Neoadjuvant therapy was discussed in a prior post, in this post I will discuss the following items
- Patient evaluation throughout neoadjuvant therapy.
- Treatment modalities in neoadjuvant therapy.
- Special patient subgroups.
- Management of the axilla.
The following table and remarks below will summarize evaluation of patients undergoing neoadjuvant therapy.
|Breast focused physical exam.||Basic|
|Pre treatment||Yes||- Mammography and breast US with tumor clip placement is mandatory.|
-All patient must have axillary US.
-Patient with palpable nodes, or positive US must undergo biopsy with clip placement(1).
|- MR not on all cases, consider in special circumstance (2).
- PET only in stage III or inflammatory breast cancer.
every two weeks.
|- Not routinely performed.|
- Consider if tumor progression is suspected (3).
|- Not routinely performed.
- Consider if tumor progression is suspected (4).
and proceed to surgery as soon as chemotherapy recovery
|- Not routinely performed.||- Not routinely performed.|
- Most centers will prefer to proceed with neoadjuvant therapy and defer sentinel lymph node sampling to the time of definitive surgery, clip placement facilitates targeted axillary dissection, please see below for management of the axilla.
- MR can be helpful in patients with dense breast or when tumor multicentricity ins suspected.
- Identifying tumor progression in patients undergoing neoadjuvant therapy is important to change treatment accordingly.
- There are published data on the value of during treatment MR in predicting pathologic response, however, while valuable, no therapeutic implications can be applied. MR prediction of response is discussed here.
Chemotherapy: chemotherapy (NACT) of some form remains to be the backbone of all neoadjuvant therapy. Please refer to treatment tumor characteristics for variation of neoadjuvant therapy treatment protocols.
As discussed in a prior post, click here, NACT was shown improve chances of proceeding with breast conserving surgical therapy, and no impact on overall survival or disease free survival. However, a survival benefit was shown with additional chemotherapy in patients who do not achieve a pathologic complete response, for details please click here.
The most commonly used regimen is dose dense AC followed by T. Other non-anthracycline based regimens such as TC for patients who have underlying congestive heart failure or do not accept the toxicity of Adriamycin.
The value of adding a taxane to AC in NACT was studied in the NSABP B27 trial and demonstrated higher rates of clinical response, a higher rate of pathologic response but no significant change in either overall survival or disease free survival. For the patient who develops hypersensitivity reactions to a taxane therapy, the use of nabpaclitaxel is may be warranted, published data from the GeparSepto GPG-69 indicate higher pathologic response rate in the nabpaclitaxel arm when compared to paclitaxel for further details please click here.
Multiple other studies looked into the incorporation of angiogenesis inhibitors in NACT, suffice to say, such approach is not widely used in clinical practice for issues related to toxicities. Other ongoing trials are looking into incorporating PARP-inhibitors as well as carboplatin, the use of carboplatin will be discussed below.
Endocrine therapy: The use of endocrine therapy as neoadjuvant therapy is used in the following patient categories, a. Postmenopausal hormone positive tumors, and comorbidities precluding chemotherapy, b. in can also be considered as a second option for medically fit postmenopausal patient with hormone positive tumors with the following characteristics
- strongly ER positive such as ≥50% staining or an Allred score of 7-8
- Low proliferative index, eg. Ki67 < 10%-15%
The endocrine therapy is an AI, however, Tamoxifen can be used in a specific circumstance.
neoadjuvant endocrine therapy is not recommended in the premenopausal setting.
Endocrine therapy can be used as neoadjuvant therapy in a specific patients subsets.
Neoadjuvant treatment by tumor characteristics:
HER2 positive tumors: the indications for use of upfront therapy in HER2 positive tumors are the same as non-HER2 positive tumors, however, neoadjuvant therapy is now becoming the standard for medically fit HER2 positive tumors measuring ≥ 2cm. All regimens must include an HER2 targeting agent.
Multiple Anthracycline based plus HER2 targeting agent regimens, as well as multiple non-Anthracycline based plus HER2 targeting agent(s) regimens were studied in large trials. The TCH-P regimen as used in the TRYPHAENA trial appears to be emerging as being the most commonly used regimen, it avoids the toxicities associated with Anthracycline containing regimen, the addition of pertuzumab is yielding a higher pathologic complete response, however, no data is available on pertuzumab effect on over all survival.
For patients who are not candidates for above regimens, less intensive regimens can be utilized. Also, and in exceptional circumstance non-chemo containing regimens containing dual anti-HER2 agents were studied in multiple trials.
The following were looked at as predictors for achieving a pathologic complete response, while such predictors are interesting, no clinical implications are yet available, for example, a. ER status, with ER positive HER2 tumors achieving less pCR, b. Intrinsic subtype, c. PIK3CA expression predicting lower pCR, c. Tumor-infiltrating lymphocytes predicting higher pCR.
