A phase III trial of adjuvant ribociclib plus endocrine therapy vs endocrine therapy alone in patients with HR+/HER2- early breast cancer: final invasive disease-free survival results from the NATALEE trial.

BACKGROUND: NATALEE assessed efficacy and tolerability of 3 years of adjuvant ribociclib plus NSAI compared with a nonsteroidal aromatase inhibitor (NSAI) alone in a broad population of patients with HR+/HER2- early breast cancer, including a select group without nodal involvement. This is the final preplanned analysis of invasive disease-free survival (iDFS). PATIENTS AND METHODS: Premenopausal/postmenopausal women and men were randomized 1:1 to ribociclib (n=2549; 400 mg/day, 3 weeks on/1 week off for 36 months) plus NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 60 months) or NSAI alone (n=2552). Men and premenopausal women also received goserelin (3.6 mg once every 28 days). Patients had anatomical stage IIA (N0 with additional risk factors or N1), IIB, or III disease. The primary endpoint was iDFS. Secondary efficacy endpoints were recurrence-free survival (RFS), distant DFS (DDFS), and overall survival (OS). This final iDFS analysis was planned after ≈500 events. RESULTS: At data cutoff (21 July 2023), ribociclib was stopped for 1996 patients (78.3%); 1091 (42.8%) completed 3 years of ribociclib, and ribociclib treatment was ongoing for 528 (20.7%). Median follow-up for iDFS was 33.3 months. Overall, 226 and 283 iDFS events occurred with ribociclib plus NSAI vs NSAI alone, respectively. Ribociclib plus NSAI demonstrated significant iDFS benefit over NSAI alone (Hazard Ratio 0.749, 95% Confidence Interval [CI] 0.628-0.892; P=0.0012). The 3-year iDFS rates were 90.7% (95% CI 89.3%-91.8%) vs 87.6% (95% CI 86.1%-88.9%). A consistent benefit was observed across prespecified subgroups, including stage (II/III) and nodal status (+/-). DDFS and RFS favored ribociclib plus NSAI. OS data were immature. No new safety signals were observed. CONCLUSIONS: With longer follow-up and most patients off ribociclib, NATALEE continues to demonstrate iDFS benefit with ribociclib plus NSAI over NSAI alone in the overall population and across key subgroups. Observed adverse events remained stable.

A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4).

Background: Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. Patients and methods: BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after ≥125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. Results: As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 versus 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 versus 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (≥40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. Conclusions: Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II.

[Rationale of the method of complex treatment for localized breast cancer with the use of methodology of intraoperative radiation therapy after neoadjuvant systemic drug therapy and sentinel lymph node biopsy].

Surgery remains the primary step in the localized forms of breast cancer. To date a growing number of women in the world could be provided with organ-preserving operations (OPO). At large tumor size in relation to the volume of the breast mastectomy is needed. Neoadjuvant therapy can allow a surgeon to perform OPO. However considering the original size of tumor and the knowledge that the greatest number of local recurrences of breast cancer occur within the bed of primary tumor it is logical to settle additional radiation dose to the bed in addition to the standard external beam radiotherapy. In patients with cN- prior neoadjuvant therapy it is possible to perform sentinel lymph node biopsy in order to improve functional results.

[BREAST-CONSERVING SURGERY AFTER NEOADJUVANT THERAPY FOR BREAST CANCER].

In the randomized phase 2 study there was evaluated the efficacy of neoadjuvant endocrine treatment (anastrozole, exemestane) in comparison with chemotherapy (doxorubicin plus paclitaxel). Preoperative endocrine therapy was well tolerated. There was a trend towards higher overall rates of objective response and breast conserving surgery (BCS) among patients with tumors expressing high levels of ER (luminal A) in endocrine therapy group compared with chemotherapy group (43% vs 24%; p = 0,054). In HER2-positive breast cancer patients the addition of trastuzumab to neoadjuvant chemotherapy improved the overall and pathological complete response. Trastuzumab made possible an increasing number of breast conserving surgery (23% vs 13%; p = 0,022). No patient treated with trastuzumab and with chemotherapy had a local recurrence after BCS.

Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer.

BACKGROUND: Nonpegylated liposomal doxorubicin liposomal doxorubicin, (Myocet™; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet(®)) in combination with trastuzumabHerceptin(®) (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.) (MTP) versus trastuzumab plus paclitaxel (TP) in patients with human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to NPLD (M, 50 mg/m(2) every 3 weeks for six cycles), trastuzumab (T, 4 mg/kg loading dose followed by 2 mg/kg weekly), and paclitaxel (P, 80 mg/m(2) weekly) or T + P at the same doses until progression or toxicity. The primary efficacy outcome was progression-free survival (PFS). RESULTS: One hundred and eighty-one patients were allocated to receive MTP, and 183 to TP. Median PFS was 16.1 and 14.5 months with MTP and TP, respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. In patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors, PFS was 20.7 and 14.0 months, respectively [HR 0.68; 95% confidence interval (CI) 0.47-0.99]. Median overall survival (OS) was 33.6 and 28.9 months with MTP and TP, respectively (HR 0.79; two-sided P = 0.083). In ER- and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR 0.63; 95% CI 0.42-0.93). The frequency of adverse events was higher with MTP, but there was no significant difference in cardiac toxicity between treatment arms. CONCLUSION(S): The trial failed to demonstrate a significant clinical improvement with the addition of M to TP regimen. The clinical benefit observed in an exploratory analysis in the ER- and PR-negative population deserves consideration for further clinical trials. CLINICAL TRIAL NUMBER: NCT00294996.

[HER2-positive breast cancer: standard and double targeted therapy].

Neoadjuvant systemic therapy is frequently used option for the systemic treatment for breast cancer. Inclusion in the regimen of targeted drugs as trastuzumab (Herceptin) and pertuzumab significantly improves outcomes in HER2-positive breast cancer patients. A certain part of HER2-positive patients can be cured by using only targeted drugs without chemotherapy.

A randomized phase II trial of doxorubicin plus pemetrexed followed by docetaxel versus doxorubicin plus cyclophosphamide followed by docetaxel as neoadjuvant treatment of early breast cancer.

BACKGROUND: Neoadjuvant systemic therapy (NST) before surgery is a standard option for patients with early breast cancer (EBC) that allows in vivo chemosensitivity testing. Given the promising activity of pemetrexed plus doxorubicin in metastatic breast cancer, it was reasonable to evaluate the utility of this combination as part of an NST regimen in EBC. PATIENTS AND METHODS: Patients with untreated operable T2-T4a-c N0-2 M0 breast cancer were randomly assigned to receive either four cycles of pemetrexed 500 mg/m(2) plus doxorubicin 60 mg/m(2) every 3 weeks (q3w) followed by four cycles of docetaxel 100 mg/m(2) q3w (AP-D) or four cycles of doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) q3w followed by four cycles of docetaxel 100 mg/m(2) q3w (AC-D). Surgery was carried out within 2 months after last chemotherapy. Primary end point was pathological complete response (pCR) rate in the breast. Secondary end points included clinical response rate, rate of histologically negative axillary lymph nodes, toxicity, and disease-free survival. RESULTS: From September 2005 to August 2007, 257 patients were randomly allocated to 17 sites. Median age was 48 and 49 years for AP-D and AC-D, respectively. Overall pCR rates were 16.5% for AP-D and 20.2% for AC-D. With AP-D, pCR rate was 17.8% for hormone receptor (HR)-negative patients and 15.9% for HR-positive patients. With AC-D, pCR rates were 42.9% and 7.8% for HR-negative and HR-positive patients, respectively. Clinical response rates were 59.5% in the AP-D group and 68.1% in the AC-D group. The rate of histologically negative axillary lymph nodes was 53% in both groups. Both treatments were well tolerated. Median disease-free survival is currently not mature. CONCLUSIONS: AP-D and AC-D are well tolerated and active as NST in EBC. Of note, AC-D had a higher pCR rate in HR-negative tumors, whereas AP-D had more activity if HRs were expressed.

