navigating the scientific data to make clinical decisions based on molecular profiling results can be overwhelming for oncologists and researchers. For example, in breast cancer, Ki67 expression has been associated with luminal B phenotype, a high risk for relapse, and good response to neoadjuvant chemotherapy—but evidence does not support withholding adjuvant chemotherapy in patients with estrogen-receptor (ER)-positive, Ki67-low breast cancer and one to three positive nodes without some risk.[1] The Personalized Cancer Therapy website is an online resource that can help clinicians and researchers navigate the available data and identify potential therapy options for patients harboring oncogenic genomic alterations.[2]

According to Meric-Bernstam and others, the identification of driver mutational events remains the biggest challenge for using NGS in MBC. Few validated oncogenic drivers of breast cancer exist, with the exceptions of ER, HER2, PIK3CA and AKT1.[3] "Scenarios with clinical promise include targeting such oncogenes as PIK3CA, AKT, HER2, TRK, and other rare alterations," said Meric-Bernstam.

The PIK3CA inhibitor alpelisib used in combination with fulvestrant has shown promising early efficacy in heavily pretreated postmenopausal women with ER-positive MBC with PIK3CA-altered tumors.[4] Meric-Berstam said several other PIK3CA inhibitors are in clinical trials.

Promising AKT inhibitors include AZD5363, which induced partial responses in ER-positive AKT1 E17K mutant breast cancers, in a phase 1 trial.[5] In the phase 2 LOTUS trial, combining the AKT1 inhibitor ipatasertib with paclitaxel increased progression-free survival (PFS) in PIK3CA/AKT1/PTEN-altered patients with metastatic triple-negative breast cancer (9.0 vs 4.9 months; P = .041).[6]

HER2 somatic mutations have been shown to be an alternative mechanism to activate HER2 in breast cancer treatment, and the majority of HER2 somatic mutations in patients with breast cancer are activating mutations that probably drive tumorigenesis.[7] Patients with these mutations may benefit from HER2-targeted drugs. In a sample of breast cancer cases, 10.6% had HER2 amplifications, 2.4% had HER2 mutations, and 0.7% had co-occurring amplifications and mutations.[8] Irreversible HER2 inhibitors, predominantly neratinib, look promising, said Meric-Berstam. In a small trial of patients with MBC and HER2 mutations treated with neratinib, the clinical benefit ratio was 31%, with one complete response, one partial response, and three stable disease responses by 24 weeks.[9] In the SUMMIT trial of patients with HER2-mutant MBC, neratinib monotherapy resulted in a clinical benefit rate of 42%, and combining it with fulvestrant increased this to 58%.[10]

Meric-Bernstam said some patients thought to be HER2-negative are found to be HER2-positive using NGS of another, newer sample. "We are not sure whether this is genomic evolution or heterogeneity or technical issues with the first testing," she said. "We are really not as sure about the therapeutic sensitivity in this context, especially if it represents heterogeneity. However, if [HER2 is] amplified in NGS, we don't believe validation is needed." Different genomic testing platforms have different cutoffs, Meric-Bernstam continued, so if NGS doesn't show HER2 amplification, there still might be a lower-level amplification or overexpression of HER2. The issue needs clarification on different platforms.

TRK inhibitors are also potentially useful for breast cancer. TRK fusions are very rare alterations found in several tumor types, including secretory breast cancer, that account for less than 1% of breast cancers and occur in patients as young as 3 years of age.[11] ETV6-NTRK3 fusion is the pathognomonic genomic alteration found in 93% of cases of human secretory breast cancer.[11] "Secretory breast cancer is indolent; however, TRK fusions are pathognomonic," said Meric-Bernstam. "TRK mutations are rare, so I'm not advocating for fusion testing across the board, but if you do have a secretory breast cancer, do TRK fusion testing."

