O’Shaughnessy Explores Mechanisms of Resistance to CDK4/6 Inhibition in ER+ Breast Cancer

Joyce O’Shaughnessy, MD

Celebrating Women Chair in Breast Cancer Research

Baylor University Medical Center

Director, Breast Cancer Research Program

Texas Oncology

US Oncology

Dallas, TX

CASE SUMMARY

• A 62-year-old woman presented with palpable right breast mass that had been slowly growing for 1 year with palpable axillary nodes.
• Medical history: hypertension, hyperlipidemia, and depression; taking anti-depressants for mild depression
• Mammography and ultrasound: 5-cm tumor, invasive ductal carcinoma
• Liver function tests within normal limits
• Breast biopsy: grade 2 invasive ductal carcinoma; estrogen receptor (ER) positive, progesterone receptor (PR) positive, HER2 0 by immunohistochemistry, germline panel testing negative
• Axillary lymph nodes: enlarged
• T3 cN1 M0, stage IIIA; ECOG performance status: 0
• Underwent breast-conserving surgery with sentinel lymph node biopsy. Pathological examination of tissue from breast and lymph node showed regression of the tumor.
• Four positive lymph nodes
• Adjuvant treatment:
  • Radiation therapy to breast and regional lymph nodes
  • Received doxorubicin and cyclophosphamide followed by paclitaxel for 6 cycles
  • Followed with anastrozole for 5 years\
• No clinical evidence of disease for 2 years post anastrozole
• At follow-up visit, patient complained of increased bone pain in hips and lower back and increased fatigue.
• PET-CT scan confirmed liver lesions and bone scan identified lesions in the pelvis, spine, and femur.
• Circulating tumor DNA (ctDNA) was sent for genomic testing. Did not show PIK3CA, ESR1 or other actionable mutations.
• Biopsy of bone metastasis: ER positive/PR negative, HER2 1+

What is the role of cyclin-dependent kinase (CDK) 4/6 inhibitors in treating metastatic ER-positive breast cancer?

O’SHAUGHNESSY: CDK4/6 inhibitors have become the ingrained standard in the first-line metastatic setting, whether patients are premenopausal or postmenopausal. Even for patients with visceral disease that’s symptomatic and is quite advanced, as long as the patients are not in organ failure where they are needing to be admitted to the hospital…or where their liver function tests are so abnormal that you’re looking to give them the smallest amount of chemotherapy…[they used].

Aside from those very rare situations, there’s no question that CDK4/6 inhibitors offer our patients much more in the way of benefit. Whether the patient is pre- or postmenopausal, whether they had been off adjuvant endocrine therapy or have nonmetastatic disease, in which case you’re going to give them an AI [aromatase inhibitor] plus or minus an LHRH [luteinizing hormone-releasing hormone] agonist with a CDK4/6 inhibitor, or if they’re unfortunate enough to be recurrent on adjuvant AI therapy, then we’re going to almost always give them fulvestrant [Faslodex] and a CDK4/6 inhibitor. There’s very little room for chemotherapy in the first line.

What is the mechanism of action of CDK4/6 inhibitors?

Fifteen percent of breast cancers, those with luminal B [disease], have amplification of cyclin D1. It complexes with cyclin D1 to phosphorylate RB [retinoblastoma protein] and then RB releases E2F…and E2F is the transcription factor that can drive the cell cycle.¹ It’s just a very fortuitous discovery of the nodal point of CDK4/6, and there are so many different growth and survival pathways in the breast cancer cell that phosphorylate CDK4/6 and allow it then to dimerize to bind to cyclin D1. It’s downstream from so many ways to drive growth and survival. It’s an excellent target...but it doesn’t help every patient. Still, it helps the vast majority of patients.

What causes cancer to not respond or stop responding to CDK4/6 inhibition?

There are many different mechanisms of resistance to CDK4/6 inhibitors. We don’t understand what drives primary resistance. There are approximately 20% of patients who don’t benefit from CDK4/6 inhibitors. That might be a little high, but the studies show clinical benefit rates in the first-line metastatic setting of approximately 80%, so that means approximately 20% [don’t benefit].² It seems a little high, but we have patients who…only [respond for] 6 to 9 months. We’re very disappointed in that. I don’t think we understand why that is. What we’ll probably find out is that there’s so much genomic instability in the context of homologous recombination deficiency [HRD] that even inhibiting the central proteins that drive growth and survival is not enough.

