Traina Helps Navigate Surge of New Breast Cancer Therapies

Tiffany A. Traina, MD

Nearly 15 years have passed since pathologists at Memorial Sloan Kettering Cancer Center (MSK) conducted gene expression analyses on breast cancer primary tumors and described a potential role for a novel target, which quickly became a major research focus for their colleague Tiffany A. Traina, MD.

Investigators found that a significant number of the hormone receptor–negative samples they examined demonstrated androgen receptor (AR) pathway activity.¹ The discovery suggested that androgen-targeting strategies developed to treat prostate cancer might also benefit a subset of women with breast cancer, and Traina was eager to investigate. After years of work in this area, she is poised to co-lead the first randomized trial comparing the AR inhibitor enzalutamide (Xtandi) versus chemotherapy in patients with triple-negative breast cancer (TNBC) through the Translational Breast Cancer Research Consortium.

Androgen deprivation strategies are just 1 area of research interest for Traina, a medical oncologist at MSK in New York, New York, who specializes in the exploration of novel targeted therapies for TNBC. Clinical investigations are, in turn, just part of a career that includes a full practice, leadership roles at MSK and the American Society of Clinical Oncology, and a commitment to sharing her knowledge with other physicians, both at MSK and at professional conferences around the world.

In November, Traina will cochair the 38th Annual CFS^® conference, which is hosted by Physicians’ Education Resource^®, LLC (PER^®). The 3-day event will take place November 4 through November 6 and feature live, interactive virtual presentations on the practice-changing innovations in cancer diagnosis, treatment, and supportive care that occurred over the past year.

Traina is organizing the sessions with her cochairs, Benjamin P. Levy, MD, and William K. Oh, MD. Levy is clinical director of medical oncology at Johns Hopkins Sidney Kimmel Cancer Center in the DC Region, and Oh is chief of hematology and medical oncology and deputy director at The Tisch Cancer Institute at Icahn School of Medicine at Mount Sinai in New York, New York.

The conference provides clinically useful insights into best practices and emerging approaches for a broad range of cancer types, including hematologic malignancies, genitourinary cancers, and lung cancers. The agenda also will feature a section on the impact of the coronavirus 2019 disease (COVID-19) in oncology.

This year’s CFS^® will be particularly provocative for breast cancer. “There were a few areas within breast cancer that saw really exciting advances over the past year or so, and they will naturally be major areas of focus for the symposium,” Traina said in an interview with OncLive^®.

“First, in the space of women with HER2- positive advanced breast cancer, we’ve seen 2 new agents approved by the FDA since December 2019. These have both produced impressive efficacy results and offer valuable new options for our patients with HER2-positive disease,” she said, referring to fam-trastuzumab deruxtecan-nxki (Enhertu) and tucatinib (Tukysa).

“The other area with significant advances for review is triple-negative breast cancer,” Traina said. “The FDA has approved use of a novel antibody-drug conjugate [ADC] for patients with metastatic TNBC being treated in the third line or later [sacituzumab govitecan-hziy; Trodelvy]. This is an area of tremendous unmet need, with often short duration of response and poorer outcome with conventional chemotherapies. Additionally, we’re seeing an expanded role for immunotherapy in triple-negative breast cancer, both in the early-stage setting and in first-line metastatic disease.”

Traina’s expertise in translating such research developments into clinical practice also will be integrated into the breast cancer discussions, where she will serve as a moderator. “Tiffany is a respected colleague and a thought leader in triple-negative breast cancer,” said Shanu Modi, MD, a medical oncologist at MSK who has worked with Traina on several studies. “She has led the pioneering studies of androgen receptor-expressing triple negative breast cancer, and she manages a diverse portfolio of novel agents focused on this subtype of aggressive cancer.”