In patients with TRK fusions treated in a phase 1 and 2 basket trial of the pan-TRK inhibitor larotrectinib, almost every patient had an objective response and the responses were durable, said Meric-Bernstam. One 14-year-old patient with secretory breast cancer who was flown from Bangladesh to New York had a dramatic response from a TRK inhibitor, with huge tumor shrinkage in less than 2 months.[12]

If you are not testing your patients, they are not even eligible for these trials.

Few genomic alterations in breast cancer are common, which makes conducting meaningful breast cancer studies very difficult. "This is why it is really fruitful to be able to enroll patients on basket studies that are enrolling different histologies and giving genotype-selected therapy," said Meric-Bernstam. At MD Anderson, an increasing number of trials are genotype-selected. "If you are not testing your patients, they are not even eligible for these trials," said Meric-Bernstam.

ESR1 mutations are clinically relevant; they are rarely found in primary breast cancer, but commonly found in the metastatic setting. "ESR1 mutations are enriched or acquired in hormone receptor-positive patients treated with aromatase inhibitors or tamoxifen, in the adjuvant or metastatic setting," said Meric-Bernstam. "You need to test the metastatic site, rather than the primary tumor, to identify these mutations." She added that ESR1 mutations accumulate with further treatment, and there may be value in retesting or doing liquid biopsies. In the SOFEA trial, where 39% of patients had ESR1 mutations, patients with these mutations had improved PFS with fulvestrant compared with exemestane (hazard ratio, 0.52; P = .02).[13]

Researchers are increasingly focusing on the importance of germline defects in DNA damage repair genes. In a recent phase 3 trial, olaparib doubled the response rate (59.9% vs 28.8%) and added 3 months of PFS, compared with standard therapy (7.0 vs 4.2 months; P < .001).[14]

Meric-Bernstam pointed out that using NGS on tumors is not a substitute for clinical germline genetic testing, and some patients without clinical indications for genetic testing are found to have a mutation in DNA damage repair genes upon genomic testing. In a series of 1000 advanced cancers at MD Anderson, one half of the people who had a germline BRCA2 mutation were not aware they were BRCA2-positive.[15] It is important to note, said Meric-Bernstam, that these mutations can be found from tumor-only testing and would not be flagged as a germline alteration necessarily.

Several ongoing breast cancer trials are assessing PARP inhibitors in germline and somatic mutations or deletions of other DNA damage repair genes. "We have already seen responses in PARP inhibitors with PALB2 and ATM alterations in other tumor types," said Meric-Bernstam. She said other agents targeting Wee1 and CHK1 are in development.

She said that DNA damage repair alterations are also being explored as predictors of immunotherapy response, with mismatch repair deficiency as a proven response marker. Predictors of response and resistance to immunotherapy markers under evaluation include programmed cell death ligand 1 (PD-L1) amplification. "PD-L1 and PD-L2, and Janus kinase 1 (JAK1), are on the same amplicon and reported to be amplified in triple-negative breast cancer," said Meric-Bernstam. Acquired resistance markers include beta-2 microglobulin, human leukocyte antigen, and JAK 1/2, she said. Incorporating these markers could help identify patients who would not benefit from a rechallenge with immunotherapy.

Pembrolizumab is approved for microsatellite instability (MSI) high or mismatch repair deficiency tumors across histologies. "If it is not your practice to do MSI testing, if you see multiple mutations on genetic testing, that could be a flag to do testing on those patients," said Meric-Bernstam. She said some commercial platforms regularly report MSI status.

On November 30, 2017, the US Food and Drug Administration (FDA) approved FoundationOne CDx, a panel of 324 genes and two genomic signatures. "The test can identify which patients with non-small cell lung cancer, melanoma, breast cancer, colorectal cancer, or ovarian cancer may benefit from 15 different FDA-approved targeted treatment options," said Meric-Bernstam. She said Centers for Medicare & Medicaid Services issued a proposed national coverage determination of the FoundationOne CDx for Medicare beneficiaries with recurrent, metastatic, or advanced stage IV cancer who have not been previously tested using NGS technology and who continued to remain candidates for further therapy.

