Episode 057: Breast Cancer Series,Pt. 6-ER+, Early Stage Breast Cancer
After several weeks of incredible discussions with our special guests, it’s time that we dive into the medical oncology regarding breast cancer. We start our discussion with the first of our two-part discussion on early stage (AKA non-metastatic) ER+/HER2- breast cancer.
What information do we need to know in order to approach treatment for a patient with HR+ breast cancer with curative intent?
We always need to know the following information:
Concomitant HER2 status in addition to HR+
Size and grade of tumor
Nodal involvement based on clinical exam and imaging
Menopausal status
How do we define menopause?
Patients > 60 yrs old
Patients who had a BSO
Patients who are < 60 with 12 months of amenorrhea (not on any endocrine therapy)
Desire for breast conservation surgery (BCS) which will be important for those who are borderline for this procedure
Nearly every patient will get either neoadjuvant and/or adjuvant systemic therapy which could include endocrine therapy, chemotherapy, or both
For HR+ invasive breast cancer, neoadjuvant endocrine therapy does have objective response but has rare pathologic complete response so it is currently not commonly used but adjuvant endocrine therapy is a must
Adjuvant chemotherapy inclusion depends on menopausal status and molecular profile of the tumor determined at the time of surgery
Is there a role for neoadjuvant chemotherapy in HR+ / HER2- breast cancer?
In the 90’s there was more of a push for neoadjuvant chemotherapy and later we found that those who had a pathologic complete response ended up living longer (i.e. that it was a prognostic marker)
We then started using this as a surrogate marker for survival meaning that if we had higher pathologic complete response rates after neoadjuvant chemotherapy that this would translate into improved overall survival
A few limitations with this thought process for HR+ disease:
Pathologic complete response has not been validated as a true surrogate for OS
If we assume that pathologic CR is an appropriate surrogate, few patients with HR+ disease will achieve a pathologic CR with neoadjuvant chemotherapy
So when do we use it:
#1: To make surgery easier:
Make an inoperable tumor now operable
Downstage a tumor to allow for BCS
Mastectomy to BCS conversion happens to roughly 15-20% of patients, so not definite, but worth a shot
Think about patients who are T3 or higher (i.e. > 5 cm or involvement of chest wall)
#2: In premenopausal nodal disease
We will end up giving chemo anyway adjuvantly and we could downstage the axilla to prevent the need for axillary lymph node dissection (ALND)
Don’t have to do it but reasonable to do
In general, tumors with a higher chance of response are higher grade with higher Ki67
Makes sense why HR+ tumors don’t respond as much to chemotherapy because they tend be lower grade and lower Ki67
In fact, luminal B which has more of those features respond better to neoadjuvant chemotherapy than luminal A (35% vs. 18% in a meta analysis; Source: https://jamanetwork.com/journals/jamasurgery/fullarticle/2778930)
What regimens are we considering in either neoadjuvant or adjuvant settings?
HR+ disease has pathologic CR of ~15% range
Just remember two regimens when it comes to chemotherapy (whether neoadjuvant or adjuvant) for these patients
How do you know which regimen to pick?
Clever design:
Three adjuvant trials were running from cooperative groups randomizing various regimens
So they did a pre-planned joint analysis to compare TC x 6 (docetaxol + cyclophosphamide) vs. TaxAC x 6 (same drugs + doxorubicin)
Included over 4000 patients with primary endpoint of invasive disease free survival
Clear benefit of anthracycline for those with node positive disease by ~10% in HR negative patients and ~5% for HR+ patients (mainly driven by those with 4 or more nodes)
No difference with additional of anthracycline for node negative disease
Really no benefit in HR negative, node negative disease
Analysis limited by lack of clear testing of HER2 status
The Fellow on Call Takeaways:
Use an anthracycline based approach improves outcomes for node positive disease → so consider ddAC-T in neoadjuvant setting
Very reasonable to omit anthracycline in HR+, node positive if <4 nodes after surgery
Don’t need anthracycline for patients with node negative disease
Why docetaxel in TC instead of taxol?
First we found that docetaxel was better than taxol in metastatic setting
We wanted to try non anthracycline based chemotherapy regimens in the adjuvant setting
Docetaxel based TC x 4 compared to AC x 4 in an older trial → TC x 4 was actually superior with 7 year OS improvement from 75% to 80% which is why we use it in non-anthracycline based regimens (source: https://pubmed.ncbi.nlm.nih.gov/19204201/)
Note this is why we do 4 cycles instead of the 6 cycles from that ABC trial though we don’t definitively know which is better
Why taxol instead of docetaxel in ddAC-T?
Looked at paclitaxel weekly vs. docetaxel
No difference in efficacy with less toxicity
Also looked at weekly vs. q3week and found weekly was better which is how we got to ddAC-T
In a patient who undergoes lumpectomy and had negative SLNB, how do we ensure we achieve systemic control?