The use of upfront chemotherapy in HER2 positive tumors, and triple negative tumors are subject to intense research and numerous trials, I will have to dedicate individual posts to cover much more information.
Triple negative tumors: Triple negative breast cancer (TNBC) have shown the higher rate of pCR with NACT as compared to non TNBC. TNBC tumors achieving pCR were found to have comparable overall survival comparable to non-TNBC, however, patients with TNBC who continue to have residual disease following NACT have a poor prognosis.
There is a unique similarity between sporadic TNBC and BRCA1 tumors in the presence of high frequency of DNA repair defects and susceptibility to cross linking agents such as platinum compound. Two major published studies (GeparSexto and CALGB 40603 (Alliance) ) looked into the use of addition of carboplatin to a neoadjuvant regimen, both trials yielded encouraging results with higher pCR in the platinum containing arms, however, this came with a higher rate of neutropenia, also there no long term follow up data available. At the moment (7/2017) the use of carboplatin is not the standard of care in NACT of TNBC.
Several ongoing phase III trials are looking specifically in using carboplatin in the sporadic TNBC and BRCA1 associated tumors.
Hormone positive tumors: this was discussed above under endocrine therapy. In addition, it is worth noting again that hormone positive tumors achieve the least pCR with NACT as compared to non-hormone positive tumors, and the prognostic significance of that will be discussed below.
As discussed as above, endocrine neoadjuvant therapy in medically fit postmenopausal patient who refuses chemotherapy have strong ER positive tumors may be considered, data supporting equivalence of outcome between chemotherapy and endocrine therapy in such group is limited but in this small phase II study this notion is supported, please click here.
Management of the axilla:
The optimal surgical management of the axilla is yet to be defined, with multiple approaches utilized, some important trials are ongoing and are expected to further define the optimal management further. The subject management of the axilla in patients undergoing NACT can be best presented by asking the following questions,
Is post NACT Sentinel lymph node biopsy is acceptable alternative to ALND?
A. in Clinically Node-Negative Patients (cN0), patients who had non-paplable node and no evidence of disease by US prior to NACT can proceed with sentinel lymph node biopsy (SLNB) following the NACT. This approach was validated by multiple studies and meta-analysis examining the false negative rate (FNR), the FNR in patients with cN0 following NACT is low (less than 10), and similar to the FNR of SLNB performed before NACT.
B. in Clinically Node-Positive Patients (cN+), patients who had palpable nodes or biopsy proven axillary lymph node post NACT SLNB is not as clear, with concerns over the possibility of identification rate (IR) and FNR. Two prospective studies, the SENTINA and the ACOSOG Z1071 found the FNR to be high for cN+ patients at 14% and 13% respectively. This is thought to be unacceptably high FNR, in further analysis of the same two prospective studies, the FNR will fall below 10% if 3 or more sentinel lymph node is identified.
C. Methods to improve the FNR when SLNB is performed on cN+ pre NACT with cN0 following NACT. Given the above different approach with adopted.
- The NCCN guidelines recommend using dual tracer and removing more than two sentinel lymph nodes to assure FNR less than 10%.
- Other groups utilize targeted axillary lymph nodes dissection (targeting the removal of the previously clipped positive LN) plus SLNB as a method to improve the FNR.
Should Sentinel lymph node biopsy be done before or after NACT?
At the moment the NCCN guidelines allow either pre NACT SLNB or post NACT SLNB. Most surgeons prefer proceeding SLNB following NACT and at the time of definitive surgery, the advantage of such approach is that patient is undergoing one rather than two surgical procedure, it prevents any possible delays of NACT, and it gives the patient the advantage of possible downstaging of the axillary status and avoiding ALND. On the other hand the main advantage of pre NACT SLNB is to provide and accurate nodal staging and identify candidates for locoregional radiation therapy.
What are the predictors of local recurrence?
Patients with triple negative breast cancer undergoing NACT and continue to have either breast or axillary residual disease have the shortest DFS, and shortest OS.
Can axillary radiation replace ALND?
Two clinical studies are underway to answer such question, the Alliance 11202 trial is randomizing patient with post NACT positive lymph nodes will essentially compare ALND vs axillary RT in patients who are cN+ prior to NACT and continues to be cN+ after NACT. The NSABP B-51 is essentially examining if adding regional radiation therapy provide any additional benefit for patients who were cN+ prior to NACT and became cN0 after NACT.
Proposed algorithms.The two charts here assumes SLNB is performed after NACT. First chart in case of negative lymph nodes prior to NACT cN0
In case of positive lymph nodes prior to NACT, cN+
I reviewed multiple sources for this post, but primarily depended on