Borges Examines Approach to ER+, HER2 0 mBC With PIK3CA Mutation

Virginia F. Borges, MD, MMSc

Professor, Medicine–Medical Oncology

University of Colorado School of Medicine

Aurora, CO

CASE SUMMARY

• A 54-year-old postmenopausal woman presented with a palpable mass and swelling in the upper, inner quadrant of her right breast with no clinically detectable axillary lymph nodes for 4 months.
• ECOG performance status: 0
• Diagnostic mammogram: high-density mass with irregular margins and segmental microcalcifications
• Breast ultrasound: opaque, irregular 25-mm mass with spiculated margins plus anterior, focal asymmetry visualized at 2 o’clock in the right breast
• Core biopsy: grade 2 invasive ductal carcinoma (IDC), estrogen receptor positive (ER+)/progesterone receptor positive (PR+), HER2 low (immunohistochemistry [IHC] 2+/in situ hybridization negative); Ki-67, 20%
• Lumpectomy and sentinel lymph node (SLN) biopsy: 28-mm grade 2 IDC, 2 SLNs negative for malignant cells
• Reverse transcriptase–polymerase chain reaction 21-gene recurrence score: 27
• Stage: T2N0M0

Adjuvant Therapy

• Docetaxel plus cyclophosphamide given intravenously every 3 weeks for 4 cycles
• Radiation therapy
• Anastrozole planned for 5 years

After 3 Years of Anastrozole Therapy

• Patient presented with mild fatigue and persistent lower back pain radiating to the bilateral hips, which restricted strenuous activity.
• ECOG performance status: 1
• Hemoglobin: 9.8 g/dL
• Other hematologic indices within normal limits
• Fludeoxyglucose F 18 (FDG) PET-CT shows avid radiotracer uptake detected in L3-L5 vertebrae and bilateral iliac crests
• MRI spine: multiple sclerotic vertebral and pelvic bone lesions without spinal cord compromise
• Bone marrow aspiration: malignant cytokeratin-positive cells
• ER+/PR+, HER2 2+ by IHC, fluorescence in situ hybridization negative
• Stage T2N0M1a (metastatic)
  

First-Line Therapy for Metastatic Disease

• The patient continued once-daily anastrozole and added palbociclib (Ibrance) once daily, which markedly relieves bone pain.
• During her initial 6 treatment cycles, she developed grade 1 neutropenia with an absolute neutrophil count of 1750 cells/mm³.
• Complete blood count (CBC) plus differential was obtained every 3 months.
• At this time, no dose adjustment of CDK4/6 inhibitor was required.

Ten Months After Initiating Aromatase Inhibitor (AI) Plus CDK4/6 Inhibitor Therapy

• Patient reports a mild increase in lower back pain.
• She continues to ambulate without assistance, drive a car, and perform light housework.
• Repeat F 18 FDG PET-CT shows avid uptake of radioisotope now appears in new sclerotic and lytic osseous lesions.
• Circulating tumor DNA (ctDNA) analysis confirms a PIK3CA mutation.

Peers & Perspectives in Oncology: How often does HER2 expression change from the time of a primary tumor biopsy to a relapse?

Borges: Breast cancers [are tested for HER2 expression] from the primary tumor. If they were HER2 low in the primary, the odds of them being HER2 low in the metastases are good. If they were HER2 0 in the primary, we often find HER2 low [Table¹]. If you ask how many convert to HER2 positive, it is 2.4% if they were HER2 0 and 1.6% if they were HER2 low, so very small numbers.1 I haven’t [seen any], so that would make sense with the low numbers. [Tumor heterogeneity in biopsy results] is an excellent point. We’re only as good as our technologists.

What treatment would be recommended for this patient?

Our ctDNA analysis shows this patient has a PI3KCA mutation, which would have been more common if she relapsed on an AI. But it can happen even in patients who get a benefit from their endocrine therapy, so it’s important to look for.

We have 2 choices that are equally accurate: alpelisib [Piqray] or capivasertib [Truqap]. Capivasertib [targets] AKT, PTEN, and PI3 kinase [mutations]. It works in all, so you could do the capivasertib, and I would choose capivasertib because it’s an easier drug to give. I gave plenty of patients alpelisib when I didn’t have an alternative choice, but I find capivasertib just a bit easier to manage, less with the rash, less with the blood sugar [elevation].

[The schedule for capivasertib] is hard, because it is an [on-off] schedule. But I’m impressed with how well patients have done with it with the schedule. You have to be careful because capivasertib can induce very high blood sugars, [although] not as commonly as alpelisib and often not as severe. But if they are somebody who already has diabetes or has a high hemoglobin A1C, you have to monitor them. I have some patients for whom I’ve done that because it was their best choice for treatment. They didn’t want the alternatives, and they were willing to partner with their endocrinologist and me, so I have patients who have to give themselves IV [intravenous] insulin on the days they’re on the drug and then nothing on the days they’re not on the drug…but they manage it. I saw some amazing responses with alpelisib, and I agree it is a [challenging] drug, but I have a lot of support for it [compared with other oncologists]. I have a pharmacist, advanced practice providers, and nurses, and they’re tracking these patients and they’re helping monitor their glucose. My pharmacist is calling them every other day.

