Release Date: October 22, 2019
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This CE article is designed to serve as an update on cancer detection and prevention and to facilitate clinical awareness of current and new research regarding state-of-the-art care for those with or at risk for cancer.
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PARP Inhibition Can Change the Breast Cancer Treatment Paradigm
By Brielle Benyon
PARP inhibitors are moving into the breast cancer space and are showing great promise for the treatment of certain patients with metastatic disease, explained Tiffany A. Traina, MD.
Traina, who is the clinical director of the Breast Medicine Service and section head of the Triple Negative Breast Cancer Clinical Research Program at Memorial Sloan Kettering Cancer Center, as well as assistant professor at Weill Cornell Medical College in New York, New York, discussed these exciting advancements at the 18th Annual International Congress on the Future of Breast Cancer® East hosted by Physicians’ Education Resource®, LLC, and held July 19 to 20, 2019, in New York, New York.1
The phase III OlympiAD study2 examined the use of the PARP inhibitor olaparib (Lynparza) for patients with breast cancer. This study compared olaparib at 300 mg twice daily versus standard single-agent chemotherapy of physician’s choice (either capecitabine, eribulin, or vinorelbine) in patients with HER2-negative metastatic breast cancer with a deleterious germline mutation in BRCA1 or -2. Eligible patients had received 2 or fewer prior lines of chemotherapy and had prior anthracycline and taxane treatment.
The primary endpoint, median progression-free survival (PFS), was increased by 42% in the olaparib arm compared with standard chemotherapy (HR, 0.58; 95% CI, 0.43-0.80; P <.001). “That’s about a 3-month improvement in median PFS,” Traina said, adding that updated results, including final overall survival data, were presented at the 2018 American Association for Cancer Research Annual Meeting.3
“If you look at the overall trial population, overall survival was not significantly improved with olaparib in the OlympiAD data. However, when you look at the subgroup of patients who were treated in the first-line setting for metastatic breast cancer, there was a 50% improvement in overall survival with the use of olaparib compared to treatment of physician’s choice,” Traina said. “In contrast, in later lines, [such as] second-[or] third-line, there was not that same significant difference.”
The EMBRACA study4 had a design similar to that of OlympiAD, explained Traina. This phase III trial investigated talazoparib versus standard single-agent chemotherapy of physician’s choice (eribulin, vinorelbine, gemcitabine, or capecitabine) in patients with germline BRCA1/2- mutant, locally advanced or metastatic HER2- negative breast cancer who had undergone 3 or fewer cytotoxic chemotherapy regimens and had prior taxane and/or anthracycline treatment.
Patients were randomized 2:1 to receive either 1 mg talazoparib daily or standard single-agent therapy of physician’s choice. Study results showed that median PFS was increased by 46% in patients given talazoparib (HR, 0.54; 95% CI, 0.41-0.71; P <.001).
In addition to the improvement in PFS, the PARP inhibitor led to improved health-related quality of life compared with the chemotherapy regimens, Traina said.
Next Steps in PARP Inhibition
Traina also discussed the BrighTNess study,5 which examined veliparib (ABT-888) in the neoadjuvant setting for patients with early- stage disease. Patients were assigned to 1 of 3 treatment arms: paclitaxel alone; paclitaxel plus carboplatin; or paclitaxel, carboplatin, and veliparib. The primary endpoint was patho- logic complete response. Study results showed that although adding carboplatin to paclitaxel improved the response rate, there was no benefit of adding veliparib to chemotherapy.
A smaller study, TBCRC048, is investigating whether mutations in DNA repair genes other than BRCA1/2 sensitize patients with metastatic breast cancer to olaparib therapy. Patients with germline BRCA1/2 mutations are excluded from the trial, although exclusively somatic BRCA1/2 mutations are allowed. In addition, eligible patients must have a mutation (either germline or somatic) in 1 of several other DNA repair genes, including CHEK2, ATM, PALB2, RAD51, BRIP1, and NBN6.
1. Traina TA. Novel therapeutic strategies for metastatic gBRCA-mutated and triple negative breast cancers. Presented at: 18th Annual International Congress on the Future of Breast Cancer East hosted by Physicians’ Education Resource, LLC; July 19-20, 2019; New York, NY.
2. Robson M, Im S-A, Senkus E, et al. Olparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533. doi: 10.1056/NEJMoa1706450
3. Robson ME, Im S-A, Senkus E, et al. OlympiAD final overall survival: olaparib versus chemotherapy treatment of physician’s choice (TPC) in patients with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). Presented at: American Association for Cancer Research Annual Meeting; April 14-18, 2018, Chicago, IL. Abstract CT038. http://www.abstractsonline.com/pp8/#!/4562/presentation/11138.
