31.12.32 Response of Neoadjuvant Chemotherapy in Triple Negative Breast Cancer and the impact of Pathologic Complete Response on Survival

Original Article

 

Effect if Chemotherapy in  Triple Negative Breast Cancer  

Response of Neoadjuvant Chemotherapy in Triple Negative Breast Cancer and the impact of Pathologic Complete Response on Survival

Susheel Kumar1, Iqtedar Ahmed Moazzam1, Waqas Ishtiaq Ali1 and Naveed Lodhi2

ABSTRACT

Objective: To evaluate response of neoadjuvant chemotherapy (NACT) in stage I-III triple negative breast cancer (TNBC) and impact of pathologic complete response (pCR) on survival.

Study Design: Descriptive / Cross-sectional study

Place and Duration of Study: This study was conducted at the Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore, Pakistan between January 2010 to July 2016.

Materials and Methods: All patients with TNBC who received NACT were included and data was abstracted from cancer registry of hospital. The patients received NACT followed by surgery. Radiotherapy was given wherever clinically indicated. Kaplan-Meier and log-rank test was used to calculate survival.  

Results: Out of 1113 TNBC patients, 150 received NACT. Mean age was 43 ± 7 years. Fifty-two patients (34.7%) achieved pCR(defined as complete eradication of invasive or in situ carcinoma in breast and axilla (ypT0/is/ypN0) in surgical specimen). Over a median follow up of 61 months, 52 patients (34.7%) had disease progression. In pCR group, only 5 patients (9.6%)had disease progression whereas in non-pCR group, 47 patients (48%)experienced disease progression. Patients who achieved pCR had significantly better 5-yearsdisease-free survival (DFS) (p-value0.001) and 5-years overall survival (OS)(p-value0.002) in comparison to non-pCR group. The 5-years DFS was 90% in pCR group compared to 55% in non-pCR group. Similarly, 5-years OS was 94% in pCR group compared to 70% non-pCR group.

Conclusion: NACT is an effective treatment modality in management of TNBC. Achievement of pCR is a potential surrogate endpoint as it is associated with significantly better DFS and OS.

Key Words: Disease free survival (DFS), Overall survival (OS), Pathologic complete response (pCR), Triple negative breast cancer (TNBC).

Citation of article: Kumar S, Moazzam IA, Ali WI, Lodhi N. Response of Neoadjuvant Chemotherapy in Triple Negative Breast Cancer and the impact of Pathologic Complete Response on Survival. Med Forum 2020;31(12):139-143.

 

 

INTRODUCTION

Breast cancer is the most common type of cancer in women worldwide1. It is a heterogeneous disease with variable clinical behavior, response to treatment and prognosis depending on its molecular subtype. Approximately 20% of all breast cancer patients have an aggressive subtype called ‘triple negative breast cancer’.

 

 

1. Department of Oncology, Shaukat Khanum Mermorial Cancer Hospital & Research center Lahore.

2. Department of Biochemistry, Al Aleem Medical College Lahore.

 

 

Correspondence: Dr. Susheel Kumar, Consultant Clinical Oncologist, Shaukat Khanum Mermorial Cancer Hospital & Research Center, Lahore.

Contact No: 0334-3082144

Email: susheeltaurus@gmail.com

 

 

Received:    January, 2020

Accepted:    August, 2020

Printed:        December, 2020

 

Triple negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR) and there is neither expression nor the amplification of human epidermal growth factor receptor 2 (Her-2)2. It is more common among younger premenopausal women, African-American or non-Hispanic black race and is associated with high BMI and BRC Amutations3. In comparison with other breast cancer subtypes, TNBCs are predominantly high grade invasive ductal carcinomas and usually presents with larger palpable masses4. They are associated  with early disease recurrence within the first 2-3 years after treatment and propensity to metastasize to viscera, mainly lungs and brain5,6. Cytotoxic chemotherapy is the mainstay of systemic treatment in TNBC and has more sensitivity to neoadjuvant chemotherapy regimens than other breast cancer subtypes6,7. Despite overall poor prognosis, survival is comparable to other breast cancer subtypes, if pathologic complete response (pCR) is achieved6. A number of studies have demonstrated that TNBC patients who achieve pCR, experience better DFS and OS than the patients with residual disease6,8-10. Considering the outstanding prognostic importance of pCR, it is considered to be an important surrogate endpoint in clinical trials assessing the efficacy of neoadjuvant chemotherapy6,8,9.

