Episode 065: Breast Cancer Series, Pt. 10-ER+, Metastatic Breast Cancer

medicine

Jul 19

Written By TheFellowOnCall HemeOncPodcast

After several weeks of covering localized disease, this week, we shift our discussion to metastatic breast cancer, focusing first on ER+ disease.

We often hear that HR+ breast cancer tends to recur later than HER2+ or TNBC. What is the data to support this?

Bottom line: Risk of distant recurrence is a steady 1% per year extending to the 20 year mark in HR+ patients, even if they were still cancer free beyond 5-year mark
Supported by large meta analysis from the EBCTCG cooperative trial group that looked at the annual rate of distant recurrence for 20 years which we will link to our show notes

>100,000 women with ER+ early stage breast cancer included
Study limitations:

Run over 20 years, meaning standards of care changed during this time
We did not know the HER2 status of many patients
Only ½ of HER2+ patients go trastuzumab, which we now know may have affected recurrence Looked at over 100,000 women who had ER+ early stage breast cancer from the groups trial database

This is why guidelines about optimal duration of endocrine therapy can be varied (5 vs. 7 vs. 10 years)

At the time of metastatic disease is diagnosed ALWAYS BIOPSY THE METASTATIC SITE. Why?

Confirm phenotype of disease - is it still HR+? Is the disease now HER2+? Or has disease phenotype change to something like TNBC?
Assess for additional mutations that can change management:

ESR1

ESR1 mutations portend resistance to AI therapy and patients will need to be on a selective estrogen receptor degrader (SERD); found in ~15-20% of metastatic patients

These drugs ends in “-strant” including oral elacestrant or IM fulvestrant

Mechanism: activating mutation in the estrogen binding domain of the ER receptor so need to fully get rid of the receptor with the SERD to stop cell signaling and growth
keep in mind this can be acquired after many years of endocrine therapy so need to reassess at disease progression

PIK3CA: can guide treatment in later lines of therapy with targeted therapy

In patients with bone-only metastatic disease, how do we counsel patients on prognosis?

For HR+ patients the median OS is a little over 4 years compared to a little over 3 years when looking at bone only disease vs. other sites
Some studies that support this:

How should we approach treatment in metastatic ER+ breast cancer?

Our goal here is to avoid chemotherapy for as long as possible because we know that first line endocrine therapy is just as good with much less toxicity
Really our first branch point is “visceral crisis” or no crisis to determine whether we go endocrine therapy or chemotherapy first
Historically, we thought that endocrine therapy may be better for predominant bony disease while chemotherapy is better for visceral disease
There was a pivotal cochrane meta analysis that resolved this question initially published in 2003
- Included older trials where true HR status were likely underestimated
- Even with this limitation, there was no difference in overall survival with less toxicity when comparing endocrine therapy to chemotherapy
Tumor response rates were higher with chemotherapy over endocrine therapy

This result was still questioned because the two largest trials in the meta analysis trended in opposite directions and there was statistically significant heterogeneity among the trials
In general, this finding is the reason why chemotherapy is preferred in the setting of visceral crisis

What is “visceral crisis” mean?

Defined by ESMO Consensus Guidelines
We think of pulmonary lymphangitis with dyspnea, bone marrow involvement with cytopenias, diffuse liver metastasis with liver dysfunction, meningeal metastasis, and things like SVC syndrome.

How do we approach endocrine therapy selection in our patients?

Ask yourself: is my patient’s disease resistant or sensitive to aromatase inhibitors?

What does “sensitive” mean: Patients with de novo metastatic disease OR if they have had more than 1 year of disease free interval from their last endocrine therapy exposure

If patient’s disease is “sensitive” then start with non-steroidal aromatase inhibitor first (end in -ozole)
If patient is deemed “resistant”, then we start with SERD or steroidal AI (i.e. examestane)
For patients with bone mets:

Prescribe bisphosphonate therapy or denosumab therapy

Zoledronic acid is dosed q3month which was found to be the same as monthly in multiple trials
Denosumab is dosed more frequently

Start vitamin D and calcium

What about the use of CDK4/6 inhibitors?