4. Litton JK, Rugo HS, Ettl J. et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753-763. doi: 10.1056/NEJMoa1802905
5. Loibl S, O'Shaughnessy J, Untch M, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomized, phase 3 trial. Lancet Oncol. 2018;19(4):497-509. doi: 10.1016/S1470-2045(18)30111-6
6. Tung N. Olaparib in metastatic breast cancer. https://clinicaltrials.gov/ct2/show/NCT03344965. NLM identifier: NCT03344965. Accessed September 15, 2019.
Although Barriers to Treating Brain Metastases Exist, Systemic Therapies Make Progress
By Tony Berberabe, MPH
The clinical development of treatments for breast cancer that has metastasized to the brain often stalls because of the hurdle presented by the blood–brain barrier, but preclinical literature places a greater emphasis on the blood-tumor barrier than the blood brain-barrier in the metastatic setting, said Carey K. Anders, MD, medical director of the Duke Center for Brain & Spine Metastasis at Duke Cancer Institute in Durham, North Carolina, during the 18th Annual International Congress on the Future of Breast Cancer® East hosted by Physicians’ Education Resource®, LLC, and held July 19 to 20, 2019, in New York, New York.1,2
In 2017, the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research issued a joint research statement recommending the broadening of eligibility criteria affecting several patient subgroups, including patients with treated/stable brain metastases; those with new, active, or progressive brain metastases; and those with leptomeningeal disease.3,4
The National Cancer Institute (NCI) reviewed the above recommendations and adopted a modified version of them for NCI-sponsored clinical trials. Patients with stable, treated brain metastases are now allowed to enroll if no evidence of progression is confirmed by follow-up imaging after the patient has received the central nervous system (CNS)-directed therapy. Patients with active brain metastases or leptomeningeal disease may enroll if the treating physician determines that CNS specific treatment is not required immediately and is unlikely to be needed during the first cycle of therapy.5
Clinical trials involving immune checkpoint inhibitors have also encouraged enrollment of patients with brain metastases, but only in melanoma and lung cancer, noted Anders.6
Local Therapy Updates
A study led by Masaaki Yamamoto, MD, demonstrated that stereotactic radiosurgery (SRS) administered to patients with 5 to 10 lesions produced overall survival (OS) results that were not inferior to SRS given to patients with 2 to 4 lesions in a cohort of 1194 patients who had 1 to 10 brain metastases.7
Tumors with volumes smaller than 4 mL were irradiated with 22 Gy at the lesion periphery, and those with volumes of 4 to 10 mL were given 20 Gy. The findings suggest that SRS might be a suitable alternative for patients with up to 10 brain metastases. Anders pointed out, however, that the study did not involve a head-to-head comparison of SRS and whole-brain radiation therapy (WBRT).
The RTOG 0614 trial8 evaluated the neuroprotective effects of the N-methyl-D-aspartate receptor antagonist memantine (Namenda) in 508 patients with brain metastases, who were randomized to receive 37.5 Gy WBRT in 15 fractions plus either 20 mg/day memantine or placebo. The investigators reported no difference in progression-free survival (PFS) or OS. In another, ongoing phase III trial, the use of radiation techniques that avoid the hippocampal region during WBRT is being evaluated with the goal of reducing neurocognitive decline in memantine-treated patients with brain metastases, said Anders.9
In a phase III trial conducted between February 2002 and December 2013 at 34 institutions across North America, patients with 1 to 3 brain metastases were randomized to receive SRS or SRS plus WBRT. The primary endpoint was cognitive deterioration at 3 months. Although the investigators reported no significant difference in OS between the 2 cohorts, deterioration was observed much less frequently in patients receiving SRS alone compared with those undergoing SRS plus WBRT (63.5% vs 91.7%; P <.001).10
Systemic Therapy Options
Systemic therapies for HER2-positive breast cancer with brain metastases include the commercially available agents lapatinib (Tykerb), T-DM1 (ado-trastuzumab emtansine; Kadcyla), neratinib (Nerlynx), anthracyclines, and platinum salts. Anders pointed out that neratinib is currently FDA-approved for high- risk, early-stage breast cancer only. However, the National Comprehensive Cancer Network guidelines for CNS cancers were expanded in 2018 to include neratinib combined with capecitabine or paclitaxel as an option for patients with HER2-positive breast cancer brain metastases.11
In the setting of progressive brain metastases post-trastuzumab/radiation therapy, Lin et al12 reported a CNS objective response rate (ORR) of 2.6% (RECIST) for lapatinib. These findings led to a larger study that combined lapatinib with capecitabine. In the lapatinib-only arm, a 6% CNS ORR was reported, but in the lapatinib plus capecitabine arm, a 20% CNS ORR was reported.13
In the TBCRC 022 trial, Freedman et al demonstrated a CNS ORR of 49% in patients who received neratinib plus capecitabine.14 Notable gastrointestinal (GI) adverse events were associated with neratinib/capecitabine but could be managed with an antidiarrheal agent, Anders said.