MATERIALS AND METHODS

This was a cross sectional study done at Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC) Lahore, and was approved by the institutional review board. Hospital’s electronic database was queried from Jan 2010 to July 2016 to identify all patients with a diagnosis of stage I–III TNBC who received neoadjuvant chemotherapy. All women were greater than 18 years of age with biopsy proven TNBC. Patients were excluded from the study if they had received treatment previously for breast cancer, had non-invasive breast cancer or any malignancy other than breast cancer.

Medical records of 1113 TNBC patients were reviewed and 150 patients with complete information on clinical stage and receptor status were identified who received NACT. Data was collected for clinical stage according to TNM staging AJCC 8th edition, tumor grade, NACT regimen, type of surgery, date of surgery, pCR, use of radiation therapy, date of recurrence, date of last follow up and date of death.ER and PR status was assessed by immunohistochemistry (IHC) and tumors with less than 1% stained cells were considered to have negative receptor status.HER-2 status was assessed by either IHC or fluorescent in situ hybridization (FISH). HER-2 negativity was defined as either lack of HER2gene amplification (FISH) or a score of 0 or 1+ (IHC). The pCR was defined as the lack of invasive or in situcarcinoma in breast and axilla (ypT0/is/ypN0) in surgical specimen at definitive surgery11.

Statistical analysis: SPSS software (version 20.0; SPSS, Chicago, IL, USA) was used for statistical analysis of the data. Mean ± standard deviation was used for continuous variables while frequencies and percentages was reported for categorical variables. The DFS was defined as time from date of definitive surgery to date of first relapse. The OS was defined as time from date of definitive surgery to time of death of any cause or last follow-up. The Kaplan-Meier method was used to estimate survival as a function of time, and survival differences was analyzed by using log-rank test. Statistical significance will be defined as a two-tailed p-value less than 0.05.

RESULTS

We screened 1113 TNBC patients andidentified 150 patients with stage I–IIIwho were treated with neoadjuvant chemotherapy. The mean age of the study population was 43 years (standard deviation of ± 7) with 88 patients (58.6%) being < 45 years. Baseline characteristicsofpatients are shown in Table-1.

Table 1: Triple Negative Breast Cancer patient’s characteristics

Variables

Categories

Total = N* (%)

Age (years)

Mean ± standard deviation

43. ± 7

Family History

No

114 (77.0)

 

Yes

34 (23.0)

Grade

II

30 (20.0)

 

III

120 (80.0)

Histology

IDC

145 (96.7)

 

IDC + DCIS

5 (3.3)

Clinical stage

I

2 (1.3)

 

IIA

63 (42.0)

 

IIB

67 (44.7)

 

IIIA

12 (8.0)

 

IIIB

4 (2.7)

 

IIIC

2 (1.3)

Clinical tumor size

T1

5 (3.3)

 

T2

118 (78.7)

 

T3

23 (15.3)

 

T4

4 (2.7%)

Clinical nodal status

N0

78 (52.0%)

 

N1

65 (43.3%)

 

N2

5 (3.3)

 

N3

2 (1.3)

Surgery type

Breast-conserving Surgery

98 (65.3)

 

Mastectomy

52 (34.7)

 

Table No.2: Chemotherapy regimens

Variables

Categories

Total = N* (%)

Sequential Anthracyclines + taxane

 

106 (70.7)

 

-      AC/Taxol

35 (33.0)

 

-      AC/DOC

48 (45.0)

 

-      FEC/DOC

23 (22.0)

Concomitant  Anthracyclines + taxane

 

9 (6.0)

 

-      TAC

9 (100.0)

Miscellaneous

 

35 (23.3)

 

-      FAC             

20 (57%)

 

-      AC

9 (26%)

 

-      FEC           

4 (11%)

 

-      TC                

2 (6%)

One hundred and twenty-five patients (82%) had tumor sizes ≤T2 and 27 (18%) had tumor sizes >T2. All patients had invasive ductal carcinoma and out of them 120 (80%) were grade III tumors. Seventy-twopatients (48%) had clinically involved axillary nodes. Ninety-eight (65%) patients underwent breast conservation surgery (BCS) whereas remaining had mastectomies. All patients received adjuvant radiotherapy, except one who had disease progression before radiotherapy.  Different chemotherapy regimens were used, as reported in Table-2. One hundred and fifteen patients (77%) received anthracyclines-taxane based chemotherapy and out of them 106patients (92%) received sequential therapy. Thirty-five patients (23%) received other different neoadjuvant regimens.

