Impact of chemotherapy relative dose intensity on cause-specific and overall survival for stage I–III breast cancer: ER+/PR+, HER2- vs. triple-negative
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To investigate the impact of chemotherapy relative dose intensity (RDI) on cause-specific and overall survival for stage I–III breast cancer: estrogen receptor or progesterone receptor positive, human epidermal-growth factor receptor negative (ER+/PR+ and HER2-) vs. triple-negative (TNBC) and to identify the optimal RDI cut-off points in these two patient populations.
Data were collected by the Louisiana Tumor Registry for two CDC-funded projects. Women diagnosed with stage I–III ER+/PR+, HER2- breast cancer, or TNBC in 2011 with complete information on RDI were included. Five RDI cut-off points (95, 90, 85, 80, and 75%) were evaluated on cause-specific and overall survival, adjusting for multiple demographic variables, tumor characteristics, comorbidity, use of granulocyte-growth factor/cytokines, chemotherapy delay, chemotherapy regimens, and use of hormone therapy. Cox proportional hazards models and Kaplan–Meier survival curves were estimated and adjusted by stabilized inverse probability treatment weighting (IPTW) of propensity score.
Of 494 ER+/PR+, HER2- patients and 180 TNBC patients, RDI < 85% accounted for 30.4 and 27.8%, respectively. Among ER+/PR+, HER2- patients, 85% was the only cut-off point at which the low RDI was significantly associated with worse overall survival (HR = 1.93; 95% CI 1.09–3.40). Among TNBC patients, 75% was the cut-off point at which the high RDI was associated with better cause-specific (HR = 2.64; 95% CI 1.09, 6.38) and overall survival (HR = 2.39; 95% CI 1.04–5.51).
Higher RDI of chemotherapy is associated with better survival for ER+/PR+, HER2- patients and TNBC patients. To optimize survival benefits, RDI should be maintained ≥ 85% in ER+/PR+, HER2- patients, and ≥ 75% in TNBC patients.
KeywordsBreast cancer Hormone receptor positive, Triple-negative Chemotherapy Relative dose intensity
Relative dose intensity
Randomized controlled trial
Early stage breast cancer
Cyclophosphamide, methotrexate, and fluorouracil
Human epidermal-growth factor receptor 2
Triple-negative breast cancer
Pathologic complete response
Louisiana Tumor Registry
Enhancing Cancer Registry Data for Comparative Effectiveness Research
Patient Centered Outcomes Research
Centers for Disease Control and Prevention
American Joint Committee on Cancer
body surface area
National Comprehensive Cancer Network
Doxorubicin/cyclophosphamide followed by paclitaxel or docetaxel
Surveillance, Epidemiology, and End Results program
Charlson comorbidity index
Inverse probability of treatment weighting
We acknowledge the Centers for Disease Control and Prevention (CDC) for funding Enhancing Cancer Registry Data for Comparative Effectiveness Research (CER) Project (Grant Number: 1eEDSK0106) and Patient Centered Outcomes Research (PCOR) project (Grant Number: 5NU58DP003915), and the Louisiana Tumor Registry for data and administrative support. We acknowledge Dr. Gary H. Lyman and Dr. Marek S. Poniewierski for clarifying variables used in the calculation of chemotherapy relative dose intensity.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
For this type of study, formal consent is not required.
- 2.Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL, Bryant J, Dimitrov NV, Abramson N, Atkins JN, Shibata H, Deschenes L, Margolese RG (1997) Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89(22):1673–1682CrossRefPubMedGoogle Scholar
- 6.Budman DR, Berry DA, Cirrincione CT, Henderson IC, Wood WC, Weiss RB, Ferree CR, Muss HB, Green MR, Norton L, Frei E 3rd (1998) Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst 90(16):1205–1211CrossRefPubMedGoogle Scholar
- 7.Chirivella I, Bermejo B, Insa A, Perez-Fidalgo A, Magro A, Rosello S, Garcia-Garre E, Martin P, Bosch A, Lluch A (2009) Optimal delivery of anthracycline-based chemotherapy in the adjuvant setting improves outcome of breast cancer patients. Breast Cancer Res Treat 114(3):479–484. https://doi.org/10.1007/s10549-008-0018-1 CrossRefPubMedGoogle Scholar
- 10.Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC Jr (2007) American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. Journal Clin Oncol 25(33):5287–5312. https://doi.org/10.1200/jco.2007.14.2364 CrossRefGoogle Scholar
- 11.National Comprehensive Cancer Network. NCCN Guidelines for Treatment of Cancer by Site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed Aug. 2017