The NALA study involved patients with HER2- positive metastatic breast cancer who had received at least 2 prior lines of HER2-directed therapy. Results of this trial, which compared capecitabine plus neratinib versus capecitabine plus lapatinib, were announced at the 2019 ASCO Annual Meeting.15 The investigators reported that combining neratinib with capecitabine led to a 24% reduction in the risk of disease progression or death compared with lapatinib plus capecitabine.
Select ongoing clinical trials include T-DM1 plus temozolomide (NCT03190967), HER2CLIMB (NCT02614794), neratinib plus T-DM1 (NCT02236000), and high-dose trastuzumab (Herceptin; close to accrual, awaiting mature data; NCT03417544).
NCT03190967 is an NCI phase I/II study involving T-DM1 alone versus T-DM1 plus temozolomide (Temodar) for secondary prevention of HER2-positive breast cancer brain metastases following SRS. Another tyrosine kinase inhibitor, tucatinib, is highly selective for HER2. In a phase I study of tucatinib combined with capecitabine plus trastuzumab, a CNS ORR of 42% was reported.
This early trial led to the ongoing phase II HER2CLIMB study in patients with advanced HER2-positive metastatic/unresectable breast cancer, in which 612 patients have been randomized 2:1 to receive trastuzumab and capecitabine plus either tucatinib or placebo. The primary endpoint is PFS by RECIST 1.1.
1. Groothuis DR. The blood-brain and blood-tumor barriers: a review of strategies for increasing drug delivery. Neuro Oncol. 2000;2(1):45-59. doi: 10.1093/neuonc/2.1.45.
2. Anders CK. Management of breast cancer brain metastases. Presented at: 18th Annual International Congress on the Future of Breast Cancer® East; July 19-20, 2019; New York, NY.
3. Kim ES, Bruinooge SS, Roberts S, et al. Broadening eligibility criteria to make clinical trials more representative: American Society of Clinical Oncology and Friends of Cancer Research joint research statement. J Clin Oncol. 2017;35(33):3737-3744. doi: 10.1200/JCO.2017.73.7916.
4. Lin NU, Prowell T, Tan AR, et al. Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology-Friends of Cancer Research Brain Metastases Working Group. J Clin Oncol. 2017 Nov 20;35(33):3760-3773. doi: 10.1200/JCO.2017.74.0761.
5. Inclusion/Exclusion Criteria for National Cancer Institute (NCI) Sponsored Clinical Trials. NCI Recommended Protocol Text and Guidance based on Joint Recommendations of the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends). Version Date: 09/26/2018. ctep.cancer.gov/protocolDevelopment/docs/NCI_ASCO_Friends_Eligibility_Criteria.pdf
6. Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17(7):976-983. doi: 10.1016/S1470-2045(16)30053-5.
7. Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014;15(4):387-395. doi: 10.1016/S1470-2045(14)70061-0.
8. Brown PD, Pugh S, Laack NN, et al; Radiation Therapy Oncology Group (RTOG). Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 2013;15(10):1429-1437. doi: 10.1093/neuonc/not114.
9. Memantine hydrochloride and whole-brain radiotherapy with or without hippocampal avoidance in reducing neurocognitive decline in patients with brain metastases. clinicaltrials.gov/ct2/show/NCT02360215. Updated January 14, 2019. Accessed July 24, 2019.
10. Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA. 2016;316(4):401-409. doi: 10.1001/jama.2016.9839.
11. National Comprehensive Cancer Network. Central nervous system cancers, version 1.2018-March 20, 2018.
12. Lin NU, Carey LA, Liu MC, et al. Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2008;26(12):1993-1999. doi: 10.1200/JCO.2007.12.3588.
13. Lin NU, Diéras V, Paul D, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009;15(4):1452-1459. doi: 10.1158/1078-0432.CCR-08-1080.
14. Freedman RA, Gelman RS, Anders CK, et al; Translational Breast Cancer Research Consortium. TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol. 2019;37(13):1081-1089. doi: 10.1200/JCO.18.01511.
15. Saura C, Oliveira M, Feng Y-H, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: findings from the multinational, randomized, phase III NALA trial. J Clin Oncol. 2019;37(suppl 15; abstr 1002). doi: 10.1200/JCO.2019.37.15_suppl.1002.
16. Pembrolizumab in central nervous system metastases. https://clinicaltrials.gov/ct2/show/NCT02886585 Updated August 14, 2019. Accessed August 27, 2019.