New HER2-Positive Options Abound

The recent spate of breast cancer advancements began in December 2019, when the FDA accelerated approval of trastuzumab deruxtecan for patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior H ER2-targeting therapies.²

Approval for trastuzumab deruxtecan, an ADC that combines an anti-HER2 antibody with a cytotoxic topoisomerase I inhibitor, hinged upon findings from the DESTINYBreast01 trial (NCT03248492), which reported objective responses in 60.9% (95% CI, 53.4%-68.0%) of 184 heavily pretreated participants. The median response duration was 14.8 months (95% CI, 13.8-16.9), and the median duration of progression-free survival (PFS) was 16.4 months (95% CI, 12.7–not reached).³

Interestingly, trastuzumab deruxtecan also showed a high response rate among patients whose tumors had low expression of HER2 in data from a phase 1 trial (NCT02564900). In all, 20 (37%) of the 54 women who had low expression of HER2, defined as an immunohistochemistry score of 1+ or 2+ with negative in situ hybridization, responded to treatment.⁴

In April 2020, the FDA approved the oral tyrosine kinase inhibitor tucatinib for patients with advanced or metastatic HER2-positive breast cancer who have received at least 1 prior HER2-targeting regimen, based on results from the HER2CLIMB trial (NCT02614794), in which 612 patients were randomized to receive trastuzumab and capecitabine plus tucatinib or placebo.²

Median PFS in patients receiving tucatinib was 7.8 months (95% CI, 7.5-9.6) compared with 5.6 months (95% CI, 4.2-7.1) for patients enrolled in the control arm (HR, 0.54; 95% CI, 0.42- 0.71; P < .001). Median overall survival (OS) in patients who received tucatinib was 21.9 months (95% CI, 18.3-31.0) compared with 17.4 months (95% CI, 13.6-19.9) for patients in the control arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005).⁵

Tucatanib also has demonstrated efficacy in patients with brain metastases. Median PFS for patients with baseline brain metastases was 7.6 months with tucatinib (95% CI, 6.2-9.5) and 5.4 months with placebo (95% CI, 4.1-5.7), which translated into a 52% lower risk of disease progression or death (HR, 0.48; 95% CI, 0.34-0.69; P < .001).⁵

“We have these 2 powerful new agents to help improve outcomes for women with advanced HER2-positive breast cancer,” Traina said, adding that highly effective therapies for patients with brain metastases have been elusive. “CNS disease has posed a real clinical challenge.”

The FDA also expanded the indication of neratinib (Nerlynx), an orally available tyrosine kinase receptor inhibitor of EGFR, HER2, and HER4. The drug was previously approved in 2017 as monotherapy for extended adjuvant treatment of adults with early-stage HER2-positive breast cancer following trastuzumab (Herceptin)–based therapy.²

In February 2020, neratinib gained approval in combination with capecitabine for adults with advanced or metastatic HER2-positive breast cancer who have received 2 or more previous anti-HER2– based regimens in the metastatic setting.²

The new indication is based on data from the NALA trial (NCT01808573), which demonstrated a statistically significant improvement in PFS with the neratinib combination compared with lapatinib (Tykerb) plus capecitabine (HR, 0.76; 95% CI, 0.63- 0.93; P = .0059). The PFS rate at 18 months was 16.3% (95% CI, 11.3%-22.1%) for the neratinib arm compared with 7.4% (95% CI, 4.1%-12.0%) with the lapatinib regimen. The overall incidence of intervention for CNS disease also was lower with neratinib at 22.8% (95% CI, 15.5%- 30.9%) versus 29.2% (95% CI, 22.5%-36.1%) for lapatinib (Gray’s test for equality, P = .043).⁶

Recent Approvals Bolster TNBC Landscape

The treatment options for patients with TNBC also grew with the introduction of sacituzumab govitecan, an ADC that targets TROP-2. The FDA granted the agent an accelerated approval in April 2020 for patients with metastatic TNBC who have received 2 or more prior lines of therapy in the metastatic setting.²

The approval was based on findings from the phase 1/2 IMMU-132-01 trial (NCT01631552), in which sacituzumab govitecan demonstrated a response rate of 33.3% (95% CI, 24.6-43.1) and a median duration of response of 7.7 months (95% CI, 4.9-10.8) in a heavily pretreated population. Median PFS was 5.5 months (95% CI, 4.1-6.3), and median OS was 13.0 months (95% CI, 11.2-13.7).⁷

The randomized phase 3 ASCENT study (NCT02574455) testing sacituzumab govitecan versus physician's choice chemotherapy (ie, eribulin, capecitabine, gemcitabine, or vinorelbine) in relapsed/refractory TNBC has been completed and results are expected at the Virtual 2020 European Society for Medical Oncology (ESMO) Congress.