- 15.Lee HJ, Song IH, Seo AN, Lim B, Kim JY, Lee JJ, Park IA, Shin J, Yu JH, Ahn JH, Gong G (2015) Correlations between molecular subtypes and pathologic response patterns of breast cancers after neoadjuvant chemotherapy. Ann Surg Oncol 22(2):392–400. https://doi.org/10.1245/s10434-014-4054-2 CrossRefPubMedGoogle Scholar
- 16.Kuerer HM, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K, Theriault RL, Singh G, Binkley SM, Sneige N, Buchholz TA, Ross MI, McNeese MD, Buzdar AU, Hortobagyi GN, Singletary SE (1999) Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17(2):460–469CrossRefPubMedGoogle Scholar
- 17.Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, Swain SM, Prowell T, Loibl S, Wickerham DL, Bogaerts J, Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas EP, Bergh J, Semiglazov V, Justice R, Eidtmann H, Paik S, Piccart M, Sridhara R, Fasching PA, Slaets L, Tang S, Gerber B, Geyer CE, Pazdur R, Ditsch N, Rastogi P, Eiermann W, Minckwitz G (2014) Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384(9938):164–172. https://doi.org/10.1016/s0140-6736(13)62422-8 CrossRefPubMedGoogle Scholar
- 18.North American Association of Central Cancer Registries: Data standards and data dictionary. http://datadictionary.naaccr.org/. Accessed Aug. 2017
- 19.Surveillance, epidemiology, and end results program: derived HER2 Recode (2010+). https://seer.cancer.gov/seerstat/databases/ssf/her2-derived.html. Accessed Aug. 2017
- 20.Chen VW, Eheman CR, Johnson CJ, Hernandez MN, Rousseau D, Styles TS, West DW, Hsieh M, Hakenewerth AM, Celaya MO, Rycroft RK, Wike JM, Pearson M, Brockhouse J, Mulvihill LG, Zhang KB (2014) Enhancing cancer registry data for comparative effectiveness research (CER) project: overview and methodology. J Regist Manag 41(3):103–112Google Scholar
- 26.Lyman GH, Dale DC, Tomita D, Whittaker S, Crawford J (2013) A retrospective evaluation of chemotherapy dose intensity and supportive care for early-stage breast cancer in a curative setting. Breast Cancer Res Treat 139(3):863–872. https://doi.org/10.1007/s10549-013-2582-2 CrossRefPubMedGoogle Scholar
- 27.SEER Cause-specific Death Classification. http://seer.cancer.gov/causespecific/index.html. Accessed Aug. 2017
- 29.Austin PC, Stuart EA (2015) Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med 34(28):3661–3679. https://doi.org/10.1002/sim.6607 CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Austin PC, Stuart EA (2015) The performance of inverse probability of treatment weighting and full matching on the propensity score in the presence of model misspecification when estimating the effect of treatment on survival outcomes. Stat Methods Med Res. https://doi.org/10.1177/0962280215584401 Google Scholar
- 35.Loibl S, Skacel T, Nekljudova V, Luck HJ, Schwenkglenks M, Brodowicz T, Zielinski C, von Minckwitz G (2011) Evaluating the impact of Relative Total Dose Intensity (RTDI) on patients’ short and long-term outcome in taxane- and anthracycline-based chemotherapy of metastatic breast cancer- a pooled analysis. BMC Cancer 11:131. https://doi.org/10.1186/1471-2407-11-131 CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Yuan JQ, Wang SM, Tang LL, Mao J, Wu YH, Hai J, Luo SY, Ou HY, Guo L, Liao LQ, Huang J, Li Y, Xiao Z, Zhang KJ, Luo N, Chen FY (2015) Relative dose intensity and therapy efficacy in different breast cancer molecular subtypes: a retrospective study of early stage breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat 151(2):405–413. https://doi.org/10.1007/s10549-015-3418-z CrossRefPubMedGoogle Scholar
- 37.Moon HG, Im SA, Han W, Oh DY, Han SW, Keam B, Park IA, Chang JM, Moon WK, Cho N, Noh DY (2012) Estrogen receptor status confers a distinct pattern of response to neoadjuvant chemotherapy: implications for optimal durations of therapy: distinct patterns of response according to ER expression. Breast Cancer Res Treat 134(3):1133–1140. https://doi.org/10.1007/s10549-012-2145-y CrossRefPubMedGoogle Scholar
- 39.Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, Cronin M, Baehner FL, Watson D, Bryant J, Costantino JP, Geyer CE Jr, Wickerham DL, Wolmark N (2006) Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24(23):3726–3734. https://doi.org/10.1200/jco.2005.04.7985 CrossRefPubMedGoogle Scholar
- 40.Lyman GH (2006) Chemotherapy dose intensity and quality cancer care. Oncology 20(14 Suppl 9):16–25Google Scholar
- 41.Denduluri N, Patt DA, Wang Y, Bhor M, Li X, Favret AM, Morrow PK, Barron RL, Asmar L, Saravanan S, Li Y, Garcia J, Lyman GH (2015) Dose delays, dose reductions, and relative dose intensity in patients with cancer who received adjuvant or neoadjuvant chemotherapy in community oncology practices. J Natl Compr Cancer Netw 13(11):1383–1393CrossRefGoogle Scholar