Episode 064: Breast Cancer Series, Pt. 9-Triple Negative, Early Stage Breast Cancer

medicine

Jul 13

Written By TheFellowOnCall HemeOncPodcast

This week, we round out our discussion on the early stage breast cancer, turning our attention to the triple negative subtype. Once again, there are a lot of trials and data, but be sure to check out the show notes for the highlights!

This episode has been sponsored by HemOnc.org.

Brief overview of triple negative breast cancer (TNBC)

Triple negative breast cancer is very heterogeneous and tough to treat in the metastatic setting
Majority of patients are under the age of 40
Nearly all of these patients will require some form of systemic therapy
3 year OS is ~75% compared to 90% for non TNBC
There are more early recurrences and lower risk of late recurrences (late recurrence more in ER+)
All of these patients under 60 years old will need BRCA testing because this is present in up to 20% of these patients
Pathologic CR rates are high in TNBC (~60%) when giving neoadjuvant systemic therapy but those with residual disease do worse compared to other breast cancers → this will become important as we will incorporate strategies for change of therapy after surgery for those with residual disease like we did in HER2 positive localized disease with TDM-1

What does “TNBC” mean from a pathologic perspective?

ER/PR negative meaning <1% of cells express these receptors on IHC
HER2 negative meaning IHC 0-1+ or IHC 2+ and negative FISH testing (HER2 copy number < 6 or HER2/CEP17 ratio < 2 and HER2 copy < 4) → 2,4,6 mnemonic from our vocabulary episode
Molecular classification in TNBC has been more difficult to determine; unique tumor microenvironment plays a role here

Why do we include neoadjuvant chemotherapy in most patients with TNBC?

Older data from the NSABP cooperative group showed that there were equivalent survival results whether patients got adjuvant or neoadjuvant chemotherapy → keep in mind most of these patients were enrolled in the 90’s before we had things like trastuzumab → this is an interesting historical article that we will link in our show notes from 2008
As we mentioned in past episodes, neoadjuvant chemotherapy can downstage the axilla and primary tumor leading to more optimal surgical resections
This strategy works particularly well in TNBC with high responses to chemotherapy which is why for most patients neoadjuvant therapy is the standard of care with the exception of patients with very small tumors
TNBC has earlier rates of relapse; neoadjuvant therapy tries to decrease the risk of micrometastatic disease
We also know that those who achieve a pathologic CR after neoadjuvant chemotherapy have a better overall prognosis which led to this becoming the standard of care in TNBC

What does “pathologic CR” mean?

Pathologic complete response (CR) is when there is no residual breast cancer in both the primary tumor site and any involved lymph nodes.

What is residual cancer burden (RBC)?

The idea in subdividing residual disease partially comes from the fact that pathologic CR has been and is still debated as a trial level surrogate for survival. Path CR is prognostic but is not yet a validated trial endpoint.
There are 4 categories:

RCB-0 (path CR)
RCB-1 (“minimal residual disease”)
RCB-2
RCB-3

The pathologist calculates this based on multiple measurements of the residual disease in the primary tumor site and any lymph nodes.
This score will translate to one of those groups:

Score 0-1 = favorable long term outcomes
Scores 2-3 = less favorable long term outcomes

This is not clinically used to make treatment decisions currently but is an important step to subdividing patients with minimal residual disease as opposed to more extensive disease which will likely inform trial design and treatment in the future
An example:

Imagine you have 10 patients with TNBC
If you gave them standard neoadjuvant therapy, let’s say 4/10 (40%) get a path CR
If you gave them fancy neoadjuvant therapy, let’s say 6/10 (60%) get a path CR
But when you look at overall survival at 5 years, the two arms are the same
How could that be? Well the two patients who initially got a path CR and flipped with the fancy therapy had bad biology to begin with and it didn’t matter that with your eyes there was no cancer…they still had microscopic metastatic disease that ultimately recurred and led to the same overall outcomes
We will cover more details on trial level surrogacy in future episodes but that is the idea. Never forget that tough biology will trump what we can see with our eyes and that a 20% improvement in path CR might only lead to a 3% improvement in overall survival…it is not 1:1 in most cases

When do we not give neoadjuvant therapy?

Recall the dollar bill mnemonic from our vocabulary episode:

Think 1 dollar, 2 dollar (don’t forget we used to have the 2 dollar bill), and 5 dollar bill
T1C = > 1 cm
T2 = > 2 cm
T3 = > 5 cm

If the primary tumor is <2cm AND no nodal involvement → can proceed with surgery first and treat with adjuvant TC x4 (We discussed omitting anthracyclines in Episode 057, as shown in the ABC trial!)
If you have nodal disease and/or patients are stage II or III → we give neoadjuvant chemoimmunotherapy (below)

Chemotherapy treatment options in TNBC

Caveat: The optimal chemotherapy backbone in TNBC is still up for debate.