Out of 150, fifty-two patients (34.7%) achieved pathologic complete response (pCR). With respect to chemotherapy regimens, sequential anthracyclines-taxane based regimens were associated with the higher pCR rate (34%) and among them adriamycin, cyclophosphamide plus paclitaxel (AC/Taxol) was the most effective one (pCR rate 41%). The clinical T and N stage were inversely related to pCR rate. The pCR rate for tumors ≤T2 was 36.6% compared to 26% for tumors >T2. However, the proportion of patients with tumor size >T3 were much less than ≤T2. Among node negative patients, pCR rate was 41% compared to only 28% in node positive patients. 

Over a median follow up of 61months (range; 2-145 months), 52 patients (34.7%) among 150 experienced disease progression. In pCR group (n = 52), only 5 (9.6%) had disease progression whereas in non-pCR group (n = 98), 47 patients (48%) experienced disease progression. The 5-years DFS and OS were 63% and80% respectively, as shown in Figure-1.In pCR group, survival outcomes were significantly better than patients with residual disease. The 5-yearsDFS was 90% in pCR group compared to 55% in non-pCR group. Similarly,5-years OS was 94% in pCR group compared to 70% non-pCR group as shown in Figure-2. The baseline nodal involvement also affected survival outcomes with respect to achievement of pCR. In node negative patients, 5-years DFS and OS were 90% vs 60% and 95% vs 72% in pCR and non- pCR group respectively. Node positive patients who achieved pCR, experienced better 5-years DFS and OS compared to non- pCR group (95% vs 42% and 95% vs 65% respectively).

 

 

 

Figure No.1:(A)  5-years Disease-free survival (B) 5-years Overall survival

Figure No.2(A): Disease free survival with respect to pCR(B) Overall survival with respect to pCR

 

 

DISCUSSION

TNBC is an aggressive subtype of breast cancer that lacks targeted therapy and systemic treatment is limited to chemotherapy. TNBC is more chemosensitive than other breast cancer subtypes with higher pCR rates in neoadjuvant settings. Conventionally, anthracyclines-taxane based regimens have been the most optimal chemotherapy regimens12. With the development Next Generation Sequencing (NGS), molecular classification of TNBC has been done and novel targets are under investigation13-15. Cumulative evidence from review of large randomized clinical trials has shown that neoadjuvant and adjuvant chemotherapies have similar results in terms of disease free survival (DFS) and overall OS16,17. However, the role of neoadjuvant chemotherapy has much evolved in recent decades as it allows more breast conservations and enables prompt assessment of treatment response18-20. Several neoadjuvant trials have demonstrated that achievement of pCR is associated with improved DFS and OS. Therefore, it is considered apotential surrogate endpoint for long-term survival in TNBC.

Majority of our study population received sequential anthracyclines with taxane based chemotherapy regimens and 52 patients (34.7%) achieved pCR. The highest pCR rate in our study was observed in AC/ Taxol group (41%). This is in accordance with international literature that has reported pCR rates ranging from 22-45%in TNBC with use of anthracyclines-taxane based regimens6,9,11. Liedtke C et al in their prospective study at M.D. Anderson Cancer Centre published in 2008 reported that TNBC patients have higher pCR rates than other breast cancer subtypes (22% vs 11%; p value 0.034). The patients who achieved pCR had very good survival comparable to other breast cancer subtypes than those who have residual disease. The 3-years OS was 94% in pCR group compared to 68% in patients with residual disease6. Cortazar and colleagues in a large pooled analysis of 12 international randomized neoadjuvant chemotherapy trials in breast cancer (the CTNeoBC pooled analysis) studied association betweenpCR and long-term survival. TNBC and Her-2 positive patients who achieved pCR, experienced significantly better event free survival (EFS) and OSthan with residual disease8.

Similarly, Symmans et al have reported that TNBC patients who achieve pCR after  NACT, had significantly better 10-years relapse free survival compared to patients with residual disease (86%vs 23%)10. Fisher et al in their retrospective study comparing neoadjuvant and adjuvant chemotherapy in TNBC have reported OS of 92.3% for patients achieving pCR after NACT and 67.2% in patients with residual disease21. Although, survival outcomes were comparable in NACT and adjuvant treatment groups, important to note is tumors with high risk features were included in NACT group.

The findings in our study are consistent with international literature depicting the predictive value of pCR on long-term survival outcomes. Our study also demonstrated that the patients who achieved pCR, experienced significantly better 5-year DFS and 5-year OS (90% vs 55% and 94% vs 70% respectively) compared to patients with residual disease. The patients with positive axillary nodes experienced comparable survival to node negative tumors after achievement of pCR.