Efficacy and safety of CT-P6 versus reference trastuzumab in HER2-positive early breast cancer: updated results of a randomised phase 3 trial.

PURPOSE: Neoadjuvant CT-P6, a trastuzumab biosimilar, demonstrated equivalent efficacy to reference trastuzumab in a phase 3 trial of HER2-positive early-stage breast cancer (EBC) (NCT02162667). We report post hoc analyses evaluating pathological complete response (pCR) and breast pCR alongside additional efficacy and safety measures. METHODS: Following neoadjuvant treatment and surgery, patients received adjuvant CT-P6 or trastuzumab (6 mg/kg) every 3 weeks for ≤ 1 year. RESULTS: In total, 271 and 278 patients received CT-P6 and trastuzumab, respectively. pCR and breast pCR rates were comparable between treatment groups regardless of age, region, or clinical stage. Overall, 47.6% (CT-P6) and 52.2% (trastuzumab) of patients experienced study drug-related treatment-emergent adverse events (TEAEs), including 17 patients reporting heart failure (CT-P6: 10; trastuzumab: 7). Two CT-P6 and three trastuzumab patients discontinued adjuvant treatment due to TEAEs. CONCLUSION: Adjuvant CT-P6 demonstrated comparable efficacy and safety to trastuzumab at 1 year in patients with HER2-positive EBC, supporting CT-P6 and trastuzumab comparability.

[Investigation of dynamic spectral characteristics of water in blood plasma hydrosols from breast cancer patients].

Our data on spectral characteristics of water in blood plasma hydrosols from breast cancer patients and healthy subjects are presented. A substantial difference between the two groups was found. As it was shown by us earlier, in breast cancer patients, as well as in other cancer patients, changes in spectral characteristics of water influence tissue hydrosols of the whole body. They persist even after tumor is radically removed. Such differences were probably linked to those in water molecular resonance frequencies. Using infrared spectroscopy, we confirmed the evidence available on carcinogenic (promoting) effect of both native and synthetic estrogens. It is suggested that healthy adult women have a certain "frequency immunity" which protects from the monthly autogenous promoting influences of estrogens. Our findings may contribute to devising further therapeutic frequency-assisted means of impacting on malignant tissue hydrosols.

[Aromatase activity and its gene expression in tumor tissue of smokers and non-smokers with breast cancer]. / Aktivnost' aromatazy i ékspressiia eë gena v opukholevoi tkani u kuriashchikh i nekuriashchikh bol'nykh rakom molochnoi zhelezy.

Tissue was sampled from 121 tumors of the breast. The activity of aromatase (estrogen synthetase) was assessed by radiobiochemical means in 61 cases; gene expression was evaluated with the aid of polymerase chain reaction in 14 and the same--by the dot-blot procedure in 46 patients. Inveterate smokers (15 years and more) made up 16.5%. The smokers revealed a distinct tendency towards aromatase activity decreasing in tumor tissue (chiefly in menopausal patients) as well as lower intensity of aromatase gene expression assessed in terms of polymerase chain reaction. Alongside with other evidence, our finding point to long-term-smoking-related sensitivity of intratissular estrogen synthesis being higher than in general circulation. It also demonstrated local aromatization inhibition in tumor tissue, the latter being a possible mechanism which causes tumor tissue hormone sensitivity to change in smokers and affects course of disease.

[Results of a prospective randomized investigation [Russia (St.Petersburg)/WHO] to evaluate the significance of self-examination for the early detection of breast cancer]. / Rezul'taty prospektivnogo randomizirovannogo isledovaniia [Rossiia (Sankt-Peterburg)/VOZ] znacheniia samoobsledovaniia v rannem vyiavlenii raka molochnoi zhelezy.