Clinical trials of immunotherapy in TNBC have produced a mix of findings. Atezolizumab (Tecentriq), a PD-L1 immune checkpoint inhibitor (ICI), became the first immunotherapy approved for breast cancer in March 2019. The FDA granted an accelerated approval for atezolizumab in combination with nab-paclitaxel (Abraxane) for patients with unresectable locally advanced or metastatic PD-L1–positive TNBC based on PFS findings from the IMpassion130 trial (NCT02425891). PD-L1 positivity was defined as staining on tumor-infiltrating cells of any intensity covering at least 1% of the tumor area.⁸

The median PFS with atezolizumab plus nab-paclitaxel was 7.4 months (95% CI, 6.6-9.2) compared with 4.8 months (95% CI, 3.8-5.5) for those receiving placebo with nab-paclitaxel (stratified HR, 0.60; 95% CI, 0.48-0.77; P < .0001). The objective response rates were 53% versus 33% for the atezolizumab and the placebo-containing arms, respectively.⁸

However, data from the phase 3 IMpassion131 study (NCT03125902) evaluating atezolizumab in combination with paclitaxel failed to confirm a statistically significant PFS benefit compared with placebo plus paclitaxel in treatment-naïve patients with inoperable locally advanced or metastatic TNBC, according to Roche, the company developing the drug.⁹

There also was a negative trend for OS, although the study was not powered for this end point and the data were immature at the time of the analysis, Roche said. Full findings from trial are being discussed with global health authorities and are planned for presentation at the Virtual 2020 ESMO Congress.⁹

On September 8, the FDA issued an alert advising providers not to substitute paclitaxel for nab-paclitaxel in clinical practice and noted that the combination of atezolizumab plus paclitaxel is not an approved use for patients with breast cancer. The agency also said continued approval of atezolizumab plus nab-paclitaxel may be contigent upon findings from additional clinical trials.¹⁰

Traina said she would have to examine the findings before forming an opinion about the results of IMpassion131. “We haven’t seen the data yet and haven’t had an opportunity to really dive into the details for a greater understanding of how trial design and population differences may account for the unexpected outcome,” she said. “We are certainly trying to understand why the earlier IMpassion study partnered with nab-paclitaxel was a positive trial and this one missed its primary end point.”

Earlier Use of ICI Therapy Shows Benefit

Nevertheless, ICIs are displaying positive signals in earlier disease settings. Results from the phase 3 IMpassion031 trial (NCT03197935) showed a statistically significant and clinically meaningful improvement in pathological complete response (pCR) for atezolizumab as neoadjuvant therapy combined with nab-paclitaxel, followed by doxorubicin and cyclophosphamide, compared with chemotherapy plus placebo in patients with early-stage TNBC.¹¹

The benefit was observed regardless of PD-L1 expression, according to Genentech, a member of the Roche Group. Findings are planned for presentation at the Virtual 2020 ESMO Congress and will be discussed with the FDA and other regulatory authorities, the company said.¹¹

In the KEYNOTE-355 trial (NCT02819518), patients with previously untreated, locally recurrent, inoperable or metastatic TNBC were randomized to receive pembrolizumab (Keytruda), a PD-1 inhibitor, plus chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) or placebo plus chemotherapy. Results were stratified by combined positive score (CPS) of the number of PD-L1–positive tumor cells, lymphocytes, and macrophages divided by the total number of tumor cells multiplied by 100.¹²

