Effect of histological breast cancer subtypes invasive lobular versus non-special type on survival in early intermediate-to-high-risk breast carcinoma: results from the SUCCESS trials

The SUCCESS studies are a series of three consecutive clinical trials conducted between 2005 and 2017 on primary intermediate-to-high-risk breast cancer patients. The study series comprises the SUCCESS A trial ("Simultaneous Study of Gemcitabine-Docetaxel Combination adjuvant treatment, as well as Extended Bisphosphonate and Surveillance-Trial"; NCT02181101), the SUCCESS B trial ("Simultaneous Study of Gemcitabine-Docetaxel Combination adjuvant treatment, as well as Biological Targeted Treatment"; NCT00670878), and the SUCCESS C trial ("Simultaneous Study of Docetaxel-based Anthracycline-free adjuvant treatment evaluation, as well as Life Style Intervention Strategies"; NCT00847444). Overall, 8190 patients were included in the SUCCESS A, B, and C trials. Inclusion criteria were primary R0-resected epithelial invasive breast cancers (pT1-4, pN0-3, pM0) with guideline adherent treatment recommendation for adjuvant CHT (nodal positive or high-risk nodal negative (pT ≥ 2, tumor grade (G) 3, ≤ 35 years old, or negative hormone receptor status—further details in “Appendix”). Patients received obligatory radiotherapy following breast-conserving surgery or ≥ 4 axillary lymph node metastases; for patients undergoing mastectomy radiotherapy was also recommended in case of tumors > 3 cm and, in case of 1–3 involved lymph nodes and the presence of at least one of the additional risk factors multicentric growth, lymphangiosis or hemangiosis carcinomatosa, pectoralis fascia involvement, or a safety margin of < 5 mm. Adjuvant endocrine therapy was administered according to guideline standards for premenopausal and postmenopausal patients with hormone receptor positive tumors. The first follow-up was performed 4 weeks after the last course of chemotherapy and 6 weeks after the last administration of radiotherapy. Further controls were analogous to the usual follow-up of breast carcinoma: every 3 months for the first 3 years and every 6 months during the following 2 years [24, 25].

The Federal Institute for Drugs and Medical Devices (BfArM) and the relevant ethics committees approved the SUCCESS studies (Success A: Ludwig Maximilian University Munich, 076/05; Success B: Ludwig Maximilian University Munich, 395/07; Success C: Heinrich-Heine University Duesseldorf, MC-LKP-319), which were performed in accordance with Good Clinical Practice and the Declaration of Helsinki. Written informed consent was obtained from all patients.

This open-label, multicenter, 1:1 randomized phase III study was conducted with 3754 primary intermediate-to-high-risk breast cancer patients at 271 study sites. Participants were recruited between September 2005 and March 2007. The primary objective was to compare disease-free survival after adjuvant CHT with or without gemcitabine. All patients received three cycles of FEC (fluorouracil, epirubicin, cyclophosphamide; 100/500/500 mg/m²) followed by either three cycles of docetaxel alone (100 mg/m², q3w) (FEC-Doc) or gemcitabine (1000 mg/m² on days 1 and 8) and docetaxel (75 mg/m², q3w) (FEC-DocG). The second randomization was after completion of CHT to assess disease-free survival with 2 years of zoledronate treatment (every 3 months for 24 months) versus 5 years of zoledronate treatment (every 3 months for 24 months, followed by every 6 months for 36 months). If adjuvant endocrine therapy was indicated, premenopausal patients were administered with tamoxifen 20 mg q1d p.o. (and if they were < 40 years, they were additionally administered with goserelin 3.6 mg q4w s.c.); postmenopausal patients were administered with tamoxifen for 2 years followed by 3 years of anastrozole 1 mg q1d p.o. Important secondary objectives were assessment of overall survival, distant disease-free survival, toxicity, quality of life, and skeletal morbidity.

