Adjuvant Chemotherapy In Premenopausal Patients Research Articles

Adjuvant Chemotherapy in Premenopausal Patients With Hormone-Positive Breast Cancer With a Recurrence Score of 16-25: A Retrospective Analysis Using the National Cancer Database.

Results from the TAILORx trial revealed that the use of adjuvant chemotherapy along with endocrine therapy had no survival advantage in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2-negative (HER2-), node-negative (N0) breast cancer (BC) with an intermediate (11-25) 21-gene recurrence score (RS) in the overall population. However, in patients under age 50 years, adjuvant chemotherapy demonstrated a progression-free survival benefit when the RS ranged from 16-25. We studied this cohort with the population-based national database. The 2010-2018 National Cancer Database was used to include patients with BC age 18-50 years, N0, M0, RS 16-25, ER+/progesterone receptor±, and HER2-. Patients were divided into two groups on the basis of adjuvant chemotherapy use, and the survival between them was compared. Adjuvant chemotherapy use was noted in 4,808/15,792 (30.45%) patients. Median RS was 18 and 21 in patients without and with adjuvant chemotherapy, respectively. Factors associated with adjuvant chemotherapy use were higher T stage, poor and moderately differentiated tumors, age <40 years, care at an academic center, Caucasian race, patients undergoing mastectomy, regional lymph node surgery, and radiation therapy. Kaplan-Meier survival at 10 years was better with adjuvant chemotherapy (96.2% v 91.6%). Patients without adjuvant chemotherapy had more adverse outcomes (hazard ratio [HR], 1.683 [95% CI, 1.392 to 2.036]; P < .0001). Subgroup analysis showed that the benefit was significant in patients with RS scores 21-25 (HR, 1.953 [95% CI, 1.295 to 2.945]), ductal histology (HR, 1.521 [95% CI, 1.092 to 2.118]), Caucasian race (HR, 1.655 [95% CI, 1.180 to 2.322]), and 41-50 years age group (HR, 1.732 [95% CI, 1.244 to 2.411]). Our study showed an overall survival benefit for adjuvant chemotherapy use in patients with ER-positive, N0 premenopausal BC patients, age less than 50 years, with an intermediate RS score, particularly 21-25.

The Prosigna gene expression assay and responsiveness to adjuvant cyclophosphamide-based chemotherapy in premenopausal high-risk patients with breast cancer

BackgroundThe PAM50-based (Prosigna) risk of recurrence (ROR) score and intrinsic subtypes are prognostic for women with high-risk breast cancer. We investigate the predictive ability of Prosigna regarding the effectiveness of cyclophosphamide-based adjuvant chemotherapy in premenopausal patients with high-risk breast cancer.MethodsProsigna assays were performed on the NanoString platform in tumors from participants in Danish Breast Cancer Group (DBCG) 77B, a four-arm trial that randomized premenopausal women with high-risk early breast cancer to no systemic treatment, levamisole, oral cyclophosphamide (C) or cyclophosphamide, methotrexate and fluorouracil (CMF).ResultsIn total, this retrospective analysis included 460 women (40% of the 1146 randomized patients). The continuous Prosigna ROR score was prognostic in the no systemic treatment group (unadjusted P < 0.001 for disease-free survival (DFS), P = 0.001 for overall survival (OS)). No statistically significant interaction of continuous ROR score and treatment on DFS and OS was found. A highly significant association was observed between intrinsic subtypes and C/CMF treatment for DFS (Pinteraction = 0.003 unadjusted, P = 0.001 adjusted) and OS (Pinteraction = 0.04). In the adjusted analysis treatment with C/CMF was associated with a reduced risk of DFS events in patients with basal-like (hazard ratio (HR) 0.14; 95% CI 0.06; 0.32) and luminal B (HR 0.48; 95% CI 0.27; 0.84) subtypes but not in patients with Human epidermal growth factor receptor-enriched (HR 1.05; 95% CI 0.56; 1.95) or luminal A (HR 0.61; 95% CI 0.32; 1.16) subtypes.ConclusionThe Prosigna ROR score and intrinsic subtypes were prognostic in high-risk premenopausal patients with breast cancer, and intrinsic subtypes identify high-risk patients with or without major benefit from adjuvant C/CMF treatment.

Effect of Luteinizing Hormone–Releasing Hormone Agonist on Ovarian Function After Modern Adjuvant Breast Cancer Chemotherapy: The GBG 37 ZORO Study

