Episode 058: Breast Cancer Series,Pt. 7-ER+, Early Stage Breast Cancer (con’t)
This week, we continue discussing the management of early stage ER+/HER2- breast cancer. If you have not done so already, be sure to check out Episode 057 for the first part of this discussion.
What types of HR+ breast cancer histology does not typically benefit from chemotherapy?
Patients with favorable special type histologies do not need because of low metastatic potential
Pure tubular
Pure mucinous
Pure cribriform
Encapsulated or solid papillary carcinoma
Important to note that lobular histology has a poor predictive response to chemotherapy which makes it very difficult to identify an optimal treatment paradigm
What tumor characteristics do benefit from chemotherapy?
For all other histologies, we use gene expression assays to determine who would benefit from chemotherapy. The assays result in a recurrence score from 0-100.
What tumor characteristics warrant a gene expression assay to be sent?
ER+/HER2-
0.5 - 5 cm in size
Recall: Need chemo for T3 tumors which means > 5 cm → remember the dollar bills; don’t send assay in this case because does not change management
Postmenopausal women 0-3 nodes
Recall: premenopausal women with any nodal involvement are recommended to get chemotherapy, so this testing does not change management
Commonly used and commercially available gene expression assays include:
OncotypeDx score (uses 21 genes to determine recurrence score)
Mammaprint score (uses 70 genes to determine recurrence score)
OncotypeDX:
As outlined here, uses a series of indicators to evaluate risk of recurrence with scores 0-100
Essentially, we knew that patients with score <11 probably did not benefit; and we knew that patients with score >26 had the most benefit, but what about scores 11-25?
This lead to the TAILORx study
TAILORx: Study to validate the Oncotype score in node-negative patients
Outcome:
All patients with RS>26 benefited from chemotherapy
Premenopausal women with scores 11-25 had a slight benefit (so consider chemotherapy):
11-15: 1% increased benefit
16-25: 4% increased benefit
Postmenopausal women with scores 11-25 did not benefit
RXPonder: Study to validate Oncotype score in node-positive patients in patients with recurrence score 0-25
Outcomes:
Premenopausal women with 1-3 nodes positive benefited from the addition of chemotherapy in terms of disease free survival (5.2% improvement with chemo+ET)
Postmenopausal women with 1-3 nodes positive did NOT benefit from the addition of chemotherapy in terms of DFS
Mammaprint
Validated with MINDACT trial
Similar idea - how can we use recurrence score to determine who benefits from chemotherapy.
The important thing to also know about Mammaprint is the assay provides both genomic risk and clinical risk
The Fellow On Call Key Takeaway about Clinical Risk assessment:
How to remember important clinical risk factors to consider? Just remember the number “4”!
Grade 1 tumor up to 3cm (1+3 = 4) → low risk
Grade 1 but >3cm → high risk
Grade 2 tumor up to 2 cm (2+2 = 4) → low risk
Grade 2 but >2cm → high risk
Grade 3 tumor up to 1 cm (3+1 = 4) → low risk
Grade 3 but >1cm → high risk
What chemotherapy regimen is recommended?
Extensive discussion about this in prior episode
Recall:
For HR+ >4 LN → anthracycline beneficial
For HR+ <4 LN → can spare anthracycline
If patients HR 1-3 LN → good outcomes without anthracycline (TCx4)
If patient had high recurrence score >30, reach for ddACT because higher risk of recurrence and ddACT can benefit this patient
If tumor is higher grade, also consider ddACT
Your patient completes their chemotherapy and continues on their 5 years of endocrine therapy. What sort of next steps should we counsel patients on?
Should continue follow ups 1-4 times per year for first 5 years, at discretion of oncologist based on patient’s level of comfort and their risk
If they had lumpectomy, then will continue to need mammograms, should wait at least 6-12 months after radiation to begin mammogram surveillance
Germline testing is indicated, particularly for those patients with strong family history
For patients on tamoxifen, continue age-appropriate Gyn exams
Patients on AI should have DEXAs performed given risk for bone density loss
For post-surgical patients, lymphedema monitoring/treatment
Are there more targeted options for the treatment of localized ER+ HER2- breast cancer?