Metastatic Breast Cancer
CDK4/6 Inhibitor Combinations Could Have Lasting Benefits in ER+ Metastatic Breast Cancer
CDK4/6 inhibitors offer clear benefits in progression-free survival (PFS), delayed time to chemotherapy, and overall survival (OS) in both pre- and postmenopausal patients with estrogen receptor (ER)-positive metastatic breast cancer, said Angela DeMichele, MD, MSCE, the Alan and Jill Miller Professor in Breast Cancer Excellence, co-leader of the Breast Cancer Research Program, and director of the Breast Cancer Clinical Trials Unit at the University of Pennsylvania’s Abramson Cancer Center in Philadelphia, Pennsylvania.1
She delivered a presentation on the changing field of care for ER-positive metastatic breast cancer at the 18th Annual International Congress on the Future of Breast Cancer® East hosted by Physicians’ Education Resource®, LLC, and held July 19 to 20, 2019, in New York, New York.
DeMichele said that patients inevitably develop resistance to treatment, but the good news is that clinical results for the 3 FDA-approved CDK4/6 inhibitors—abemaciclib (Verzenio), palbociclib (Ibrance), and ribociclib (Kisqali)—have demonstrated efficacy in patients who have progressed following endocrine therapy. Palbociclib was initially approved by the FDA in February 2015 for use in combination with letrozole (Femara) as a frontline treatment for postmenopausal women with ER-positive, HER2- negative metastatic breast cancer.2
In findings from the phase III PALOMA-3 trial, the median PFS among patients who had progressed on endocrine therapy was 11.2 months for palbociclib plus fulvestrant versus 4.6 months for placebo plus fulvestrant (HR, 0.50; 95% CI, 0.40-0.62; P <.000001).3,4
In MONARCH 2, 669 women with HR-positive, HER2-negative advanced breast cancer resistant to endocrine therapy were assigned to abemaci- clib plus fulvestrant or to placebo plus fulvestrant. At a median follow-up of 19.5 months, the median PFS with the combination was 16.4 months compared to 9.3 months with placebo (HR, 0.55; 95% CI, 0.45-0.68; P <.001). The objective response rate was 48.1% versus 21.3%, respectively.5
Results from MONALEESA-3 showed an improvement in PFS with the combination of ribociclib plus fulvestrant in postmenopausal patients with HR-positive, HER2-negative advanced breast cancer. At the time of data cutoff in November 2017, the median PFS for the entire cohort was 20.5 months with ribociclib/fulves- trant versus 12.8 months with placebo/fulvestrant (HR, 0.59; 95% CI, 0.48-0.73; P <.001).6
In comparison, adding a CDK4/6 inhibitor in first-line therapy resulted in a median PFS of 27.6 months (HR, 0.56; 95% CI, 0.46-0.69) in PALOMA-2 and 25.3 months (HR, 0.57; 95% CI, 0.46-0.70) in MONALEESA-2. Median PFS was not reached in the frontline setting in MONALEESA-3.
PALOMA-3 was the first trial to provide evidence that treatment with a CDK4/6 inhibitor could improve median OS.7 The addition of palbociclib to fulvestrant demonstrated a trend toward improving OS compared with placebo/fulvestrant; however, the difference of 6.9 months did not reach statistical significance (34.9 vs 28.0 months; HR, 0.81; 95% CI, 0.64-1.03; P = 0.09).3 PALOMA-3 investigators also analyzed circulating tumor DNA (ctDNA) in paired blood samples from patients before and after treatment with the goal of identifying genetic changes that had emerged, driving drug resistance.
They found driver mutations in PIK3CA and ESR1 in both treatment arms, as well as palbociclib-specific mutations in RB-1.8 In the phase I/II TRINITI-1 trial, patients were assigned to a triplet regimen of ribociclib, the mTOR inhibitor everolimus (Afinitor), and the aromatase inhibitor exemestane (Aromasin) in the single-arm trial. In data from 95 evaluable patients presented at the 2019 American Society of Clinical Oncology Annual Meeting, the triplet therapy demonstrated a median PFS of 5.7 months (95% CI, 3.6-9.1 months), with a 1-year PFS rate of 33.4% (95% CI, 22.8%- 44.4%). At 24 weeks, the clinical benefit rate was 41.1% (95% CI, 31.1%-51.6%), 4 times greater than the minimum threshold for the study (>10%). The overall response rate was 8.4% (95% CI, 3.7%-15.9%), including 1 complete response and 7 partial responses.9,10
The most common gene alterations detected in ctDNA were in PIK3CA and ESR1. Additionally, 46.7% of patients with a PIK3CA or ESR1 mutation had a concomitant mutation in the other gene. The median PFS in patients with ESR1 wild-type disease was 6.9 months compared with 3.5 months for those with mutated ESR1. Patients with PIK3CA wild-type tumors had superior median PFS compared with those who had a gene alteration (7.3 vs 5.7 months).11,12
1. DeMichele A. Evolving therapeutic strategies for ER+ metastatic breast cancer. Presented at: 18th Annual International Congress on the Future of Breast Cancer East; July 19-20, 2019; New York, NY.