There are retrospective analyses from 3 different datasets, 2 in germline BRCA2, and another from the meta-analysis of the 3 ribociclib [Kisqali] trials, where tissue was looked at by PAM50, looking at basal-like HER2-enriched luminal A and luminal B, and finding out that [in] HR-positive, HER2-negative, first-line metastatic trials, that subset of the basal-like ER-positive is a small subset.³ Basal-like always [makes you think of] triple-negative breast cancer, HRD, and a lot of genomic instability. Those patients did very poorly with the ribociclib trials in the first line. In the 2 BRCA2 studies, it looked at endocrine therapy plus/minus CDK4/6 inhibitors.^4,5

They’re a small retrospective analysis, so they’re hypothesis generating, but showed that the median PFS [progression-free survival] in the germline BRCA2 [population] was approximately 7 months, which is way shorter than we expect from first-line CDK4/6 inhibitors. The primary resistance mechanisms are going to be largely in our patients who have inherited breast cancers or who have acquired breast cancers that are driven a lot by genomic instability because of substantial DNA repair problems. We don’t know that yet. We don’t have a way of [identifying] patients who are less likely to benefit.

However, when patients do benefit, and then they progress, what are the acquired mechanisms of resistance? They were clearly sensitive to start off with, [so] what drives resistance? We’re learning a lot about that. We don’t have ways to target all of those, but certainly activation of the PI3 kinase pathway is a big one, whether it be a rise in PIK3CA mutations on ctDNA, AKT mutations, loss of PTEN, for example, or others. ESR1 mutations are very common; 40% of the time you’ll find them after progression on a CDK4/6 inhibitor.⁶ If you get ctDNA on somebody newly diagnosed with ER-positive, HER2-negative metastatic breast cancer…[the] percentage of the time you will find an ESR1 mutation [in the] first-line metastatic [setting]…is 3% to 5%.

How do you use ctDNA to identify mutations in this setting?

I do ctDNA at initial presentation. We all are interested in what’s there, and that’s going to really reflect the mutations that [were] present in the primary breast cancer from the beginning and led to this developing into a metastasis. But if we want to look at the mutations that are driving resistance to therapy, we need to check after patients progress on first-line [therapy]. If you don’t find what you’re looking for [after] they’ve progressed on the first line, the National Comprehensive Cancer Network guidelines now support serial monitoring of ctDNA.⁷ If you don’t find that ESR1 mutation…that’s strictly acquired after the first line, you check again after the second line and then after the third line.

If you get a loss of function mutation in RB…the question is, would CDK4/6 inhibitors even work? Maybe I won’t pick another CDK4/6 inhibitor in the second line, but I would say that is still a work in progress. I was involved in a small retrospective study. We showed that patients getting abemaciclib [Verzenio], having progressed on palbociclib [Ibrance], still could have benefit even in the face of RB1 mutation.⁸ We can find HER2 [pathway] mutations as mechanisms of resistance. We can find FGFR1 amplification, which is a big one that we can’t target, unfortunately. We could find high cyclin D1 amplification that also is a driver of resistance. There are other ones, but I’m mainly focusing on the ones where we can do something.

How did the CDK4/6 inhibitors plus AI perform in phase 3 trials in terms of overall survival (OS)?

I’ll summarize by saying that starting with palbociclib, we did not see a statistically significant OS improvement in PALOMA-2 [NCT01740427].⁹ If you look at the hazard ratios for PFS for [palbociclib, abemaciclib, and ribociclib], they are basically all the same, so we all expected the OS results to be very similar because the HR for PFS is [approximately] 0.55.^10-12 With regard to OS with PALOMA-2, it was shocking there wasn’t a survival advantage.