For participants with a CPS of 10 or more, the median PFS for the pembrolizumab regimen was 9.7 months compared with 5.6 months for chemotherapy alone (HR, 0.65; 95% CI, 0.49-0.86; P = .0012). For those with a CPS of less than 10, median PFS was 5.8 months with the pembrolizumab combination versus 5.7 months with chemotherapy alone (HR, 0.94; 95% CI, 0.76-1.16).¹²

Investigators said the findings show the potential for adding pembrolizumab to first-line TNBC therapy. The FDA has granted a breakthrough therapy designation for pembrolizumab plus chemotherapy as neoadjuvant treatment for patients with high-risk, early-stage TNBC.¹²

Additionally, pembrolizumab plus as neoadjuvant therapy in the I-SPY 2 trial (NCT01042379) in patients with early-stage, high-risk hormone receptor–positive/HER2- negative breast cancer or TNBC.

Final estimated pCR rates were 44% versus 17%, 30% versus 13%, and 60% versus 22% for pembrolizumab plus neoadjuvant chemotherapy compared with standard neoadjuvant chemotherapy in the HER2-negative, hormone receptor–positive/HER2-negative, and TNBC cohorts, respectively.¹³

Traina believes that recent study findings are charting an effective course for ICI therapy in the treatment paradigm. “I think we’ve come to see that for select patients with metastatic TNBC, introducing these agents early in the first-line setting has greater promise than using them in a later line,” she said. “We are also now seeing from early-stage trials that moving these checkpoint inhibitors up into the neoadjuvant setting, even potentially the adjuvant setting, may have meaningful benefit.”

Novel Approaches Draw Traina's Interest

In her research, Traina focuses on investigating novel therapeutic strategies and targeted therapies to treat TNBC. Early in her career, she was among MSK investigators who established that a dose-dense adjuvant chemotherapy regimen, delivered at shorter intervals than the conventional time frame, is tolerable and feasible.¹⁴

Under the mentorship of Clifford A. Hudis, MD, and Larry Norton, MD, a 2016 Giants of Cancer Care^® award winner, Traina helped develop a 7 days on, 7 days off dosing schedule for capecitabine that allows for higher doses with decreased gastrointestinal toxicities than conventional 14-day continuous dosing.^15,16

Her current projects include testing patritumab deruxtecan (U3-1402), a HER3- directed ADC, in patients with HER3-positive metastatic TNBC; evaluating durvalumab (Imfinzi) plus olaparib (Lynparza) in TNBC; and studying postoperative atezolizumab therapy plus chemotherapy in patients with stage II or III TNBC.

Traina is particularly enthusiastic about the prospect of conducting further studies into the potential for AR-directed strategies in TNBC. In 2018, Traina and colleagues reported that patients with locally advanced or metastatic AR-positive TNBC, defined as AR greater than 0% on immunohistochemistry staining, derived clinical benefit from enzalutamide therapy in the phase 2 MDV3100-11 study (NCT01889238).¹⁷

Results demonstrated that the clinical benefit rate, defined as confirmed complete or partial responses or stable disease, with enzalutamide monotherapy was 33% (95% CI, 23%-45%) at 16 weeks and 28% (95% CI, 19%-39%) at 24 weeks among evaluable patients (n = 78) and 25% (95% CI, 17%-33%) and 20% (95% CI, 14%-29%), respectively, for the intention-to-treat population (N = 118).¹⁷

In another study (NCT02750358), Traina and coinvestigators examined the feasibility of 1 year of adjuvant enzalutamide therapy for patients with early-stage AR-positive (≥ 1%) TNBC. Overall, 33 of 47 evaluable patients were able to complete 52 weeks of therapy, according to findings presented at the 2019 American Society of Clinical Oncology Annual Meeting. The 1-year disease-free survival rate was 93.5% (95% CI, 86.6%-100%).¹⁸

The early signals have been strong enough to secure funding from the Breast Cancer Research Foundation and support from the Translational Breast Cancer Research Consortium to launch a randomized trial that will test enzalutamide against therapies chosen by individual physicians at multiple locations in the United States, Traina said.