2. Pfizer receives U.S. FDA accelerated approval of Ibrance® (palbociclib) [news release]. New York, NY: Pfizer Inc; February 3, 2015. bit.ly/2zxgshS. Accessed July 26, 2019. 3. Turner NC, Slamon DJ, Ro J, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379(20):1926-1936. doi: 10.1056/NEJMoa1810527.
4. Ibrance (palbociclib): Summary of product characteristics. Electronic medicines compendium (emc). www.medicines.org.uk/emc/product/4449/smpc. Published July 16, 2019. Accessed September 3, 2019.
5. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875-2884. doi: 10.1200/JCO.2017.73.7585.
6. Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-posi tive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465-2472. doi: 10.1200/JCO.2018.78.9909.
7. FDA expands ribociclib indication in HR-positive, HER2-negative advanced or metastatic breast cancer. FDA website. www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-ribociclib-indication-hr-positive-her2-negative-advanced-or-metastatic-breast-cancer. Published July 18, 2018. Accessed July 26, 2019.
8. New option for women with advanced breast cancer resistant to hormone therapy [ESMO 2018 press release]. Munich, Germany: European Society for Medical Oncology; October 20, 2018. www.esmo.org/Press-Office/Press-Releases/PALOMA3-breast-cancer-palbociclib-fulvestrant-Cristofanilli. Accessed September 3, 2019.
9. O’Leary B, Cutts RJ, Liu Y, et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 2018;8(11):1390-1403. doi: 10.1158/2159-8290.CD-18-0264.
10. Bardia A, Hurvitz SA, DeMichele A, et al. Triplet therapy (continuous ribociclib, everolimus, exemestane) in HR+/HER2− advanced breast cancer postprogression on a CDK4/6 inhibitor (TRINITI-1): efficacy, safety, and biomarker results. J Clin Oncol. 2019;37(suppl 15; abstr 1016). doi: 10.1200/JCO.2019.37.15_suppl.1016.
11. Triplet therapy confers benefit among certain patients with advanced breast cancer. Healio HemOnc Today website. www.healio.com/hematology-oncology/breast-cancer/news/online/%7Be782030f-fd3f-47d2-9735-ad3c2d4cd2e6%7D/triplet-therapy-confers-benefit-among-certain-patients-with-advanced-breast-cancer. Published June 13, 2019. Accessed September 3, 2019.
Patricia Jakel, MN, RN, AOCN
UCLA Solid Tumor Program
THE ADDITION OF CDK4/6 inhibitors offers patients living with metastatic or locally advanced breast cancer a new, easily tolerated, and exciting treatment option. Oncology nurses have a pivotal role in preventing resistance by educating patients and their caregivers on the importance of adherence to these oral agents.
Maintaining a blame-free environment and praising patients for adherence helps establish trusting and effective relationships with the healthcare provider, leading to improved adherence. We must also understand the barriers, know the adverse event profiles, and educate patients at their appropriate grade level.
CDK4/6 inhibitors put more responsibility on patients, caregivers, and/or family members to ensure that individuals take these medications on time. In your daily practice, assess the oral adherence, offer interventions, reassess, and involve the patient and family. Remind patients and caregivers that medication nonadherence has been associated with poor cancer outcomes and can lead to increased physician visits, more frequent or longer hospitalizations, disease progression, development of resistance, and even death.
ER+ Breast Cancer
Strategies for Overcoming Resistance to CDK4/6 Inhibition Emerge in ER+ Breast Cancer
Both cell cycle-specific and -nonspecific mechanisms of acquired resistance to CDK4/6 inhibition in estrogen receptor (ER)-positive breast cancer are targeted by multiple promising agents and combinations developed for the second-line management of metastatic disease.
“CDK4/6 inhibitors in combination with anti-ER agents have clearly played a major role in the frontline setting for ER-positive disease,” said Dejan Juric, MD, to an audience at the 18th Annual International Congress on the Future of Breast Cancer® East hosted by Physicians’ Education Resource®, LLC, and held July 19 to 20, 2019, in New York, New York. “Novel agents will be critical in developing combination strategies and delaying the use of chemotherapy agents in these patients.”