Observational studies suggested that luteinizing hormone-releasing hormone agonists (LHRHa) might prevent premature ovarian failure resulting from adjuvant chemotherapy in premenopausal patients. We aimed to test the efficacy of ovarian function preservation with the LHRHa goserelin in patients with breast cancer. In a prospective, randomized, open-label, controlled multicenter study, 60 patients younger than age 46 years with hormone-insensitive breast cancer were allocated to receive anthracycline/cyclophosphamide (with or without taxane) -based neoadjuvant chemotherapy with or without goserelin. The first goserelin injection was administered at least 2 weeks before the first chemotherapy cycle, continuing at 3.6 mg subcutaneously every 4 weeks until the end of the last cycle. The primary objective was the reappearance of normal ovarian function, defined as two consecutive menstrual periods within 21 to 35 days at 6 months after end of chemotherapy. Fifty-three patients (88.3%) experienced temporary amenorrhea (93.3% with v 83.3% without goserelin). No significant difference was observed regarding the reappearance of menstruation at 6 months after chemotherapy (70.0% with v 56.7% without goserelin; difference of 13.3%; 95% CI, -10.85 to 37.45; P = .284). All but one evaluable patient reported regular menses at 2 years after chemotherapy. Time to restoration of menstruation was 6.8 months (95% CI, 5.2 to 8.4) with goserelin and 6.1 months (95% CI, 5.3 to 6.8) without goserelin (P = .304). Chemotherapy resulted in a decreased ovarian reserve measured by inhibin B and anti-Müllerian hormone during follow-up, supporting the other findings. Premenopausal patients with breast cancer receiving goserelin simultaneously with modern neoadjuvant chemotherapy did not experience statistically significantly less amenorrhea 6 months after end of chemotherapy compared with those receiving chemotherapy alone.

Goserelin versus control after adjuvant, risk-adapted chemotherapy in premenopausal patients with breast cancer. GABG trial IV-B-93

588 Background: The role of medical ablation after adjuvant chemotherapy in endocrine sensitive or non-sensitive tumors is not yet clearly defined. Methods: We initiated a prospective, randomized multicenter study comparing goserelin (3.6 mg every 28 days for 2 years) and control after adjuvant chemotherapy consisting of three cycles of CMF (500/40/600 mg/m2, i.v. on days 1, 8 q 29) in patients with 0–3+ lymph nodes (LN) and four cycles of EC (90/600 mg/m2, i.v. day 1 q 22) followed by 3 x CMF in patients with 4–9+ LN. At first only patients with hormone receptor (HR)-negative breast cancer were included. However, the study was extended to patients with HR-positive breast cancer and 1–9+ LN, when the ZEBRA study was closed. Results: 776 patients were included (goserelin: n=384; control: n=392), 60% had negative HR, 40% were LN-, 23% had 4–9+ LN; 30% of the patients were 40 years or younger, and 60% received breast conserving surgery. 215 events were observed after a median follow-up of 4.7 years. The first event of failure (goserelin vs control) was an isolated locoregional recurrence (43 vs 29), a distant failure (59 vs 82) and death without previous recurrence (0 vs 2). Five-year event-free survival rates were 71.3% (95% confidence interval (CI), 66.3% to 76.3%) and 67.6% (95% CI, 62.2% to 73.0%) in the goserelin and in the control group, respectively. The estimated hazard ratio of goserelin vs control was 0.92 (95% CI 0.70 to 1.21; P > 0.5) indicating no long-term benefit of goserelin in these patients. In an analysis restricted to LN+ patients, there was no indication of a differential treatment effect in HR+ as compared to HR- patients. Conclusions: The results of this study do not support the use of a GnRH analogue after adjuvant chemotherapy in premenopausal patients with breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca; Pfizer; Deutsche Krebshilfe

Goserelin versus control after adjuvant, risk-adapted chemotherapy in premenopausal patients with breast cancer. GABG trial IV-B-93

588 Background: The role of medical ablation after adjuvant chemotherapy in endocrine sensitive or non-sensitive tumors is not yet clearly defined. Methods: We initiated a prospective, randomized multicenter study comparing goserelin (3.6 mg every 28 days for 2 years) and control after adjuvant chemotherapy consisting of three cycles of CMF (500/40/600 mg/m2, i.v. on days 1, 8 q 29) in patients with 0–3+ lymph nodes (LN) and four cycles of EC (90/600 mg/m2, i.v. day 1 q 22) followed by 3 x CMF in patients with 4–9+ LN. At first only patients with hormone receptor (HR)-negative breast cancer were included. However, the study was extended to patients with HR-positive breast cancer and 1–9+ LN, when the ZEBRA study was closed. Results: 776 patients were included (goserelin: n=384; control: n=392), 60% had negative HR, 40% were LN-, 23% had 4–9+ LN; 30% of the patients were 40 years or younger, and 60% received breast conserving surgery. 215 events were observed after a median follow-up of 4.7 years. The first event of failure (goserelin vs control) was an isolated locoregional recurrence (43 vs 29), a distant failure (59 vs 82) and death without previous recurrence (0 vs 2). Five-year event-free survival rates were 71.3% (95% confidence interval (CI), 66.3% to 76.3%) and 67.6% (95% CI, 62.2% to 73.0%) in the goserelin and in the control group, respectively. The estimated hazard ratio of goserelin vs control was 0.92 (95% CI 0.70 to 1.21; P > 0.5) indicating no long-term benefit of goserelin in these patients. In an analysis restricted to LN+ patients, there was no indication of a differential treatment effect in HR+ as compared to HR- patients. Conclusions: The results of this study do not support the use of a GnRH analogue after adjuvant chemotherapy in premenopausal patients with breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca; Pfizer; Deutsche Krebshilfe

Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: Preliminary results of a randomised trial: S6

The aim of this study was to assess a potential advantage in survival by neoadjuvant as compared to adjuvant chemotherapy. 414 premenopausal patients with T2-T3 N0-N1 M0 breast cancer were randomised to receive either four cycles of neoadjuvant chemotherapy (cyclophosphamide, doxorubicin, 5-fluorouracil), followed by local-regional treatment (group I) or four cycles of adjuvant chemotherapy after primary irradiation ± surgery (group II). Surgery was limited to those patients with a persisting mass after irradiation, and aimed to be as conservative as possible. 390 patients were evaluable. With a median follow-up of 54 months, we observed a statistically significant difference ( P = 0.039) in survival in favour of the neoadjuvant chemotherapy group. A similar trend was seen when the time to metastatic recurrence was evaluated ( P = 0.09). At this stage, no difference in disease-free interval or local recurrence between these two groups could be observed. The mean total dose of chemotherapy administered was similar in both groups. On average, group I had more intensive chemotherapy regimes (doxorubicin P = 0.02) but fewer treatment courses ( P = 0.008) as compared to the treated patients in group II. Haematological tolerance was reduced when chemotherapy succeeded to exclusive irradiation. Breast conservation was identical for both groups at the end of primary treatment (82 and 77% for groups I and II, respectively). Of the 191 evaluable patients in the neoadjuvant treatment arm, 65% had an objective response (>50% regression) following four cycles of chemotherapy. The objective response rate to primary irradiation (55 Gy) was 85%. Improved survival figures in the neoadjuvant treatment arm could be the result of the early initiation of chemotherapy, but we cannot exclude that this difference might be attributable to a slightly more aggressive treatment. So far, the trend in favour of decreased metastases was not statistically significant. The local control appeared similar in both subgroups.

Prognostic role of amenorrhea induced by adjuvant chemotherapy in premenopausal patients with early breast cancer

The prognostic role of drug-induced amenorrhea (DIA) was restrospectively evaluated in 221 out of 254 consecutive premenopausal patients treated with adjuvant CMF or a CMF-containing regimen; 33 patients were eliminated because of lack of menstrual data. All patients had metastatic axillary nodes; drug regimens were: CMF x 9 courses +/- Tamoxifen (TM) and CMF x 6 courses; median age was 43 (range 26-54). Premenopausal status was defined as last normal menses within the 6 weeks preceding initiation of chemotherapy: DIA as cessation of menses for at least 3 months not later than 3 months from the end of chemotherapy. DIA occurred in 166,221 (75.1%) patients and was strictly related to the age of the patients; also, the older the patients the shorter the time required to develop DIA. At median follow up of 69 months, Mantel-Byar analysis showed a longer disease free survival (DFS) for patients who developed DIA as compared with non amenorrheic women (P less than 0.001). DIA prognostic value was independent of age, number of involved nodes, tumour size and number of CMF cycles, as assessed by the Cox model (RH 0.43, 95% C.I. 0.24-0.77), in which DIA was entered as a time dependent covariate.

Adjuvant chemotherapy in premenopausal patients with primary breast cancer; relation to drug-induced amenorrhoea, age and the progesterone receptor status of the tumour

Adjuvant chemotherapy with cyclophosphamide, 5-fluorouracil and methotrexate (CMF)-induced permanent ovarian suppression in 47 of 77 ( 61%) premenopausal patients with axillary node positive breast cancer. After a median observation time of 37 months the relapse-free and overall survival times were significantly longer for patients with permanent amenorrhoea. A strongly positive correlation between CMF-induced amenorrhoea and age of the patients, as well as between age and the tumour PgR status, was found. The induction of ovarian suppression predominantly occurs in patients wih PgR positive tumours and may add an endocrine effect to the cytotoxic action of adjuvant chemotherapy in this particular group of older premenopausal women.

An Evaluation of Early or Delayed Adjuvant Chemotherapy in Premenopausal Patients with Advanced Breast Cancer Undergoing Oophorectomy

We treated randomly 75 premenopausal patients with advanced breast cancer with combination chemotherapy (5-fluorouracil, cyclophosphamide and prednisone), either as an early adjunct to oophorectomy or as a delayed treatment upon appearance of progressive metastatic disease after operation. The group receiving early systemic chemotherapy enjoyed an improved response rate, an improved survival rate and, most importantly, an improved progression-free interval (median of 53 versus 17 weeks). With the exclusion of the group with early (within three weeks after oophorectomy) progression, the progression-free intervals had a median duration of 77 weeks in the early-treatment group versus 33 weeks in the control group. The early-progression group did exceedingly poorly, although systemic chemotherapy was employed at that juncture, having a median survival of 22 weeks as compared to 144 weeks in the immediate-treatment group and 105 weeks in the control group.