Although, the impact of addition of carboplatin on survival outcomes with achievement of pCR is still to be established, we suggest the use of additional carboplatin to standard chemotherapy regimens in selected patients. We think it would be a suitable practice in young fit patients with locally advanced disease to achieve better local control of disease in the form of pCR. As only conventional chemotherapy regimens were used in our study, the pCR rate was comparatively lower than demonstrated in recent clinical trials.

Selection bias was an important limitation of our study. We had a skewed population with young fit patients as per institutional acceptance criteria for treatment at SKMCH & RC. This might have affected the survival results demonstrated in our study. Further, BRCA testing was not available by that time in our institute so we lack the information and treatment response in possible BRCA positive patients.

CONCLUSION

Our study has shown the benefit of NACT in TNBC patients in terms of improved survival with achievement of pCR, in concordance with other neoadjuvant studies. Outcome is worse in patients with residual disease in breast and/or axilla in terms of significantly lower DFS and OS. So NACT is helpful to identify the chemoresistant patients (i.e. those who have not achieved pCR) and considering them for salvage treatments as residual disease. Further trials are needed to develop novel neoadjuvant approaches in TNBC patients to increase pCR rates.

Author’s Contribution:

Concept & Design of Study:

Susheel Kumar

Drafting:

Iqtedar Ahmed Moazzam

Data Analysis:

Waqas Ishtiaq Ali, Naveed Lodhi

Revisiting Critically:

Susheel Kumar, Iqtedar Ahmed Moazzam

Final Approval of version:

Susheel Kumar

Conflict of Interest: The study has no conflict of interest to declare by any author.

 

REFERENCES

1.      Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer J Clinicians 2018;68(6):394-424.

2.      Hammond MEH, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Archives of Pathol Laboratory Med 2010; 134(7):e48-e72.

3.      Newman LA, Reis-Filho JS, Morrow M, Carey LA, King TA. The 2014 society of surgical oncology Susan G. Komen for the cure symposium: triple-negative breast cancer. Annals Surgical Oncol 2015;22(3):874-82.

4.      Thike AA, Cheok PY, Jara-Lazaro AR, Tan B, Tan P, Tan PH. Triple-negative breast cancer: clinicopathological characteristics and relationship with basal-like breast cancer. Modern Pathol 2010; 23(1):123-33.

5.      Anders CK, Abramson V, Tan T, Dent R. The evolution of triple-negative breast cancer: from biology to novel therapeutics. Am Society Clin Oncol Educational Book 2016;36:34-42.

6.      Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 2008; 26(8):1275-81.

7.      Berry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, Goldstein LJ, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 2006;295(14):1658-67.

8.      Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384(9938):164-72.

9.      Von Minckwitz G, Untch M, Blohmer J-U, Costa SD, Eidtmann H, Fasching PA, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012;30(15):1796-804.

10.  Symmans WF, Wei C, Gould R, Yu X, Zhang Y, Liu M, et al. Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol 2017;35(10):1049.

11.  Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007;13(8):2329-34.

12.  Oakman C, Viale G, Di Leo A. Management of triple negative breast cancer. The Breast 2010; 19(5):312-21.

13.  Network CGA. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490(7418):61.

14.  Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Investigation 2011;121(7):
2750-67.

15.  Burstein MD, Tsimelzon A, Poage GM, Covington KR, Contreras A, Fuqua SA, et al. Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clinical Cancer Res 2015;21(7):1688-98.

16.  Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, et al. Preoperative chemotherapy: updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27. J Clin Oncol 2008;26(5):778-85.

17.  Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J National Cancer Institute 2005;97(3):188-94.

18.  Bear HD, Anderson S, Smith RE, Geyer Jr CE, Mamounas EP, Fisher B, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2006;24(13):2019-27.

19.  Colleoni M, Goldhirsch A. Neoadjuvant chemotherapy for breast cancer: any progress? The Lancet Oncol 2014;15(2):131-2.

20.  Thompson A, Moulder-Thompson S. Neoadjuvant treatment of breast cancer. Annals Oncol 2012; 23(suppl_10):x231-x6.

21.  Fisher CS, Ma CX, Gillanders WE, Aft RL, Eberlein TJ, Gao F, et al. Neoadjuvant chemotherapy is associated with improved survival compared with adjuvant chemotherapy in patients with triple-negative breast cancer only after complete pathologic response. Annals Surg Oncol 2012;19(1):253-8.