Premenopausal women:
ER+/PR+: backbone is always going to be therapy directed at the hormone receptors
Treatment options:
Tamoxifen (selective estrogen receptor modulator)
Mechanism: It blocks the binding of estrogen to estrogen receptors, thereby impairing the ability for estrogen to be involved in cell proliferation
How long do we keep premenopausal patients on adjuvant endocrine therapy for?
Important trials:
The Fellow on Call Takeaways: Both showed that 10 years of tamoxifen superior to 5 years of tamoxifen
10 year DFS and OS improved by 3% absolute points when comparing 5 year vs. 10 year
Fellow on Call Takeaway:
For premenopausal women with low risk disease and low recurrence scores then very reasonable to stop after 5 years given this difference is likely driven by higher risk patients (i.e. oncotype RS < 11)
Try to get to 10 years if possible
Postmenopausal women:
Treatment options: Aromatase inhibitor
Mechanism: Blocks aromatase in adipocytes, which convert testosterone and androstenedione to early precursors of estrogen (estradiol). Therefore, need to turn off these aromatase proteins
Why aromatase inhibitors in postmenopausal women?
Performed by Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
Total 31,920 post-menopausal women included who had ER+ early breast cancer.
Included data from trials comparing the following:
5 years of AI vs. tamoxifen
5 years of AI vs. 2-3 years tamoxifen → AI
2-3 years of tamoxifen → AI vs. tamoxifen
Tamoxifen vs. AI
Absolute improvement in recurrence by ~3.5% with AI
Absolute improvement in mortality by ~3% with AI
Sequential tamoxifen to AI vs. AI
No difference in endpoints
When compared to tamoxifen vs. sequential tamoxifen to AI there is a benefit with AI
The Fellow on Call Takeaways:
AI better than tamoxifen in postmenopausal women
Reasonable to go for switch therapy if there are many side effects with AI but try to use AI throughout if possible
Do we extend AI therapy to 10 years in high risk postmenopausal women?
most of the time no, more fractures with the same OS (Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2104162)
Is there benefit to ovarian suppression in premenopausal women with HR+ early breast cancer?
In select cases, yes. But the side effects can be severe so it is about risk vs. benefit, which includes quality of life
Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer
Published in NEJM 2018 with combined data from two studies:
SOFT: Suppression of Ovarian Function
TEXT: Tamoxifen vs. Exemestane Trial
A little about the study design:
SOFT:
All premenopausal patients
Patients who were deemed appropriate to receive chemotherapy received it before enrollment in the trial
Three arms: 1:1:1
Tamoxifen alone (SERM)
Tamoxifen + OS
Exemestane + OS (Aromatase inhibitor)
TEXT:
All premenopausal patients
Patients did NOT receive chemotherapy before enrollment, but those that warranted chemo received it while on study
Two arms: 1:1
Tamoxifen + OS
Exemestane + OS
Primary end point of combined studies was:
Disease free survival (defined as survival free of the first occurrence of one of the following: invasive recurrence of breast cancer (local, regional, or distant),
Invasive contralateral breast cancer, a second (non-breast) invasive cancer, or
Death without recurrence or a second cancer
Really interesting data when they combined the data
Be sure to look at the article for the graphs to see this breakdown but briefly:
Combined DFS: 4% better with E+OS vs. T-OS
Combined freedom from distant recurrence: 2.1% better
OS 0.1% better
BUT when stratified by patients who received chemotherapy (SOFT) or were receiving chemotherapy (TEXT), this benefit was magnified, as compared to those who did not receive chemotherapy
So what does this tell us:
In patients who are high risk enough to receive chemotherapy, there appears to be a benefit for ovarian suppression; put another way: patients who have higher risk of recurrence given the characteristics of their tumor (size, grade, nodal involvement, etc.) are more likely to derive benefit from the addition of OS
If possible using aromatase inhibitor + OS > tamoxifen + OS
Something to keep in mind is that 25% patients who received OS withdrew given side effects
The Fellow on Call Takeaways: No benefit to OS if they’re not getting chemotherapy
References:
https://jamanetwork.com/journals/jamasurgery/fullarticle/2778930: Study showing luminal B breast cancer responds better than luminal A
https://ascopubs.org/doi/full/10.1200/JCO.2016.71.4147: ABC Trial analyzing role of anthracycline in breast cancer
https://ascopubs.org/doi/10.1200/JCO.2015.60.9271?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed: ECOG 1199 trial looking into docetaxel vs. paclitaxel in ddAC-T
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61963-1/fulltext#:~:text=at%205%20years.-,Methods,5%20years%20(open%20control: ATLAS Trial looking at duration of tamoxifen in premenopausal women, performed in US
https://ascopubs.org/doi/10.1200/jco.2013.31.18_suppl.5: aTTom Trial looking at duration of tamoxifen in premenopausal women, performed in UK
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61074-1/fulltext: Study investigating efficacy of aromatase inhibitors in postmenopausal patients
https://www.nejm.org/doi/full/10.1056/NEJMoa2104162: Study suggesting higher risk of fractures if AI extended to 10 years in postmenopausal patients
https://www.nejm.org/doi/full/10.1056/NEJMoa1803164: Composite data for SOFT and TEXT trials
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
