Addition of carboplatin-gemcitabine as second-line neoadjuvant chemotherapy in non-responsive locally advanced breast cancer patients to standard neoadjuvant chemotherapy and evaluation of factors affecting response: a randomized controlled trial.
BACKGROUND
Neoadjuvant chemotherapy (NACT) is the prime approach to the management of locally advanced breast cancer (LABC). Influenced by different factors such as pathologic tumor characteristics, hormone receptor status, HER2 and proliferation marker expressions, response to therapy cannot be easily predicted. Pathologic complete response (pCR) has been considered as an endpoint to NACT; however, pCR rates have been unsatisfactory in such patients. In this randomized trial, we studied the efficacy of carboplatin/gemcitabine as second-line NACT while evaluating the impact of different factors affecting response.


METHODS
In this randomized controlled trial, 52 clinically non-responsive (confirmed by palpation and/or ultrasonography) LABC patients to 4 cycles of doxorubicin/cyclophosphamide followed by 4 cycles of paclitaxel ± trastuzumab were randomly allocated to two groups. "Control" group underwent breast surgery and were further evaluated for pCR (ypT0/is ypN0). "Intervention" group received 2 cycles of carboplatin/gemcitabine and patients were further evaluated for pCR following surgery.


RESULTS
In a total of 52 patients, pCR rate was 30.7%. pCR and response rate in lymph nodes were higher in carboplatin/gemcitabine recipients (32% vs 29.7 and 44% vs 40.7% respectively), however differences were insignificant. In both the "intervention" group and total study population, most pCR cases were of the hormone receptor (HR)+/HER2+ subtype (87.5% and 75% respectively). HER2 positivity, ki67 expression, lower extent of ER positivity, higher tumor grade and tumor-infiltrating lymphocyte (TIL) lead to higher pCR rates. Adverse events following addition of carboplatin/gemcitabine were mostly hematologic and none required hospitalization. Anemia was the most common grade 3 adverse event observed. No grade 4 toxicity was evident.


CONCLUSION
Although the proposed carboplatin/gemcitabine combination could not improve pCR rates as expected, probability of immune activation following use of carboplatin in achieving response to NACT may be considered. Accounting for the highest number of pCR cases in the "intervention" group, the HR+/HER2+ subtype with high TILs may be considered as most responsive to the proposed regimen in this study. It is noteworthy that the proposed combination imposed minimal toxicity.


TRIAL REGISTRATION
This trial was prospectively registered in IRCT.ir ( IRCT2017100136491N1 ). Date of registration: 19 November 2017.
['Firouzabadi|Dena|D|https://orcid.org/0000-0003-0257-8984', 'Dehghanian|Amirreza|A|https://orcid.org/0000-0003-0360-7468', 'Rezvani|Alireza|A|https://orcid.org/0000-0003-1805-4261', 'Mahmoudi|Laleh|L|https://orcid.org/0000-0003-3866-8519', 'Talei|Abdolrasoul|A|']
D000293:Adolescent D000328:Adult D000368:Aged D000369:Aged, 80 and over D000971:Antineoplastic Combined Chemotherapy Protocols D001943:Breast Neoplasms D016190:Carboplatin D003841:Deoxycytidine D005260:Female D005500:Follow-Up Studies D006801:Humans D008875:Middle Aged D020360:Neoadjuvant Therapy D011379:Prognosis D011446:Prospective Studies D016879:Salvage Therapy D055815:Young Adult
Neoadjuvant chemotherapy Locally advanced breast cancer Pathologic complete response Carboplatin Gemcitabine Lymph node ki67 Tumor-infiltrating lymphocytes