In his presentation at SABCS, Fabrice André, MD, PhD, professor in the Department of Medical Oncology at Gustave Roussy in Villejuif, France, pointed out that there are targeted therapies given without genomic tests that have clinical activity in breast cancer, such as CDK4 and mTOR inhibitors. Studies have also shown that genomic alterations do not have the same meaning across tumor types.[16] "Seventeen years after the first description of the breast cancer genomic landscape, there is no approved [breast cancer] drug that requires a genomic test, and the reason is because the current way of interpreting DNA sequencing is not useful in MBC," said André.

In January, however, this changed when the FDA extended the approval of olaparib to include the treatment of MBC in patients who carry the specific inherited BRCA mutation.[17]

During his presentation, André deconstructed the utility of NGS applications in MBC. André pointed out that secretory breast cancer is detectable by phenotype, so you don't need to do NGS. He said that although there are several genetic alterations for which responses have been observed in clinical trials, pointing to AKT1, PIK3CA, ERBB2, and ESR1 mutations, there is no evidence that giving the targeted therapy is better than standard of care. "In addition, rather than using NGS," he said, "it is better to detect these alterations by polymerase chain reaction (PCR) or circulating tumor DNA, which would be less expensive." André said mutations present in MBC with high mutational load are not clonal and these cancers are unlikely to respond to anti–PD-1.

In a study of 226 cases of triple-negative breast cancer and 90 non–triple-negative tumors, only four triple-negative carcinomas (1.8%) showed loss of mismatch repair proteins (three lost MLH1 and PMS2, and one lost MSH2 and MSH6), whereas none of the 90 non–triple-negative carcinomas showed loss of protein.[18] Rather than using NGS for these rare mutations, immunohistochemistry or PCR should be used, André said.

While sequencing detects genetic variants, said André, the likelihood of drug access is very low. In a study testing FGFR inhibition, there was a 0% objective response in patients with FGFR1/2 mutant breast cancer who were given an FGFR inhibitor.[19] "By reporting targetable alterations that are not relevant or by recommending wrong drugs, NGS reports are deleterious since they recommend ineffective therapy and deny effective therapies," said André.

The researchers concluded that off-label use of molecularly targeted agents should be discouraged.

He pointed out that two large trials, SHIVA and MOSCATO 01, tested large panels and had efficacy as a first endpoint. In the SHIVA trial, the use of molecularly targeted agents outside their indications did not improve PFS compared with treatment of physician's choice in heavily pretreated patients with advanced cancer.[20] The researchers concluded that off-label use of molecularly targeted agents should be discouraged, but enrollment in clinical trials should be encouraged to assess predictive biomarkers of efficacy. In MOSCATO 01, only 7% of the patients with hard-to-treat cancers who underwent high-throughput genomics benefited from this approach.[21]

"Is it ethical to order a test that will generate false hopes without informed consent? This can only be sorted out by the implementation of informed consent stating the likelihood of success," said André. Sequencing, he said, is cheap but generates extra cost for biopsies and off-label use of expensive drugs.

"NGS does not provide benefit in 2017 in patients with MBC because targeting relevant targets do not translate into benefit and because the vast majority of targets are not relevant," said André.

He said ethical, regulatory, and financial issues surrounding NGS in MBC include issues of analytical validity, what to do about incidental findings, drug access, and indirect costs. "The reporting of large panels of genes lead to major ethical, regulatory, financial issues that have not been sorted out," said André.

Dr André has disclosed being a paid consultant for Dialecta, Sumitomo Dainippon Pharma. He contracted research with Novartis, AstraZeneca, Pfizer, and Lilly. Dr Meric-Bernstam disclosed grant/research support from Novartis, AstraZeneca, Taiho, Genetech, Calithera, Debiopharma, Bayer, Puma, Aileron, CytoMx, Effector Therapeutics, Zymeworks, PUMA, Curis, and Pfizer.


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