More data supporting their use in the metastatic setting. Options limited in the adjuvant setting
Abemaciclib (CDK4/6 inhibitor) in MonarchE study
MonarchE study was investigating if this there is benefit in patients with high risk HR+ HER2- early breast cancer with high risk of recurrence
Included in this study were:
“High risk”: 4+ positive axillary lymph nodes OR
1-3+ lymph nodes with at least one of the following:
Tumor size >/= 5 cm
Grade 3 histology
KI-67 >/=20%
HUGE study! Phase III study with 5637 patients from 603 sites in 38 countries were randomly assigned 1:1 to abema+ET vs. ET alone. Original study published in 2020 in JCO
Primary endpoint was “invasive disease free survival”
At planned 24 month analysis
IDFS rates: 92.2% in abema arm vs. 88.7% in ET arm; hazard ratio of 0.75 (CI 0.60 to 0.93)
Secondary endpoint was “distant disease free survival”
DDFS: 93.6% abema vs. 90.3% control; HR 0.72 (CI 0.56-0.92)
Of note, only a small subset of patients had completed their 2 years of treatment at the time of analysis; so this suggested that the drug improved outcomes, but was the effect limited to just the time that the patient was receiving treatment?
Most recently, there were analyses at 3 (10.1016/j.annonc.2021.09.015) and 4 years (https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00694-5/fulltext) . Most recently, the four-year data was published in The Lancet Oncology:
IDFSl was 85.8% in abema vs. 79.4% in ET arm (HR 0.664)
DDFS was 88.4% in abema vs. 82.5% in ET (HR 0.659)
At this point, all patients are off trial drug, and despite that, there continues to be great outcomes
The Fellow on Call Key Takeways:
Consider addition of abemaciclib in the adjuvant setting for patients with high risk features outlined above
Recall important side effect of abema to counsel patients on is diarrhea (see our prior Pharmacology episode for discussion on this drug)
Phase 3, double blind, randomized trial involving patients who were high risk, HER2 negative early stage with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants
The study was trying to see if olaparib, a poly-ADP polymerase (PARP) inhibitor is effective as adjacent therapy
Inclusion criteria:
Germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants and high risk HER2 negative primary breast cancer after definitive local treatment and neoadjuvant or adjuvant chemotherapy
Patients could have HR+ or triple negative disease; in fact approximately 82% of patients in placebo and experimental arm were triple negative
Received 52 weeks of BID olaparib or placebo
Outcomes:
Invasive disease free survival at 3 years: 85.9 vs. 77.1% (HR 0.58 CI 0.41-0.82)
DDFS at 3 years: 87.5 vs. 80.4% (HR 0.57 CI 0.39-0.83)
OS at 3 years: 92.0 vs. 88.3% HR 0.68 (CI 0.44 - 1.05)
Only 5% of patients with breast cancer carry BRCA1 or 2 mutations that are pathogenic or likely pathogenic
References:
https://pubmed.ncbi.nlm.nih.gov/18258979/ : Good review which highlights why TailoRx study was needed
https://www.nejm.org/doi/full/10.1056/nejmoa1804710 : TailoRX trial validating OncotypeDX score in node-negative patients
https://www.nejm.org/doi/full/10.1056/NEJMoa2108873: RxPonder study validating OncotypeDX in node-positive patients with recurrence scores 0-25
https://www.nejm.org/doi/full/10.1056/nejmoa1602253 : MINDACT study validating Mammaprint
https://pubmed.ncbi.nlm.nih.gov/32954927/ : MonarchE study for use of adjuvant abemaciclib
https://www.nejm.org/doi/full/10.1056/nejmoa2105215: OlympiA trial for adjuvant olaparib
The crew behind the magic:
Show outline: Ronak Mistry, Vivek Patel
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Ronak Mistry
Social media management: Ronak Mistry
We are proud to partner with HemOnc.org!
Want to learn more about the trials that lead to the regimens discussed today? What about dosing schedules? See links in the show notes for a link to HemOnc.org