Typically, hormonal and targeted therapy combinations are used to treat patients with ER-positive disease, although chemotherapy is still a viable option in some patients, with overall response rates between 15% and 25%.1 Three trials, in part, established the role of CDK4/6 inhibitors in ER-positive, HER2-negative breast cancer: PALOMA-2 (NCT01740427), MONALEESA-3 (NCT02422615), and MONARCH 3 (NCT02246621) investigated palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio), respectively. All 3 trials had impressive hazard ratios (<0.60) for progression-free survival (PFS) compared with the placebo arm, said Juric, director of the Termeer Center for Targeted Therapies and program director of investigational cancer therapeutics at Massachusetts General Hospital Cancer Center in Boston, Massachusetts. “These results point to the fact that CDK4/6 is important to the ER axis,” he said, explaining that the agents are not identical.
The first step in progression through G1 phase of the cell cycle involves the cyclin D–CDK4/6 axis and is driven by CDK4/6. However, the second (and frequently forgotten) step toward S phase entry is mediated by CDK2 bound to cyclin E. Beyond CDK2, loss of the retinoblastoma (RB) tumor suppressor and amplification of the drug targets CDK4 and CDK6 are some examples of cell cycle-specific mechanisms of resistance to these agents. For example, loss-of-function mutations in FAT1 lead to marked elevations in CDK6 and to poorer outcomes.2 Cell cycle-nonspecific mechanisms of resistance may include loss of ER or progesterone receptor expression as well as activation of the FGFR pathway.3
Treatment of Nonmutant Disease
In the phase III BOLERO-2 trial, the combination of everolimus (Afinitor), an mTOR inhibitor, plus endocrine therapy with exemestane (Aromasin) in patients with recurrent disease following aromatase inhibitor (AI) treatment led to longer PFS with the combination versus placebo plus exemestane (6.9 vs 2.8 months; HR, 0.43; 95% CI, 0.35-0.54; P <.001).4 Results of the phase II PrE0102 study indicated that patients with AI-resistant disease receiving fulves- trant (Faslodex) also had longer PFS with the addition of everolimus compared with placebo (10.3 vs 5.1 months; HR, 0.61; 95% CI, 0.40-0.92; stratified log-rank P = .02).5
PI3K/AKT/MTOR Pathway Alterations
The top target for treatment of ER-positive, HER2- negative disease, particularly in the second-line setting, is mutated PIK3CA, which is found in approximately 40% of patients in this population. The efficacy of alpelisib (Piqray), a PI3Ka-specific inhibitor, was assessed in the phase III SOLAR-1 trial. The results showed improved PFS for alpelisib over placebo (11.0 vs 5.7 months) when combined with fulvestrant in patients with PIK3CA-mutated tumors (HR, 0.65; 95% CI, 0.50-0.85; P <.001).6
In a subgroup analysis of SOLAR-1 presented at the 2019 American Society of Clinical Oncology Annual Meeting, alpelisib plus fulvestrant showed the greatest benefit in endocrine-resistant patients in the second-line setting. These patients experienced a 39% reduction in the risk of disease progression or death compared with patients in the placebo arm (HR, 0.61; 95% CI, 0.42-0.89).7
Juric noted that PIK3CA-mutant tumors have a complex genomic landscape and that multiple oncogenic drivers co-occur frequently. It is rare to encounter a patient whose tumor harbors a PIK3CA mutation and no others. “We need to continuously think about the genomic landscape of these tumors, the so-called conditional effect,” he said. An additional consideration in treatment selection is that PI3K inhibition causes rapid increases in the mRNA and protein levels of ER as well as in the transcription of ER target genes, thus limiting the efficacy of the PI3K-inhibiting agent. The addition of an ER-inhibiting agent to the drug regimen may counteract this effect.
Dual-vertical inhibition may be necessary to overcome single-agent resistance caused by frequently co-occurring genomic alterations and bypass pathways.8 Strategies that simultaneously target two vertical nodes within the PI3K pathway—CDK4/6 and either PI3K, AKT, or mTOR—are now being investigated in ER-positive disease and may represent an important step forward in the treatment of PIK3CA-mutant, ER-positive breast cancer, Juric said.
Inactivating alterations in AKT also drive the PI3K pathway and are commonly seen in ER-positive disease. The phase II FAKTION trial examined the efficacy of the potent and selective AKT inhibitor capivasertib (AZD5363) plus fulvestrant in patients with ER-positive tumors following progression or relapse on an AI. PFS was significantly extended in the intent-to-treat population, from 4.8 months in the fulvestrant/ placebo arm to 10.3 months in the combination arm (unadjusted HR, 0.58; 95% CI, 0.39-0.84; P =.004). The objective response rate (ORR) with capivasertib was 41% versus 12% with placebo.9
Cell Cycle-Nonspecific Targets
Activating mutations in estrogen receptor 1 (ESR1), a drug target without a direct role in the cell cycle, are common in AI-pretreated patients. In the BOLERO-2 trial, patients with ESR1 mutations had worse overall survival (OS) than those who had wild-type ESR1, with particularly short OS associated with the ESR1 Y537S point mutation. Juric suggested that, unlike the ESR1 D538G mutation, patients with ESR1 Y537S tumors may not experience an improvement in PFS from the addition of everolimus to exemestane (HR, 0.98; 95% CI, 0.49-1.94; P = .95).10 Two classes of drugs are being developed that will be particularly beneficial for patients with ESR1-mutant disease. The selective ER degrader elacestrant (RAD1901) has shown promise in patients following endocrine therapy, with an ORR of 23% despite the large number of heavily pretreated patients.11,12 A phase III study is currently ongoing (NCT03778931).