I think it’s a legitimate choice to say alpelisib is for the brave and for those who have a lot of resources to support their patients. But it also is an amazing drug that gives good responses. Capivasertib has come along. Everolimus…is also a legitimate choice, although in the setting of a PI3 kinase [mutation], I’d be a little bit worried it might not work that well, but there is no reason not to give it a try.²

What would you do if the patient had a PIK3CA mutation and an ESR1 mutation?

I would go with the PIK3CA because that is a driver mechanism [important] to how those cancers behave, and that’s a targeted therapy to the driver. The ESR1 mutation is an outgrowth, and the selective estrogen receptor degraders [SERDs] can work there.

There are some newer SERDs coming down the pipeline that might be more interesting. There’s a selective estrogen receptor modulator coming down the pipeline that might be more interesting. I think elacestrant [Orserdu] is a great choice, but if they had both, and I didn’t have a clinical trial option for them, I think I would give them capivasertib.

CASE UPDATE

• Patient begins capivasertib twice daily (4 days on, 3 days off) plus fulvestrant once monthly, which attenuates her bone pain.
• Intermittent episodes of diarrhea are controlled with loperamide as needed.
• On reevaluation, 18F-FDG PET-CT demonstrates reduced avidity in osseous lesions.
• CBC with differential and fasting Sequential Multi-Analyser Biochemistry 12 panel are obtained at every follow-up visit.

What data supported the approval of capivasertib?

This is the phase 3 CAPItello-291 trial [NCT04305496].… This is relatively newer data.³ It [investigated] capivasertib with fulvestrant vs placebo with fulvestrant with…708 patients randomly assigned 1:1. They could have had 2 or fewer prior lines of endocrine therapy and 1 line of chemotherapy in the advanced setting. They were allowed to have CDK4/6 inhibitors, and 51% of the patients who came on the trial had a CDK4/6 inhibitor because they wanted real-world data. No prior SERDs were allowed. Everolimus was excluded. Alpelisib was excluded [as was] any other AKT inhibitor, which there are none currently approved. They had to have OK but not pristine hemoglobin A1C levels. They only needed A1C levels below 8.0%, and diabetes that did not require insulin was allowed. This was an all-comers study.

The dual primary end point was progression-free survival [PFS] in the AKT pathway–altered population. This is [the indication where] it’s approved. The median PFS was 7.3 months with capivasertib vs 3.1 months with placebo with an HR of 0.50 [95% CI, 0.38-0.65; 2-sided P < .001]. There was a big separation in the curves.

For everybody, regardless of mutation [status], there was an overall survival [OS] benefit with an HR of 0.74 [95% CI, 0.56-0.98]. The curves separated nicely in favor of the capivasertib. That was the basis of why the drug got FDA approved. The HR for OS for the AKT-altered pathway was 0.69 [95% CI, 0.45-1.05].

When do you recommend repeating next-generation sequencing?

I do it when I feel like there’s an answer I need to know. In the frontline setting, [treatment] is going to be a CDK4/6 inhibitor, and I have the data I need to know, so I don’t do it then. I do it before they [experience progression] because I need to know their mutation status for figuring out if they’re going to go on capivasertib or alpelisib. But I have the option of going back and getting that on the primary tumor, so I can do it while they’re [proceeding] along happily on their CDK4/6 inhibitor.

Sometimes in our patients, we get the result back and it’s progression, but it’s only a couple millimeters [of growth], but that tumor marker has ticked up a bit. The patient is still perfectly fine and asymptomatic, with less evidence of active disease than when you first met her, but you can feel it coming. That’s when I start thinking about whether I know her PI3K status.

I will start doing it more frequently to look for the ESR1 mutation. Particularly, we have a lot of clinical trials for drugs that would be great for somebody with an ESR1 mutation, and, of course, we have elacestrant. The other reason I look for the ESR1 mutation is there are a couple of versions of the ESR1 mutation that I would say are not going to benefit from everolimus. I like to use that information to guide my choice.

Once they are endocrine refractory and on the chemotherapy pathway, and I already know their HER2 expression, if they’re not HER2 0 where I feel like I have to keep finding something until I get HER2 1+…there is evidence to show the probability of finding it converts to HER2 low if you keep doing biopsies or looking for it over time just goes up. For those patients, by the time you’ve done 3 to 5 biopsies, you will get that result.⁴ It helps to talk to your pathologist about why you’re doing it again. In a not too distant future, we may have data to suggest that everyone has the right to try [accessing HER2-targeted treatment].

REFERENCES:

1. Miglietta F, Griguolo G, Bottosso M, et al. Evolution of HER2-low expression from primary to recurrent breast cancer. NPJ Breast Cancer. 2021;7(1):137. doi:10.1038/s41523-021-00343-4

2. Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(1):85. doi:10.1186/s13058-021-01462-3

3. Turner NC, Oliveira M, Howell SJ, et al; CAPItello-291 Study Group. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131

4. Bar Y, Dedeoglu AS, Fell GG, et al. Dynamic HER2-low status among patients with triple negative breast cancer (TNBC): the impact of repeat biopsies. J Clin Oncol. 2023;41(suppl 16):1005. doi:10.1200/JCO.2023.41.16_suppl.1005