SUCCESS B was another open-label, multicenter, 1:1 randomized phase III study that enrolled 793 intermediate-to-high-risk breast cancer patients between June 2008 and September 2011. Study participants were positive for human epidermal growth factor receptors (HER2neu) and received the same adjuvant CHT as in the SUCCESS A study (i.e., FEC-Doc vs FEC-DocG). Following CHT, all patients received HER2neu targeted therapy with trastuzumab (8 mg/kg intravenous (IV) loading dose followed by 6 mg/kg IV every 3 weeks for a total of 52 weeks). The primary study objective was to compare disease-free survival between the two randomization arms. The secondary objectives were to compare overall survival, distant disease-free survival, toxicity, and change in quality of life. If adjuvant endocrine therapy was indicated, patients received 5 years of tamoxifen 20 mg q1d p.o. plus goserelin 3.6 mg q4w s.c. (for premenopausal patients) or 5 years of letrozole 2.5 mg q1d p.o. (for postmenopausal patients). In contrast to SUCCESS A, the use of adjuvant bisphosphonates was allowed for primary prophylactic treatment but was not generally recommended.

The SUCCESS C trial was a multicenter, prospective randomized phase III study comprising 3643 patients with primary HER2neu negative early breast cancer that were enrolled between February 2009 and August 2011 at 231 German study sites. The first randomization examined disease-free survival in patients receiving either anthracycline-free CHT treatment (6 cycles of docetaxel-cyclophosphamide, Doc-C) or anthracycline-containing CHT treatment with FEC-Doc. The second randomization compared disease-free survival in patients with a body mass index (BMI) of 24–40 kg/m² who received either an individualized lifestyle intervention program or general healthy lifestyle recommendations. The individualized lifestyle intervention program comprised a two-year standardized and structured telephone intervention aimed at moderate weight loss through dietary changes and physical activity, supported by educational materials and patient diary. If adjuvant endocrine therapy was indicated, patients received 5-year treatment with tamoxifen 20 mg q1d p.o. and goserelin 3.6 mg q4w s.c. if indicated or exemestane 25 mg q1d p.o. As in the Success B study but in contrast to the SUCCESS A study, the use of adjuvant bisphosphonates was allowed but not generally recommended.

We categorized age as ≤ 50 years, 51–65 years and > 65 years and BMI according to the World Health Organization (WHO) classification into the categories < 18.5 kg/m² (underweight), 18.5–24.9 kg/m² (normal weight), 25.0–29.9 kg/m² (overweight) and ≥ 30.0 kg/m² (obese). Primary tumor stage (pT1-4) and nodal status (pN0-3) were defined using the American Joint Committee on Cancer and International Association Against Cancer (UICC) revised TNM classification system criteria [26].

Histological grading (G1, G2, G3) was performed according to Elston–Ellis modification with Scarff–Bloom–Richardson criteria [27]. For hormone receptor status, tumors were graded as positive or negative. Tumors were classified as hormone receptor positive if ≥ 10% of the cells in the tumor tissue had estrogen and/or progesterone receptors. Tumors were classified as HER2neu positive if they had strong immunohistochemical amplifications of HER2neu receptors (3+) or if they had moderate immunohistochemical amplifications of HER2neu receptors (2+) and a positive result in FISH analysis. Biological tumor subtypes were defined in the absence of consistent Ki-67 determinations as follows. Luminal A-like: hormone receptor positive, HER2neu negative, G1-2; Luminal B-like: hormone receptor positive, HER2neu negative, G3; HER2 type: HER2neu positive; triple negative breast carcinoma: hormone receptor negative, HER2neu negative [28‐31].

HER2neu targeted therapy comprised mainly, but not exclusively, treatment with trastuzumab, asrastuzumab was approved in the adjuvant setting in 2006 during the recruitment of the SUCCESS A study. Endocrine therapy was not documented consistently for all patients, as some patients received their endocrine therapy at their general practitioners or gynecologists practice rather than at the study center, not always providing this information to the study center for documentation purposes. Thus, some of these patients may have been misclassified as having received no endocrine therapy.

Tumor classification into histological type (ductal, lobular, other) was based on the current WHO histopathologic classification [32, 33].