1. Juric D. New agents and markers for endocrine therapy resistance. Presented at: 18th Annual International Congress on the Future of Breast Cancer East hosted by Physicians’ Education Resource, LLC; July 19-20, 2019; New York, NY.
2. Li Z, Razavi P, Li Q, et al. Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway. Cancer Cell. 2018;34(6):893-905.e8. doi: 10.1016/j.ccell.2018.11.006.
3. Pandey K, An HJ, Kim SK, et al. Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: a review. Int J Cancer. 2019;145(5):1179-1188. doi: 10.1002/ijc.32020.
4. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer. N Engl J Med. 2012;366(6):520-529. doi: 10.1056/NEJMoa1109653.
5. Kornblum N, Zhao F, Manola J, et al. Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102. J Clin Oncol. 2018;36(16):1556-1563. doi: 10.1200/JCO.2017.76.9331.
6. André F, Ciruelos E, Rubovszky G, et al; SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi: 10.1056/NEJMoa1813904.
7. Juric D, Loibl S, Andre F, et al. Alpelisib (ALP) with fulvestrant (FUL) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC): primary or secondary resistance to prior endocrine therapy (ET) in the SOLAR-1 trial. J Clin Oncol. 2019;37(suppl 15; abstr 1038). doi: 10.1200/JCO.2019.37.15_suppl.1038.
8. Vora SR, Juric D, Kim N, et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell. 2014;26(1):136-149. doi: 10.1016/j.ccr.2014.05.020.
9. Jones RH, Carucci M, Casbard AC, et al. Capivasertib (AZD5363) plus fulvestrant versus placebo plus fulvestrant after relapse or progression on an aromatase inhibitor in metastatic ER-positive breast cancer (FAKTION): a randomized, double-blind, placebo-controlled, phase II trial. J Clin Oncol. 2019;37(suppl 15; abstr 1005). doi: 10.1200/JCO.2019.37.15_suppl.1005.
10. Chandarlapaty S, Chen D, He W, et al. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol. 2016;2(10):1310-1315. doi: 10.1001/jamaoncol.2016.1279.
11. Bardia A, Kabos P, Elledge R, et al. Evaluation of RAD1901, a novel investigational, selective estrogen receptor degrader (SERD), for the treatment of ER-positive (ER+) advanced breast cancer. J Clin Oncol. 2017;35(suppl 15; abstr 1014). doi: 10.1200/JCO.2017.35.15_suppl.1014.
12. Radius (RDUS) Announces Positive Data on Breast Cancer Drug. Yahoo! Finance. https://finance.yahoo.com/news/radius-rdus-announces-positive-data-152603559.html. Published June 5, 2017. Accessed September 11, 2019.
Practical Assesment Tools Guide Treatment Decisions in Geriatric Oncology
Despite advances in therapeutic treatment for patients with breast cancer, assessment tools and access to investigative treatments for older patients need to be expanded. Aging is not a homogeneous process, and treatment decisions for geriatric patients with breast cancer should be individualized based on the fitness and frailty of the patient, according to Armin Shahrokni, MD, MPH.
In a presentation at the 18th Annual International Congress on the Future of Breast Cancer® East, hosted by Physicians’ Education Resource®, LLC, and held from July 19 to 20, 2019, in New York, New York, Shahrokni, a geriatrician and oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, emphasized the importance of performing a comprehensive geriatric assessment for each patient to determine optimal treatment.1
Seventy percent of patients with cancer are ≥65 years old, and the population of geriatric patients with cancer is projected to significantly increase over the next 20 years. For men and women aged ≥70, the lifetime probability of developing cancer is 1 in 3 and 1 in 4, respectively.2
Breast cancer is most frequently diagnosed in women aged 55 to 64 years, with a median age at diagnosis of 62 years. However, the highest percentage of deaths due to breast cancer (22.9%) occurs in women aged 65 to 74 years, with a median age at death of 68 years.3
However, this population comprises a spectrum of patients, some of whose physical condition does not match the age on their chart. Assessment of fitness and frailty, determination of life expectancy, and a balance of the toxicity and potential benefits of treatment should replace age when making clinical decisions, according to Shahrokni.