Option #1: ddAC-T

First let’s talk about ddAC-T and how we got to where we are (remember that this is doxorubicin + cyclophosphamide followed by paclitaxel)

Why ddAC: There was a pivotal CALGB cooperative group trial in 2003 that showed dose dense AC was better than standard dosing (q2week + GCSF as opposed to q3week) with ~7% improvement in DFS
Why paclitaxel: Based on results of pivotal ECOG trial E1199 that compared paclitaxel (“taxol”) vs. docetaxel

Found that weekly paclitaxel is better than q3week
Found that q3week docetaxel is better than weekly docetaxel
Found that weekly paclitaxel had a survival advantage over all other strategies but this did not hold up in long term follow up with similar efficacy to q3week docetaxel
We go with weekly taxol generally because it is less toxic and there was an OS advantage in the TNBC subgroup in this trial

TL;DR: ddAC-T is one option for patients with TNBC, particularly in patients who cannot get immunotherapy

Option #2: TC-AC+pembro (carboplatin + paclitaxel + doxorubicin + cyclophosphamide + pembrolizumab)

How did carboplatin make it’s way into treatment in the TNBC space?

Platinum agents work well in cancer cells with DNA repair deficiency, and we know that there are high rates of homologous DNA recombination defects in tumors in TNBC!
Multiple trials have looked at the addition of carboplatin in neoadjuvant therapy in TNBC and have shown improved pathologic CR rates of ~20%

CALGB 40603

Path CR rates improved by 15% from ~40% to 55%
No difference in EFS or OS → another point to question the surrogacy of path CR

BrighTNess
- Path CR rates improved by over 20%
- Notable design flaws: Control arm got taxol monotherapy and no athracycline (not standard of care)
Newest phase III RCT from Tata Memorial hospital in India presented at San Antonio Breast Conference in 2022

Unlike CALGB trial, carboplatin dose was AUC 2 instead of AUC 6 and given weekly instead of q3week allowing for more patients to complete therapy
This trial showed improve path CR by ~20% as well as improved EFS and OS by a little over 10%
Interestingly subgroup analysis showed benefit only in younger women under the age of 50

Publication is pending at this time

Important to note that the addition of carboplatin comes with more toxicities (more myelosuppression, neuropathy, mucositis among others)

Where does pembrolizumab come into play?

Approval from the KEYNOTE-522 trial

Included stage II and III patients
Patients were randomized to:

Chemo + pembro → surgery → adjuvant pembro
(Control): Chemo → surgery → adjuvant placebo

Chemotherapy regimen

Neoadjuvant phase 1: carboplatin (given either weekly or q3week) + weekly taxol x 12 weeks followed by
Neoadjuvant phase 2: doxorubicin + cyclophosphamide q3week x 12 weeks (not dose dense)

If patient on pembro arm then they got pembro q3week during both phases of neoadjuvant treatment and then got 9 cycles of adjuvant pembro after surgery and radiation

Primary endpoint was path CR and EFS…not OS

Path CR improved by 15% from about 50% to 65%
3 year EFS was improved by 8% (85% in the pembro arm)

Regardless of which arm they got, there were no differences in EFS for those who achieved path CR

Comment on study limitations:

Patients in both arms were not permitted to receive adjuvant capecitabine if they did not receive path CR, which is standard of care (more below)
Adjuvant pembro was given regardless of path CR status (is this overtreatment? Need to consider possible toxicities of drugs, time toxicity, financial toxicity)

What is our approach to adjuvant treatment for patients who have residual disease after neoadjuvant therapy?

Options: capecitabine and olaparib
Capecitabine:

Approval based on the CREATE-X Trial

Included patients with Stage 1-3 HER2 negative breast cancer (not just TNBC) who got neoadjuvant therapy and did not achieve path CR
Randomized to capecitabine q3week x 6-8 cycles vs. placebo
DFS improved by ~15% and OS improved by ~8% over placebo in those with TNBC
No difference in DFS or OS for those with ER+ disease
Main side effect to think about is hand-foot syndrome, GI issues, and leukopenia
Standard of care for those with residual disease after neoadjuvant therapy in TNBC

Olaparib:

For those with BRCA 1 or 2 mutation there was also a trial for HER2 negative patients called OLYMPIA
Included patients who completed neoadjuvant or adjuvant therapy (6 cycles of chemotherapy so higher risk patients), had one of these mutations, and had residual disease after neoadjuvant therapy (if that’s what they got)
Randomized to olaparib x 1 year vs. placebo
Primary endpoint was iDFS
82% of patients were triple negative
Improved 3 year invasive disease free survival and distant disease free survival by ~8% which was great because ~85% of patients were disease free in the olaparib arm
No difference in 3 year OS
Comment on study limitation: No capecitabine which we know improves DFS and OS in TNBC patients with residual disease after neoadjuvant therapy

In a patient who does not achieve path CR AND has BRCA mutation, what do we do?

There is no correct answer → could go with either capecitabine or olaparib

No head-to-head comparison between the two drugs

The other question is do we continue the pembro x 9 cycles and we don’t have an answer

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

If patient has tumor <2cm and no nodal involvement: adjuvant TC x4
If patient has tumor >2cm and/or nodal involvement: neoadjuvant TC-AC+pembro
If patient has residual disease: adjuvant Capecitabine
If patient has residual disease AND BRCA mutation: also option to use Olaparib