They were [in follow-up for 7 years] when they presented the primary OS. There was an imbalance in patients lost to follow-up. On the placebo arm, it was 22% compared with half of that on the palbociclib arm.⁹ It makes you wonder. We’re not going to have another definitive study of AI plus/minus palbociclib, but the real-world evidence, the P-REALITY X trial [NCT05361655], for example, [is ongoing]. We all know that you have to take real-world evidence with a grain of salt. But these are the Flatiron Health Analytic Database real-world evidence data. They said if you look at patients in the first-line metastatic [setting] treated with palbociclib/AI vs AI, there’s an OS advantage if you look at real-world evidence.¹³

There will be other studies, not the definitive AI plus palbociclib [studies]… but there will be other studies coming out where palbociclib and AI are in the first-line setting. If we look at the first-line studies, [patients] in the first-line setting with ribociclib and abemaciclib are living in the 64- to 67-month range.^14,15 If we ever see data with palbociclib, it’s not going to be level 1 evidence.

We’ve got the 67 months [with abemaciclib] and the 64 months [with ribociclib], but for palbociclib, median OS is 54 months, so it’s considerably less than what we see with abemaciclib and ribociclib. We have some real-world evidence that says palbociclib added to an AI substantially improves OS.¹³ We’ll have to stay tuned for other studies that look at AI plus palbociclib that can give us mature survival data, so we can see if we’re in the ballpark of 67 months. Because those numbers, 67 months and 64 months median OS, are way longer than we’ve ever seen in the first-line setting with any therapeutic.

PALOMA-3 [NCT01942135], which was fulvestrant plus/minus palbociclib, gave us an interesting piece of information. The OS data didn’t meet statistical significance [but] it came very close.¹⁶ That trial had approximately 25% of patients who had prior chemotherapy. It was a different second-line trial. The other second-line fulvestrant plus/ minus [CDK4/6 inhibitor trials] didn’t allow any prior chemotherapy. It wasn’t exactly the same trial design, but what’s interesting about PALOMA-3 is that when you look at the 20% of patients in PALOMA-3 whose breast cancer was primary refractory to endocrine therapy, they [progressed after] adjuvant endocrine therapy in 2 years or they [progressed after] first-line AI within 6 months.

There was zero survival advantage for primary refractory patients.¹⁷ In fact, the [Kaplan-Meier] curves were slightly going in the opposite direction. But if you look at the patients with endocrine therapy– sensitive breast cancer, which was defined as not being one of those [bad] actors with recurrence within 2 years of adjuvant therapy or [quickly progressing] through first-line AI, it was a 10-month improvement in OS.¹⁷ I’ve learned that palbociclib is not a good choice for our patients with more endocrine therapy– resistant disease. The more you’re worried that this patient’s cancer is not going to benefit from single-agent endocrine therapy, that’s good reason not to go with palbociclib.

What was the significance of the different trials of ribociclib?

MONALEESA-2 [NCT01958021] was AI plus/minus ribociclib in postmenopausal patients, MONALEESA-7 [NCT02278120] was AI plus/minus ribociclib with an LHRH agonist in premenopausal women, and then MONALEESA-3 [NCT02422615] was the first- and second-line trial of fulvestrant plus/minus ribociclib. All 3 showed statistically significant OS advantage.^14,18,19 The HRs were 0.73 to 0.76. The preponderance of data with regard to survival on CDK4/6 inhibitors is with ribociclib. That’s the CDK4/6 inhibitor that has accumulated the most positive survival data.

MONALEESA-2 was in postmenopausal patients [who received] first-line AI plus/minus ribociclib. There was a very nice OS benefit of 64 months.¹⁴ That was the longest OS we had ever seen in any first-line metastatic trial, and the [curves] just continue to pull apart over time.

MONALEESA-3 is in the first and second line, fulvestrant plus/minus ribociclib. We see a very nice improvement there in OS with an HR of 0.72.¹⁹ The first and second line were still benefiting from ribociclib with regard to survival. Then we have MONALEESA-7, for premenopausal women with AI. Tamoxifen is not used with ribociclib because tamoxifen can prolong the QTc. It doesn’t amount to anything clinically, but it’s a cautionary note. The FDA chose not to approve tamoxifen and ribociclib in combination. [The trial] is nonsteroidal AI with an LHRH agonist plus/minus ribociclib, and the [HR for] OS is 0.76.¹⁸ Clearly, these are by far the strongest OS data we have in premenopausal women. Whether they had a prior AI or whether they had prior tamoxifen, there is survival in both groups of patients.

