Dose-Dense and/or Metronomic Schedules of Specific Chemotherapies Consolidate the Chemosensitivity of Triple-Negative Breast Can

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Cancer Chemother Pharmacol. 2008 Sep;62(4):667-72. Epub 2007 Dec 7.

Dose-Dense and/or Metronomic Schedules of Specific Chemotherapies Consolidate the Chemosensitivity of Triple-Negative Breast Cancer: A Step Toward Reversing Triple-Negative Paradox


Rita S. Mehta

Departments of Division of Hematology/Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California at Irvine School of Medicine, Irvine, CA

To the Editor:

Liedtke et al1 report a progression-free survival of 63% inpatients with triple-negative breast cancer predominantly treatedwith anthracyline-based first and second regimens in the neoadjuvantsetting. They suggest that third generation regimen are importantconsiderations in triple-negative subtypes of breast cancerin their discussion, but we feel it needs to be emphasized thatthird generation regimens should be standard in treatment oftriple-negative breast cancer. Combining the four subgroups(based additionally on progesterone receptor status and humanepidermal growth factor receptor 2 [HER-2] status) of 483 patientswith estrogen receptor–negative breast cancer, the 3-yearprogression-free survival is similarly 63% and overall survivalis 74%.1 These combined group results are comparable with the5-year progression-free survival of 63% and overall survivalof 68% in 327 patients with estrogen receptor–negativebreast cancer updated by Citron et al2 in the adjuvant setting(possibly smaller tumors, but longer time outcome) using thestandard once-every-3-weeks doxorubicin, cyclophosphamide, andpaclitaxel. In the comparator arm, the 5-year progression-freesurvival improved statistically significantly to 70% and overallsurvival to 75% in 336 patients with estrogen receptor–negative(includes triple-negative subset) breast cancer with use ofdose-dense (once every 2 weeks) administration of doxorubicin,cyclophosphamide, and paclitaxel—a third generation regimen(23% hazard reduction).2 Another trial showed an estimated 5-yearevent-free survival of 71% in the triple-negative cohort treatedwith two cycles of dose-dense epirubicin and cyclophosphamidefollowed by high-dose cyclophosphamide, thiotepa, and epirubicinchemotherapy compared with only 26% in the four cycles of dose-denseepirubicin and cyclophosphamide followed by dose-dense cyclophosphamide,methotrexate, and flurouracil arm, but the poor survival incomparator arm suggest that rapid cycling to an alternate effectiveregimen may be the underlying mechanism of superiority of dose-denseand dose-intensified regimen.3 Similarly, weekly paclitaxelsignificantly improved the 5-year progression-free hazard rateby 40% in hormone receptor–negative (including triple-negativesubset) breast cancer and 20% in hormone receptor–positivesubsets compared with these subsets treated with once-every-3-weeksscheduling.4 A parallel phase III neoadjuvant study demonstrateda pathologic complete response of 43% with denser doxorubicin(weekly) and cyclophosphamide (continuous) compared with 26%with once-every-3-weeks doxorubicin and cyclophosphamide, botharms receiving weekly paclitaxel in locally advanced breastcancer, suggesting an additive benefit of denser administrationdoxorubicin and cyclophosphamide, in addition to the denseradministration of paclitaxel.5 Taken together, studies showbenefit of accelerated schedules (weekly or once every 2 weeks)of doxorubicin, cyclophosphamide, and paclitaxel. Importantly,comparing across trials, weekly paclitaxel achieves a higherhazard rate reduction than once-every-2-weeks paclitaxel whenboth accelerated schedules are compared to once-every-3-weekspaclitaxel.2,4


Of note, Liedtke et al1 show that 22% of patients who achievedpathologic complete response had an overall survival of 94%,and 78% of patients who did not achieve a pathologic completeresponse had a 68% overall survival—a 26% difference.An absolute 50% increment in pathologic complete response overa baseline of 22% would move an additional 50% of patients from68% to 94% survival (an absolute 26% improvement for the 50%patients), a 13% increment in survival above a baseline 3-yearsurvival of 74% for 100 patients would result in overall survivalimprovement to 87% (a 25% increment in pathologic complete responsewould move 25% of patients from 68% to 94% survival, nettinga 6.5% improvement in 3-year survival; ie, each 10% incrementin pathologic complete response will translate into an absolute2.6% 3-year survival). Green et al6 show doubling of pathologiccomplete response from 23% to 48% with weekly paclitaxel, andan absolute 25% improvement of pathologic complete responsein the hormone receptor–negative subset. On projecting,this will translate into an absolute 6.5% survival benefit,that is an improved 3-year overall survival of 81.5%, a 25%hazard reduction at a minimum. Speculatively, additional survivalbenefit may accrue with increase in the minimal residual disease.6Indeed, the actual benefit in the trial reported by Sparanoet al 4 was 40% hazard reduction with weekly paclitaxel comparedto once-every-3-weeks paclitaxel in hormone receptor–negativesubset.