“It’s been exciting to move from that initial observation, that the androgen receptors existed, to multiple phase 1 trials to establish that these prostate cancer drugs are safe in women with breast cancer, to early phase 2 trials and now to a randomized trial,” Traina said.

“If your cancer is very driven by hormones, then actually targeting that pathway instead of using chemotherapy may offer a really well-tolerated approach. The idea is that you could start with an endocrine approach in these androgen-driven triple-negative cancers and, at some point, introduce chemotherapy if necessary, not unlike the way we manage an estrogen-driven cancer with [estrogen receptor]– targeted therapies,” she said.

COVID-19 Casts a Shadow

For Traina, specializing in medicine in general and oncology in particular was a natural choice. “I unfortunately had the experience of losing my mother to cancer while I was quite young, and I believe that is what first inspired me to enter into this field,” she said. “I couldn’t imagine doing anything else, to be honest. This is such meaningful work, and it is a privilege to partner with my patients and their families during this experience.

“It is empowering to be able to offer guidance and hope for my patients through their individual journeys,” she added. “Also, this is a tremendously exciting time in the science of oncology. It’s humbling to be a part of the research that is [affecting] survival for women with breast cancer.”

Traina has spent more than 20 years in the medical field, having obtained her medical degree from Weill Cornell Medicine in 1999. She joined the staff at MSK after participating in a fellowship in medical oncology and hematology at the center. She completed a residency in internal medicine at NewYork-Presbyterian Weill Cornell and served as chief resident and chief fellow at MSK.

As Traina and colleagues continue their search for better therapies, they now face an entirely novel challenge—delivering care safely and effectively amid the COVID-19 pandemic. This year’s CFS^® agenda features presentations on the association of inflammation, cancer, and COVID-19 and a panel discussion on experiences with COVID-19 in the oncology arena. Norman E. “Ned” Sharpless, MD, director of the National Cancer Institute, is scheduled to provide the agency’s perspective on COVID-19.

“It’s impossible to ignore the global pandemic and how it’s [affecting] our delivery of care, so it’s one of the major issues that will be addressed at the symposium,” Traina said. “We are all finding innovative ways to continue to deliver high-quality care in a safe environment, one that incorporates social distancing, appropriate PPE [personal protective equipment], psychosocial support, and family safety. Speakers and panelists and, presumably, many participants will be talking about their personal experiences.

“There’s a portion of the agenda that is dedicated to telemedicine and how there’s a digital transformation going on in health care delivery, one that may remain, at least in part, after the pandemic is over,” she added.

The medical field’s understanding of the risk that COVID-19 poses to patients with cancer, including those undergoing active treatment, continues to evolve. Findings from a study of 423 patients with COVID-19 treated at MSK indicate that age older than 65 years and treatment with ICIs were associated with higher rates of hospitalization and severe disease, but chemotherapy and major surgery were not.¹⁹ Meanwhile, concern is growing about the future burden of cancer among patients who delay screenings or medical visits that could lead to a diagnosis.

“When the pandemic began, patients were fearful of leaving their homes to receive important cancer care. People also have delayed age-appropriate screening studies, where the risk-benefit balance might have favored avoiding coronavirus and putting off screening and surveillance studies,” Traina said.

“There is a body of literature that suggests we’ll see a wave of cancer diagnoses ahead, perhaps at a later stage, because of the delays in diagnosis that have happened as a result of the pandemic,” she noted.

In addition to necessitating changes in the delivery of cancer care, the pandemic has altered the realm of continuing medical education conferences. PER^® quickly adapted its offerings to a live, interactive, virtual format, and Traina anticipates a smooth experience for CFS^® attendees.

“Now that we are several months into the COVID-19 pandemic, we have become quite familiar with using virtual platforms to effectively convey meeting content,” she said. “Our presenters will be able to deliver the content as effectively via the internet as they could do in person.”