_REFERENCES

_{1. Spring LM, Wander SA, Andre F, Moy B, Turner NC, Bardia A. Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet. 2020;395(10226):817-827. doi:10.1016/S0140-6736(20)30165-3}

_{2. Nabieva N, Fasching PA. CDK4/6 Inhibitors-overcoming endocrine resistance is the standard in patients with hormone receptor-positive breast cancer. Cancers (Basel). 2023;15(6):1763. doi:10.3390/cancers15061763}

_{3. Carey L, Solovieff N, André F, et al. Correlative analysis of overall survival by intrinsic subtype across the MONALEESA-2, -3, and -7 studies of ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer. Cancer Res. 2022;82(suppl 4):GS2-00. doi: 10.1158/1538-7445.SABCS21-GS2-00}

_{4. Safonov A, Bandlamudi C, Tallón de Lara P, et al. Comprehensive genomic profiling of patients with breast cancer identifies germline-somatic interactions mediating therapy resistance. Cancer Res. 2022;82(suppl 4):GS4-08. doi:10.1158/1538-7445.SABCS21-GS4-08}

_{5. Collins JM, Nordstrom BL, McLaurin KK, et al. A real-world evidence study of CDK4/6 inhibitor treatment patterns and outcomes in metastatic breast cancer by germline BRCA mutation status. Oncol Ther. 2021;9(2):575-589. doi:10.1007/s40487-021-00162-4}

_{6. Liao H, Huang W, Pei W, Li H. Detection of ESR1 mutations based on liquid biopsy in estrogen receptor-positive metastatic breast cancer: clinical impacts and prospects. Front Oncol. 2020;10:587671. doi:10.3389/fonc.2020.587671}

_{7. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 1.2024. Accessed January 25, 2024. http://tinyurl.com/2khn5xtm}

_{8. Wander SA, Han HS, Zangardi ML, et al. Clinical outcomes with abemaciclib after prior CDK4/6 inhibitor progression in breast cancer: a multicenter experience. J Natl Compr Canc Netw. Published online March 24, 2021. doi:10.6004/jnccn.2020.7662}

_{9. Finn RS, Rugo HS, Dieras VC, et al. Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/HER2− ABC): Analyses from PALOMA-2. J Clin Oncol. 2022;40(suppl 17):LBA1003. doi:10.1200/JCO.2022.40.17_suppl.LBA1003}

_{10. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936. doi:10.1056/NEJMoa1607303}

_{11. Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019;5:5. doi:10.1038/s41523-018-0097-z}

_{12. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541-1547. doi:10.1093/annonc/mdy155}

_{13. Rugo HS, Brufsky A, Liu X, et al. Real-world study of overall survival with palbociclib plus aromatase inhibitor in HR+/HER2- metastatic breast cancer. NPJ Breast Cancer. 2022;8(1):114. doi:10.1038/s41523-022-00479-x}

_{14. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med. 2022;386(10):942-950. doi:10.1056/NEJMoa2114663}

_{15. Goetz MP, Toi M, Huober J, et al. MONARCH 3: Interim overall survival (OS) results of abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+, HER2- advanced breast cancer (ABC). Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/j.annonc/2022.08.009}

_{16. 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}

_{17. Cristofanilli M, Rugo HS, Im SA, et al. Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3. J Clin Oncol. 2021;39(suppl 15):1000. doi:10.1200/JCO.2021.39.15_suppl.1000}

_{18. Slamon DJ, Neven P, Chia S, et al. Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Ann Oncol. 2021;32(8):1015-1024. doi:10.1016/j.annonc.2021.05.353}

_{19. Tripathy D, Im SA, Colleoni M, et al. Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib. Cancer Res. 2021;81(suppl 4):PD2-04. doi:10.1158/1538-7445.SABCS20-PD2-04}