Of the prospectively maintained database of 14 patients withstage IIA-IIIB (including inflammatory breast cancer) or localrelapse HER-2–negative, estrogen receptor–negative,and progesterone receptor–negative, infiltrating ductalcarcinoma (excluding two patients with metaplastic carcinoma)of breast who received dose-dense doxorubicin and cyclophosphamide(maximum four doses, except one who relapsed after doxorubicin,cyclophosphamide, and flurouracil) followed either by dose-densepaclitaxel (n = 2; four doses), or by weekly paclitaxel (cremophor[80 mg/m2] or albumin bound [100 mg/m2]) with carboplatin (atarea under the curve of 2, both 3 weeks on, 1 week off; maximum12 doses, n = 12) plus or minus maximum eight doses of bevacizumabevery 2 weeks (n = 4; maximum 8 doses), 10 of 14 patients (71%;95% CI, 42% to 92%) achieved pathologic complete response. Twoadditional patients had scattered cells in the breast with nolymph node involvement. Thus, 13 of 14 (93%; 95% CI, 66% to100%) patients had no evidence of residual lymph node involvement.The progression-free survival of 86% (95% CI, 57% to 98%) andoverall survival of 93% (95% CI, 66% to 100%) of 14 patientsat a median follow-up of 36 months (range, 22 to 68 months)compared with the projected survival improvement of 87% basedon pathologic complete response of 71% is promising. Assessedanother way, a reversal of pathologic response incidence from22% reported by Liedtke et al1 to 71% is likely to show improvementin survival closer to 94% for the majority of patients, a resultseen with our data—a 73% hazard reduction. Therefore,the high pathologic complete response reported by us parallelsthe benefit of once-every-2-weeks anthracyclines (or denser),and once-every-2-weeks or once-weekly paclitaxel schedulingin phase III trials.5,6 Faster delivery of anthracyclines allowsadministration of targeted or alternate effective treatmentearlier. For example, hormone receptor blocker for hormone receptor–positivebreast cancer, trastuzumab for HER-2–positive breast cancer,and once-weekly paclitaxel, an alternate effective treatmentfor all subsets of breast cancer, specifically triple-negativesubset. Therefore, for patients with triple-negative tumors,optimally scheduled doxorubicin and cyclophosphamide (once every2 weeks) and paclitaxel (once weekly) should be standard.2,4As 12 of 14 patients also received carboplatin, the use of carboplatinmay be considered in any patient with large (as seen in neoadjuvantsetting) triple-negative breast cancer.7,8 While carboplatinbased adjuvant phase III studies are limited to docetaxel, trastuzumab,and carboplatin combination, extrapolation of docetaxel, trastuzumab,and carboplatin combination to paclitaxel and carboplatin (andtrastuzumab in HER-2–positive breast cancer) after anthracyclinesmay be reasonable pending large adjuvant or neoadjuvant trialsin triple-negative breast cancer. Importantly, carboplatin isstandard treatment for ovarian and lung cancer, and thereforelong-term outcome is known. Moreover, the BRCA-ness of the triple-negativetumors makes these tumors specifically susceptible to the DNA-damagingaction of carboplatin give support to our use of carboplatinin triple-negative breast cancer.9 Additional small studiesthat used platinums have similarly shown a promising outcomeeither in pathologic complete response (20% with single-agentcisplatin to 67% with platinum combination regimens) or in progression-freesurvival (75% to 84%) in triple-negative breast cancer.10-12,14-15We did not see any progression while patients were receivingchemotherapy, unlike the studies by Torissi et al10,13 wherethey show a substantial progression while patients were eitheron weekly paclitaxel or dose-dense docetaxel regimen. This maybe secondary to delayed switch to alternate effective therapyof weekly paclitaxel in the first case, or switch to a lesseffective dose-dense docetaxel switch in the second case.


The potential additional benefit of bevacizumab over optimumscheduling of standard chemotherapy needs to be tested in randomizedtrials, as the follow-up is shortest for the four patients receivingbevacizumab. While the small number, short follow-up, and heterogeneityof chemotherapy are limitations of our small study, the chemotherapywas uniformly delivered in accelerated fashion. Achievementof high pathologic complete response and the corresponding survivalbenefit tied to high pathologic complete response are the strengthsof the study. Despite a short follow-up, the follow-up wouldbe considered adequate for progression-free survival in triple-negativesubtype of breast cancer as the hazard rates of relapse arehighest in the first year, and taper off quickly after 3 years.1We emphasize that third generation chemotherapeutic regimensare the most important treatment regimens for triple-negativebreast cancer in achieving a higher pathologic complete response,and thereby higher survival, where the only current targetedtreatment is the accelerated and optimized chemotherapy thattargets the Gompertzian growth model as first shown by Nortonet al.16 Moreover, poor clinical outcome seen in patients withtriple-negative despite initial chemosensitivity as demonstratedby Carey et al17 can be overcome by consolidating the gainsobtained by initial chemosensitiviy of accelerated anthracyclineswith accelerated optimal chemotherapy, which at a minimum shouldinclude weekly paclitaxel.