All categorical data are described in terms of absolute and relative frequencies, whereas the continuous variables, age and BMI, are additionally described by reporting mean ± SD, median, and range. Associations of patient or tumor characteristics with histological type (NST and ILC) were assessed using Chi-square tests for all categorical variables and with Mann–Whitney U tests for the continuous variables age and BMI. As we were also interested in possible interaction effects involving nodal status (see below), we categorized nodal status into the two categories pN0/pN1 and pN2/pN3 for all subsequent analyses to facilitate 2-way interaction tests while retaining meaningful sample sizes for the analyzed subgroups.

Survival parameters were analyzed using the Kaplan–Meier method and summarized with medians and 95% confidence intervals, and survival curves were compared using log-rank tests. Survival times were measured from the date of randomization to the date of the event or, if no endpoint was reached, to the data of last appropriate follow-up (censoring). Four different survival endpoints defined according to the Standardized Definitions of Efficacy Endpoints (STEEP) criteria were analyzed [34]. Disease-free survival (DFS) included local, contralateral, and distant metastatic disease, secondary primary tumors, and death from any cause as an event. Distant disease-free survival (DDFS) included only distant recurrences (metastases and secondary primary tumors) and death from any cause as events; ipsilateral or regional disease recurrences and contralateral breast cancer were excluded. Overall survival (OS) included death from any cause as an event. Breast cancer-specific survival (BCSS) included only deaths from breast cancer-related causes (e.g., metastasis-related organ failure or breast cancer progression) as an event, while patients that died for other reasons were censored at the date of death.

To evaluate whether the histological tumor type (NST, ILC) is an independent prognostic factor, we used multivariable Cox proportional hazards regression models adjusted for age (≤ 50, 51–65, > 65), BMI (underweight, normal weight, overweight, obese), tumor size (pT1, pT2, pT3, pT4), nodal stage (pN0/pN1, pN2/pN3), tumor grade (G1, G2, G3), hormone receptor status (positive, negative), HER2 status (positive, negative), menopausal status (premenopausal, postmenopausal), type of surgery (breast conserving, mastectomy, other), chemotherapy treatment (FEC-Doc, FEC-DocG, Doc-C), endocrine therapy (yes, no), radiotherapy (yes, no), and bisphosphonate therapy (yes, no). Please note that we have not adjusted for duration of bisphosphonate treatment, as a comprehensive analysis of the randomized SUCCESS A trial revealed no difference in survival between 2 and 5 years of adjuvant bisphosphonate (zoledronate) treatment [35].

To investigate whether the effect of histological tumor type on survival was influenced by nodal stage, we first ran Cox regression models with the main effects of histological tumor type and nodal stage together with the two-way interaction term between histological tumor type and nodal stage for all four survival endpoints. If the two-way interaction was significant, we subsequently ran a multivariable fully adjusted Cox regression model to test whether the two-way interaction term remained significant when all main effects of known prognostic factors were accounted for.

The median age of the 7236 study participants was 54 years (range 22–86 years). Table 1 shows the comparison of clinicopathological factors between patients with NST (n = 6284) or ILC (n = 952) tumors. Significant differences between NST and ILC were found with regard to all parameters investigated, except BMI. NST patients were more likely to be < 50 years old and more often premenopausal compared to ILC patients (39.1% vs. 28.7% and 41.3% vs. 32.9%, respectively). Breast-conserving surgical treatment was performed more often on the NST tumors (75.5% vs. 54.0%); accordingly, ILC patients were significantly less likely to receive adjuvant radiotherapy (80.7% vs. 85.3%).

ILC tumors were diagnosed in more advanced tumor stages (18.2% vs. 4.5% pT3/pT4 tumors) and with more frequent lymph node infiltration (23.1% vs. 14.6% pN2/pN3 tumors) compared to NST. However, ILC tumors showed poorly differentiated tumors with grading G3 less often than NST tumors (18.3% vs. 49.1%). The ILC histological type was associated with a higher rate of hormone receptor positive tumors (93.9% vs. 71.1%) than NST. Accordingly, ILC tumors were more often of the luminal subtype (87.5% vs. 59.6%), while the biological subtypes HER2neu positive and triple negative were observed less often compared to NST tumors (7.5% vs. 17.4% and 4.2% vs. 22.1%). For more data and results concerning the comparison of clinicopathological factors between ILC and NST tumors, see Table 1.