Comprehensive Geriatric Assessment
Implementation of geriatric assessments in practice can aid in the identification of conditions that are often overlooked in routine care. In 1989, the National Institutes of Health first proposed comprehensive geriatric assessment as a way to identify patient problems in order to coordinate care plans.1 Both the American Society for Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have issued guidelines for geriatric oncology for the practical assessment and management of this patient population.2,4
Traditional oncology performance measures do not comprehensively assess geriatric patients, who are at higher risk of adverse events caused by chemotherapy. With uniform treatment recommendations by age rather than by fitness and frailty, some patients may experience overtreatment, whereas others may be undertreated. The principal components of a geriatric assessment include functional status, comorbidities, cognition, and psychological, social, and nutritional status.1
The Cancer and Aging Research Group (CARG) provides a brief Geriatric Assessment Tool5 designed to identify patients at high risk of chemotherapy toxicity. The predictive tool allows patients to complete a 20- to 30-minute self-assessment that includes activities of daily living, instrumental activities of daily living, number of falls in the prior 6 months, number and types of comorbid conditions, number of medications, vision and hearing status, mental health condition, social activity limitations, social support, and any unintentional weight loss in the prior 6 months.
Physicians then follow up with an estimated 10-minute assessment in the clinic, where they perform a cognitive examination through the Blessed Orientation Memory Concentration test, assess functional status with the Karnofsky Performance Scale (KPS) and timed up and go test, and evaluate nutritional status through body mass index calculation.1
CARG also provides a Chemo-Toxicity Calculator,5 which combines geriatric assessment variables with the patient’s medical history to generate a risk score that estimates the specific likelihood of chemotherapy toxicity. In a study comparing this tool and physician-rated KPS, only the Chemo-Toxicity Calculator successfully predicted grade 3 to 5 chemotherapy toxicity in older patients.6
Balancing Life Expectancy With Treatment Goals
Defining the goals of treatment for geriatric patients with cancer must take the life expectancy of the patient into consideration. One resource recommended in the ASCO and NCCN guidelines is ePrognosis, an online repository of geriatric prognostic indices developed by the University of California, San Francisco, that incorporates noncancer comorbidities such as alcohol abuse, renal failure, pulmonary circulation disorders, and HIV/AIDS status into mortality risk calculation.2
Treatment selection should also focus on the patient’s goals, which may not always include longevity. “There are times that patients are not in agreement with [treatment decisions], so [clinicians should] explore that,”said Shahrokni.
In a secondary analysis of a Cancer and Leukemia Group B study (NCT00024102) focusing on adjuvant treatment of older patients with breast cancer (N = 256), investigators reported that 42% of patients experienced a decline in physical function from before until the end of chemotherapy. At the 12-month follow-up, 47% of those patients had recovered physical function within 10 points of their baseline value based on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire physical function subscale.
Regardless of whether a decline in physical function had occurred by the end of chemotherapy, 30% experienced a decline at 12 months. The authors noted that further research is needed to determine specific types and timing of interventions aimed at increasing functional recovery to improve outcomes for these patients.7
Expanding research to benefit this population includes access to investigational treatments that are limited for older patients, who are often excluded from clinical trials because of comorbidities. Among patients enrolled in National Cancer Institute Cooperative Group clinical trials, less than 25% are aged 65 to 74 years, and less than 10% are 75 years or older.2
1. Shahrokni A. Treatment considerations for older patients. Presented at: 18th Annual International Congress on the Future of Breast Cancer® East, hosted by Physicians’ Education Resource®, LLC; July 19-20, 2019; New York, NY.
2. Mohile SG, Dale W, Somerfield MR, et al. Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology. J Clin Oncol. 2018;36(22):2326-2347. doi: 10.1200/JCO.2018.78.8687.
3. SEER Cancer Stat Facts: Female Breast Cancer. National Cancer Institute. Bethesda, MD. https://seer.cancer.gov/statfacts/html/breast.html. Accessed August 30, 2019.
4. NCCN Clinical Practice Guidelines in Oncology. Older Adult Oncology, version 1.2019. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/senior.pdf. Updated January 8, 2019. Accessed July 26, 2019.
5. Geriatric assessment tools. CARG Cancer and Aging Research Group. http://www.mycarg.org/SelectQuestionnaire. Accessed August 30, 2019.
6. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011;29(25):3457-3465. doi: 10.1200/JCO.2011.34.7625.
7. Hurria A, Soto-Perez-de-Celis E, Allred JB, et al. Functional decline and resilience in older women receiving adjuvant chemotherapy for breast cancer. J Am Geriatr Soc. 2019;67(5):920-927. doi: 10.1111/jgs.15493.