Treatment of Non Metastatic Triple Negative Breast Cancer (TNBC) Equal or Greater Than 0.5 cm in Size

The neoadjuvant or adjuvant chemotherapy options for patients with TNBC:
- Are similar to the approaches used in other breast cancer phenotypes
- The principles for the surgical management of and radiation therapy options for breast cancer are also applied in a similar way across breast cancer subtypes
Tumors equal or greater than 0.5 cm:
- Chemotherapy:
  - Chemotherapy is recommended for women with:
    - TNBC equal or greater than 0.5 cm or with node-positive TNBC (regardless of tumor size):
      - These patients have a higher risk of relapse compared with other breast cancer phenotypes and are not candidates for other forms of targeted therapy (ie, HER2-directed treatment or endocrine therapy)
- Neoadjuvant versus adjuvant administration:
  - Neoadjuvant chemotherapy (NACT) is the preferable approach in patients with:
    - Locally advanced breast cancer or for those who are not candidates for or unlikely to have a good cosmetic outcome with breast conservation
  - For patients receiving NACT:
    - Pathologic complete response:
      - Is associated with improvement in disease-free survival (DFS)
  - Additionally, patients with smaller (eg, T1c) TNBCs:
    - May be offered neoadjuvant therapy:
      - Particularly if they might be candidates for additional treatments in the adjuvant setting if residual disease is identified
  - Benefits:
    - Stage for stage, there is a larger absolute benefit to adjuvant chemotherapy among patients with TNBC compared with those with hormone-positive diseas:
      - In an analysis of three randomized trials that involved a total of 6644 women with node-positive breast cancer, compared with those with ER-positive breast cancer, patients with ER-negative breast cancer:
        
        Had the following significant outcomes at five years following adjuvant chemotherapy:
        
        A larger reduction in the risk of recurrence:
        
        55% versus 26%:
        
        This translated into a higher absolute improvement in DFS:
        
        23% versus 7%
        
        A larger reduction in the risk of death:
        
        55% versus 23%:
        
        This translated into a higher absolute improvement in overall survival (OS):
        
        17% vs 4%
        
        These data emphasize the importance of neoadjuvant chemotherapy for women with TNBC:
        
        Who (unlike those with ER-positive or HER2-positive breast cancer) are not eligible for targeted therapies
Choice of regimen:
- Preferred regimen:
  - Anthracycline-, alkylator-, and taxane-based chemotherapy regimens remain the standard regimens for TNBC:
    - For example, dose-dense doxorubicin and cyclophosphamide followed by paclitaxel (AC-T)
  - Taxanes have significant activity in the treatment of TNBC:
    - There are no meaningful data regarding regimens lacking alkylator-based therapy:
      - As an example of the benefits of a taxane:
        
        In the GEICAM 9906 trial of adjuvant fluorouracil, epirubicin and cyclophosphamide (FEC) versus FEC followed by paclitaxel:
        
        The addition of paclitaxel was associated with an improvement in DFS at seven years:
        
        74% vs 56%
      - The ABC trials:
        
        Tested anthracycline / taxane-based regimens versus docetaxel and cyclophosphamide (TC) given for the same duration:
        
        Finding a benefit overall for incorporation of the anthracycline:
        
        Particularly in TNBC in subset analysis:
        
        However, the absolute benefit in node-negative TNBC appears modest
Non-anthracycline-based regimens:
- Are an appropriate alternative for patients with lower-risk TNBC:
  - Node-negative
  - Less than 1 cm
  - Those with cardiac risk factors
  - Those who prefer to avoid the risks associated with anthracyclines
- TC:
  - Is an alternative in low-risk disease
    - For example, in a randomized trial of nearly 650 patients with operable TNBC:
      - Those assigned to six cycles of adjuvant paclitaxel and carboplatin (administered on days 1, 8, and 15 every 28 days):
        
        Had a longer DFS relative to those assigned to an anthracycline and taxane based regimen:
        
        Five-year DFS 87% vs 80%:
        
        With similar OS
- Is there a role for an antimetabolite agent?
  - For patients with stage II or III TNBC, neoadjuvant regimens such as AC-T or TC are standard:
    - Followed by capecitabine for those with residual disease:
      - Given results of a randomized trial showing an OS benefit with the adjuvant addition of capecitabine when residual disease is present:
        
        However, for patients with stage I disease, adjuvant rather than neoadjuvant treatment is appropriate:
        
        Using standard regimens such as AC-T or TC
  - In general, for patients who have not received neoadjuvant chemotherapy:
    - Adding antimetabolite agents such as capecitabine or gemcitabine to adjuvant chemotherapy:
      - Has not improved OS outcomes in TNBC
        
        A Chinese trial demonstrated improvement in DFS, but not OS, with capecitabine following standard adjuvant regimens:
        
        Among 434 women with early-stage TNBC who received standard adjuvant treatment (94% of whom had not received neoadjuvant therapy):
        
        Low-dose capecitabine maintenance therapy for one year improved five-year DFS compared with observation only:
        
        83% versus 73%; hazard ratio [HR] 0.64, 95% CI 0.42-0.95)
        
        The five-year OS was similar between the groups:
        
        86% vs 81%:
        
        With and without capecitabine, respectively; HR 0.75, 95% CI 0.47-1.19)
        
        The trial had important limitations; notably, there was an imbalance in randomization, with a higher proportion of older women assigned to placebo, which could have favored the capecitabine group
  - In a separate phase III trial of 876 women with early-stage TNBC who had received standard adjuvant chemotherapy:
    - Subsequent treatment with capecitabine versus placebo resulted in numerically:
      - But not statistically, improved five-year DFS and OS (DFS, 80% versus 77%, HR 0.79, 95% CI 0.61-1.03; OS, 86.2% versus 85.9% , HR 0.92, 95% CI 0.66-1.28)
    - Similarly, trials looking at adjuvant gemcitabine have proven negative.
- Given the sum of data, most medical oncologist opt for standard anthracycline- and/or taxane-based chemotherapy regimens as adjuvant therapy in patients with TNBC who have not received neoadjuvant treatment:
  - As discussed, in practice, only lower-risk patients (ie, stage I TNBC) are treated with adjuvant rather than neoadjuvant chemotherapy:
    - As most patients with higher-risk disease receive neoadjuvant therapy
Is there a role for platinums?
- There is controversy as to whether adding platinum-based chemotherapy should be “standard” in stage II or III TNBC:
  - Trials have shown that adding platinum-based chemotherapy to neoadjuvant regimens can improve the rate of complete pathologic response:
    - However, to date, this has not improved OS in women also receiving anthracycline-, alkylator-, and taxane-based treatment
PARP inhibitors for BRCA carriers:
- The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib:
  - Has regulatory approval by the US Food and Drug Administration for the adjuvant treatment of adult patients with deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated, HER2-negative, high-risk early breast cancer:
    - Who have been treated with neoadjuvant or adjuvant chemotherapy
Is there a role for immunotherapy?
- Pembrolizumab has regulatory approval with chemotherapy for the neoadjuvant treatment of patients with high-risk, early-stage TNBC