Indeed, Traina believes that the virtual symposium could improve upon standard conferences in several ways. For example, live chat features will allow all participants to engage in the meeting in a way that might not have been possible in person.

The real challenge involves translating a conference’s social element to the virtual realm. “We are working to create that sense of community and reinvent the social aspect of the meeting,” Traina said. “We are looking for ways to facilitate interactions between participants and leaders in the field. I’m optimistic that we’ll meet that goal.”

References:

1. Doane AS, Danso M, Lal P, et al. An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene. 2006;25(28):3994-4008. doi:10.1038/sj.onc.1209415
2. Hematology/oncology (cancer) approvals & safety notifications. FDA. Updated September 1, 2020. Accessed September 1, 2020. https://bit.ly/2EA9iRS
3. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510
4. Modi S, Park H, Murthy RK, et al. antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low–expressing advanced breast cancer: results from a phase Ib study. J Clin Oncol. 2020;38(17):1887-1896. doi:10.1200/JCO.19.02318
5. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609. Published correction appears in N Engl J Med. 2020;382(6):586
6. Saura C, Oliveira M, Feng YH, et al; NALA Investigators. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol. Published online July 27, 2020. doi:10.1200/JCO.20.00147
7. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Eng J Med. 2019;380(8):741-751. doi:10.1056/NEJMoa1814213
8. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. FDA. Updated March 18, 2019. Accessed September 1, 2020. https://bit.ly/3gMHeYg
9. Roche provides update on phase III study of Tecentriq in combination with paclitaxel for people with metastatic triple-negative breast cancer. News release. Roche. August 6, 2020. Accessed August 7, 2020. https://bit.ly/3knjIEk​
10. FDA alerts health care professionals and oncology clinical investigators about efficacy and potential safety concerns with atezolizumab in combination with paclitaxel for treatment of breast cancer. News release. FDA. September 8, 2020. Accessed September 9, 2020. https://bit.ly/328EFvy
11. Genentech’s Tecentriq in combination with chemotherapy (including Abraxane) meets primary endpoint of improved pathological complete response, regardless of PD-L1 status, as initial treatment for people with early triple-negative breast cancer. News release. Genentech. June 18, 2020. Accessed August 25, 2020. https://bwnews.pr/3ehYynM
12. 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(suppl 15):1000. doi:10.1200/JCO.2020.38.15_suppl.1000
13. 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
14. Drullinsky P, Sugarman SM, Fornier MN, et al. Dose dense cyclophosphamide, methotrexate, fluorouracil is feasible at 14-day intervals: a pilot study of every-14-day dosing as adjuvant therapy for breast cancer. Clin Breast Cancer. 2010;10(6):440-444. doi:10.3816/CBC.2010.n.057
15. Traina TA, Dugan U, Higgins B, et al. Optimizing chemotherapy dose and schedule by Norton-Simon mathematical modeling. Breast Dis. 2010;31(1):7-18. doi:10.3233/BD-2009-0290
16. Cadoo KA, Gajria D, Suh E, et al. Decreased gastrointestinal toxicity associated with a novel capecitabine schedule (7 days on and 7 days off): a systematic review. NPJ Breast Cancer. 2016;2:16006. doi:10.1038/npjbcancer.2016.6
17. Traina TA, Miller K, Yardley DA, et al. Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol. 2018;36(9):884-890. doi:10.1200/JCO.2016.71.3495
18. Traina TA, Boyle LA, Arumov A, et al. Adjuvant enzalutamide for the treatment of early-stage androgen receptor-positive (AR+) TNBC. J Clin Oncol. 2019;37(suppl 15):546. doi:10.1200/JCO.2019.37.15_suppl.546
19. Robilotti EV, Babady NE, Mead PA, et al. Determinants of COVID-19 disease severity in patients with cancer. Nat Med. 2020;26(8):1218-1223. doi:10.1038/s41591-020-0979-0