Indications for puncture or excision biopsy were significantly higher in the study group (7.5%) as compared with control (3.5%) (p < 0.01) in a randomized prospective controlled trial of a comprehensive breast cancer screening (123,748) carried out in the framework of a self-examination education program. In the self-examination group, detection rates were higher both for benign (1.1%) and malignant (0.85%) tumors than in control (0.5% and 0.69%, respectively) (p < 0.05). Early stage (T1NOMO, Tis) distribution difference in the study group and controls was insignificant--23 and 17.6%, respectively. Compliance with the program requirements including monthly or bimonthly self-examination was followed by higher 15-year survival rates (53.2%) in 70-75% as compared with controls(45.8%) (p = 0.05105): yet it did not affect mortality.

[Interim results of a prospective randomized study of self-examination for early detection of breast cancer (Russia/St.Petersburg/WHO)]. / Promezhutochnye rezul'taty prospektivnogo randomizirovannogo issledovaniia (Rossiia/Sankt-Peterburg/VOZ) znacheniia samoobsledovaniia v rannem vyiavlenii raka molochnoi zhelezy.

Training in breast self-examination (BSE) technique involved 57,712 women, aged 40-64, at 14 out of randomly selected out-patient hospitals in St. Petersburg (1985-1989). Another 64,759 women selected at another 14 out-patient hospitals were in control. All patients with detected tumor pathology of the breast were biopsied and treated at the Institute's Clinic. The study focused on breast cancer incidence, survival and mortality. More women in the BSE group sought medical advice for suspected pathology (4,300) than those in control (2,438; p < 0.05). There were 493 cases of breast cancer in the BSE group with 157 fatalities, 446 cases of breast cancer with 167 fatalities in the control group. There was no significant difference in tumor stage. Nine-year survival (after Kaplan-Meyer) from the time of tumor detection was 65% in the study group and 55% in control (log rank 0.774; p > 0.05). There has been no significant difference in death rates in both groups for the past ten years. The study is to continue until the year 2001.

Surgery following neoadjuvant therapy in patients with HER2-positive locally advanced or inflammatory breast cancer participating in the NeOAdjuvant Herceptin (NOAH) study.

AIM: To describe surgical outcomes in patients with HER2-positive locally advanced (LABC) or inflammatory breast cancer (IBC) participating in the NeOAdjuvant Herceptin (NOAH) study (ISRCTN86043495). PATIENTS AND METHODS: A total of 235 patients with HER2-positive disease were randomized to neoadjuvant trastuzumab plus chemotherapy (doxorubicin plus paclitaxel, followed by paclitaxel, followed by cyclophosphamide, methotrexate and fluorouracil) or neoadjuvant chemotherapy alone. Of these patients, 228 received their allocated treatment (115 received trastuzumab plus chemotherapy and 113 received chemotherapy alone) and were potentially eligible for surgery. Mastectomy was required for all patients with IBC and was recommended for all patients with LABC. However, breast-conserving therapy could be considered for patients with peripheral neoplasms measuring ≤ 4 cm in diameter at diagnosis, with a favorable ratio of tumor to breast volume, or at the patient's request if there had been a good response to treatment. RESULTS: As previously reported, the addition of trastuzumab to neoadjuvant chemotherapy improved the overall, complete and pathological complete response to therapy and significantly improved event-free survival (the primary endpoint of the study). Trastuzumab also enabled more patients to have breast conserving surgery (BCS) (23% versus 13% respectively) without an apparent detrimental effect on local disease control (no patient treated with trastuzumab plus chemotherapy had experienced a local recurrence after BCS at the time of analysis). CONCLUSIONS: Although this was not an aim of the trial, neoadjuvant trastuzumab given concurrently with chemotherapy enabled 23% of patients with HER2-positive LABC/IBC to avoid mastectomy (including a small number of patients with IBC).