Growth of ER positive breast cancers rely on something called cyclin D1

The gene is amplified in 15% of these cancers
It is one of the key genes promoted by estrogen receptor signaling and mitogenic signaling
Cyclin D1 activates CDK4/6 promoting cell cycle

Three CDK 4/6 inhibitors were developed and all have different side effects (refer back to our pharm episode)

All end in -ciclib
Palbociclib

Key side effect: Neutropenia
Did not work adjuvantly with concern for possible less efficacy than the other drugs though this is speculation

Ribociclib

Key side effects: QT prolong + LFT abnormalities
Most selective CDK4 → worked adjuvantly in NATALEE trial presented at ASCO 2023

Abemaciclib

Key side effect: diarrhea
CNS efficacy → more CDK2 → worked adjuvantly in high risk patients based on MONARCHE trial that we previously discussed

Drug class: Small long term risk of pneumonitis and ILD

Let’s talk about the 1st line metastatic setting though. Three randomized phase III trials looked at the combination of each CDK 4/6 inhibitor and AI vs. AI alone

In each trial primary endpoint was PFS and OS was secondary endpoint (underpowered)
All improved PFS

Ribociclib improved OS
Abemaciclib showed trend for improved OS in interim analysis
Palbociclib did now have same OS benefit

Important to note that the data is maturing
Key studies in this space:

Prior to these studies, all of these agents were shown to improve PFS and OS in the second line metastatic setting

How should we think about second line treatment at the time of progression?

A little more complicated.
At the time of progression, consider repeat biopsy if not already done.
Again reassess for visceral crisis → if yes then reach for chemo or antibody drug conjugates
If no visceral crisis then:

Single agent endocrine therapy switch to SERD (fulvestrant typically, but elacestrant if ESR1 mutated) or steroidal AI (examestane) but can add the following

If PIK3CA mutated, add PIK3CA targeting agent: alpelisib

SOLAR-1 phase III RCT: alpelisib + fulvestrant vs. fulvestrant
Caveat: None of these patients had CDK 4/6 inhibitor so hard to interpret to current patients
Be aware of high rates of hyperglycemia, diarrhea, nausea, rash, poor appetite with 25% of patients discontinuing treatment
No OS benefit but does have PFS benefit of 2-3 months with higher ORR (35% vs. a little over 15%)

If not mutated, consider examestane + everolimus

BOLERO-2 trial
Randomized exemestane + everolimus vs. exemestane alone
Be aware of stomatitis and pneumonitis
No OS benefit and ~4 month PFS benefit

What is the data to support the approval of elecestrant?

Approved though phase III EMERALD trial looking at this oral elecestrant vs. “dealer’s choice” (fulvestrant or non steroidal AI or steroidal AI) after progression on CDK4/6 inhibitor + endocrine therapy (AI therapy or fulvestrant)
Key finding: Improved PFS: In patients with ESR1 mutation, elecestrant had improved 6 month PFS at 40% compared to 20% in those who received fulvestrant in comparator arm

If disease progresses again, where do we go from here?

At this point (or if she had visceral disease), we move away from endocrine based therapy
This is where BRCA mutation status matters as well:

If BRCA Mutation: Start olaparib based on the OlympiAD trial (will discuss in other episodes)
Trial outcomes:

ORR 65% vs. 36% for standard therapy in ER positive group with BRCA mutation
In total cohort, PFS improved by a little over 2 months

If no BRCA mutation:

Chemo monotherapy: choose your own adventure (taxane, doxil, eribulin, capecitabine, gemcitabine, vinorelbine)

Many patients tolerate capecitabine 7-on-7-off regimen

For HER2-low (IHC 1+ or 2+ with negative FISH):

ADC known as trastuzumab deruxtecan (AKA Enhertu), this will come up again in our HER2 metastatic episode
Phase III DESTINY Breast-04 trial

Included HER2 low patients (either HR positive or TNBC) who had progressed after one or two lines of chemotherapy (regardless of CDK 4/6 inhibitor use)
In HR+ group, improved PFS at 10 months vs. 5 months and OS improved 24 months vs. 17 months
Note on study: Hard to really interpret PFS and OS as 30% of patients in the control arm did not get a CDK 4/6 inhibitor but nonetheless it it still has clear activity and high response rates particularly helpful for those with more symptomatic disease

For all patients after 2-4 lines of systemic therapy:

ADC called sacituzumab-govetecan (antibody to trop-2 which is universal expressed on breast cancer cells)
Phase III TROPiCS-02 trial

Included patients HR+, HER2- metastatic breast cancer after at least 2 lines of systemic therapy including a CDK 4/6 inhibitor
Randomized to sacituzumab-govetcan vs. investigator choice (as in the prior trial)
Median PFS was 6 months from 4 months and PFS rate at 1 year was 20% compared to 7%
ORR 21% vs. 14%

Let’s put this all together (our approach based on the data):