Breast Conserving Surgery (BCS) after Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy:
- Usually has been administered in cases of:
  - Inoperable or locally advanced breast cancer:
    - To downsize the primary tumor and nodal disease:
      - To facilitate local-regional therapy:
        With surgery and / or radiation
- Given the success of this approach in locally advanced disease:
  - Combined with the known benefits of adjuvant systemic therapy:
    - Neoadjuvant chemotherapy has also been assessed for the management of patients with operable breast cancer
A well-recognized role of neoadjuvant chemotherapy:
- Is the ability to improve surgical options for patients by:
  - Downsizing tumors and increasing the chances for breast conservation
In the landmark National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial:
- 1523 patients with primary operable breast cancer
- Were randomized to either preoperative or postoperative systemic therapy with:
  - Four cycles of standard doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) (AC) given every three weeks
- The administration of preoperative therapy in this trial:
  - Increased the proportion of patients able to receive breast conservation surgery by 12%:
    - The breast conservation therapy rate increased from:
      - 60% to 68%
- This result has been confirmed in other studies:
  - Suggesting that neoadjuvant chemotherapy can:
    - Enable downsizing of tumors and reduce mastectomy rates in favor of breast conservation therapy
- Critical to the success and widespread adoption of this approach was:
  - The demonstration of comparable distant disease control with neoadjuvant chemotherapy vs adjuvant chemotherapy
- In the NSABP B-18 trial:
  - At a mean of 9.5 years of follow-up:
    - No significant differences were seen in:
      - Disease-free and overall survival rates between the two randomized groups:
        69% vs 70%, P = .80; 55% vs 53%, P = .50, respectively
- Similar results have been observed in other randomized studies, and a recent pooled meta-analysis demonstrated that:
  - Both approaches provide equivalent survival outcomes for patients:
    - Consequently, neoadjuvant chemotherapy is a safe alternative to adjuvant therapy, especially in patients in whom breast conservation therapy is desired
Data from multiple studies has shown that when the same regimens are utilized:
- No survival advantage has been identified between neoadjuvant and adjuvant chemotherapy
The two landmark trials that established that there is no survival advantage between neoadjuvant and adjuvant chemotherapy were the:
- NSABP B-18:
  - Roughly 1500 patients treated with adriamycin and cyclophosphamide, 16 years follow-up
- NSABP B-27:
  - Approximately 2300 patients treated with adriamycin, cyclophosphamide, and a taxanes, 8.5 years follow-up
Evolving evidence is demonstrating that:
- The degree of pathologic response:
  - Correlates with both disease-free survival (DFS) and overall survival (OS) outcomes
  - These has been shown to be breast cancer subtype dependent:
    - With the more aggressive subtypes, like triple negative breast cancers (TNBC) and HER2 positive breast cancers:
      - Having a much higher pathologic response rates compared to hormone receptor positive cancers
    - TNBC have a pathologic complete response (pCR) rate of :
      - 34%
    - HER2 positive hormone receptor negative cancers have a pCR rate of:
      - 50%
    - HER2 positive hormone receptor positive cancers have a pCR rate of:
      - 30%
    - Hormone receptor positive cancers have a pCR rate of:
      - 7% to 16%
  - This data will help refine adjuvant therapy options in patients with TNBC and HER2 positive breast cancers
An advantage of neoadjuvant chemotherapy is that:
- It allows for down-staging of the disease making breast conservation surgery (BCS) a possible option in patients with large tumors and it reduces the need for axillary node dissection (Table 1):
  - In these trials tumor shrinkage was seen in 79% of patients with 36% have a clinical complete response rate (cCR) and 43% having a clinical partial response rate (cPR
  - The NSABP B-18 identified that the patients who had the largest tumors (5 cm or greater):
    - Had the best benefit of neoadjuvant therapy in terms of BCT (Table 2)
Multiple studies have shown:
- That BCT after neoadjuvant chemotherapy is safe and did not result in higher rates of local or regional recurrence:
  - The long-term results of NSABP B-18 and B-27 showed no difference in local and regional recurrence after neoadjuvant chemotherapy by surgery type (Table 3)
- More recent data from MD Anderson Cancer Center, in a series of 751 patients (between 2005 to 2012) in which all participants received appropriate preoperative Taxane based chemotherapy and appropriate HER2 targeted therapy:
  - All women undergoing BCT had excellent outcomes across all molecular subtypes with 5-year local and regional recurrence free survival between 93% and 97% (Table 4)
  - The highest pCR rate (72.4%) was seen in patients whose tumors where hormone receptor negative / HER2 positive and the lowest pCR (16.5%) was seen in patients whose tumors where hormone receptor positive / HER2 negative
  - One important point to note from the study is that:
    - Not achieving a pCR in the hormone receptor positive / HER2 negative patients was not associated with an inferior outcome however:
      - In the high-risk hormone receptor negative subtypes not achieving a pCR does result in higher rates of local and regional failure (Table 4), something that will also occur if the patients would have undergone mastectomy instead of BCT
A study from the National Cancer Data Base (NCDB) from 2006 to 2011 of 354,202 patients with stage I to stage III breast cancer (47.8% of the study population underwent BCT) shows:
- That the use of neoadjuvant chemotherapy in patients undergoing BCT is gradually increasing, from approximately 14% in 2006 to approximately 20% in 2018:
  - The use of neoadjuvant chemotherapy requires a multi-disciplinary approach

Table 1. Neoadjuvant Therapy and Breast Conservation Therapy (BCT)

Trial	% BCT Neoadjuvant Therapy	% BCT Surgery First
Royal Marsden	89%	78%
Institut Curie	82%	77%
NSABP B-18	67%	60%
EORTC	37%	21%

Table 2: NSABP B-18 Breast Conservation Therapy (BCT) in Neoadjuvant Therapy

Tumor Size	Planned Lumpectomy	Lumpectomy Performed
All Patients	65%	67%
Equal or Less than 2 cm	89%	81%
2.1 cm to 5 cm	68%	71%
Equal or Greater than 5 cm	3%	22%

Table 3: Combined Analysis of the NSAB B-18 / 27

Surgery	10-Year Incidence of Local or Regional Recurrence	Local	Regional
Mastectomy	12.3%	8.9%	3.4%
Breast Conservation Surgery	10.3%	8.1%	2.2%

Table 4: Neoadjuvant Chemotherapy and BCT – pCR and LRR by Subtype

Variable	HR+/HER2- (n=369)	HR+/HER2+ (n=105)	HR-/HER2+ (n=58)	HR-/HER2- (n=219)
pCR Rate	16.5%	45.7%	72.4%	42.0%
5-yr LRR-Free Survival: pCR No pCR	100% 95.3%	100% 94.6%	97.4% 86.7%	98.6% 89.9%
5-yr LRR-Free Survival	97.2%	96.1%	94.4%	93.4%