Systematic review and meta-analysis of post-progression outcomes in ER+/HER2- metastatic breast cancer after CDK4/6 inhibitors within randomized clinical trials.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and endocrine therapy (ET) deeply transformed the treatment landscape of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer. Randomized clinical trials suggest that second progression-free survival (PFS2) was not compromised and time to subsequent chemotherapy (TTC) may be delayed. We carried out a meta-analysis to assess the benefit on PFS2 and on delaying the TTC. METHODS: We conducted a systematic literature search of randomized clinical trials with CDK4/6 inhibitors and ET reporting PFS2 or TTC of HR+/HER2- pre- or postmenopausal metastatic breast cancer. We also reviewed abstracts and presentations from all major conference proceedings. We calculated the pooled hazard ratios (HR) for PFS2 and TTC using random-effects models with 95% confidence intervals (CI). I2 was used to quantify heterogeneity between results of the studies. RESULTS: Eight studies (MONALEESA-2/3/7, MONARCH-2/3, PALOMA-1/2/3) were included in this analysis (N = 4580 patients). PFS2 benefit was observed in patients who received CDK4/6 inhibitors plus ET (pooled HR = 0.68, 95% CI = 0.62-0.74, I2 = 0%) and also a delay in subsequent TTC (pooled HR = 0.65, 95% CI = 0.60-0.71, I2 = 0%). A benefit in terms of PFS (pooled HR = 0.55, 95% CI = 0.51-0.59, I2 = 0%) and overall survival (pooled HR = 0.76, 95% CI = 0.69-0.84, I2 = 0%) was also observed. CONCLUSIONS: CDK4/6 inhibitors plus ET compared with ET alone improve PFS2 and TTC. The delay of chemotherapy may postpone the start of a more toxic treatment option, delaying related toxicities and potentially maintaining a better quality of life for patients, for a longer time. The benefit in PFS2 may postpone the onset of endocrine resistance and help further validate this treatment approach.

Evaluation of endocrine therapy and patients preferences in early breast cancer: results of Elena study.

PURPOSE: The development of the adjuvant therapy requires that clinicians and patients should discuss the magnitude of benefit of treatment for individual patient, estimating the pros and cons and the personal preferences. The aim of the present study was to determine the preferences of women treated with adjuvant hormonal therapy (HT) for breast cancer. METHODS: The analyses were conducted into three different groups of early breast cancer patients to evaluate the survival benefit needed to make treatment worthwhile before starting HT (A), after a few months from the beginning (B) and after several years of HT (C). The questionnaires, showing hypothetical scenarios based on potential survival times and rates without HT, were used to determine the lowest gains women judged necessary to make the treatment worthwhile. RESULTS: A total of 452 patients were included in the study: 149 in group A, 150 in group B and 153 in group C. In group C, 65% of patients were receiving HT with aromatase inhibitors (with or without a LHRH analogue). In the groups A, B, C 8%, 20% and 26%, respectively, received adjuvant chemotherapy. Overall, 355 women (79%) had children. The responses were quite similar between the three groups. A median gain of 10 years was judged necessary to make adjuvant HT worthwhile based on the hypothetical scenario of untreated mean survival time of 5 and 15 years. Median gain of 20% more women surviving was judged necessary to make adjuvant HT worthwhile based on an untreated 5-year survival rate expectation of 60%. Cognitive dysfunction was considered the side effect least compatible with the continuation of treatment in all three groups. CONCLUSIONS: This is a large study of patient preferences on HT. Compared with other studies with similar design, the patients included in the present study required larger benefits to make adjuvant therapy worthwhile.

Sentinel node biopsy after neoadjuvant treatment in breast cancer: Five-year follow-up of patients with clinically node-negative or node-positive disease before treatment.

PURPOSE: It is controversial whether sentinel node biopsy (SNB) without axillary dissection (AD) should be performed in cN1/2 breast cancer patients who become cN0 after neoadjuvant treatment, since the false negative rate (FNR) may be unacceptably high. We assessed outcomes to address this issue. METHODS: We retrospectively assessed 396 cT1-4, cN0/1/2 patients, who became or remained cN0 after neoadjuvant treatment and underwent SNB with at least one sentinel node (SN) found, and AD not performed if the SN was negative. RESULTS: After a median follow-up of 61 months (interquartile range 38-82), five-year overall survival was 90.7% (95% CI, 87.7-93.7) in the whole cohort, 93.3% (95% CI, 90.0-96.6) in those initially cN0, and 86.3% (95% CI, 80.6-92.1) in those initially cN1/2 (P = 0.12). Axillary failure occurred in only 1 (0.7%) initially cN1/2 patient who became cN0. In initially cN0 patients, and also initially cN1/2 patients who responded well to neoadjuvant treatment (ypT0/ypTx), SN-negativity was a significant predictor of good outcome, consistent with the known prognostic significance of axillary status, and suggesting that SN status accurately reflected axillary status. By contrast, in initially cN1/2 patients found to be ypT1/2/3, SN status (and whether or not AD was performed) had no influence on survival. CONCLUSIONS: These findings suggest that SNB is acceptable in cN1/2 patients who become cN0 after neoadjuvant therapy.

Progesterone receptor loss identifies Luminal B breast cancer subgroups at higher risk of relapse.

BACKGROUND: The immunohistochemical (IHC) evaluation of estrogen receptor (ER), progesterone receptor (PgR), Ki-67 and HER2 is considered a surrogate means for identifying the molecular subtypes of breast cancer with different prognosis. PATIENTS AND METHODS: We explored patterns of recurrence in 4837 women with breast cancer defined as Luminal B (ER-positive and/or PgR-positive, HER2 positive and/or Ki-67≥14%) by IHC classification. We evaluated four subgroups within the Luminal B subtype according to HER2 expression and PgR status. RESULTS: Patients within the ER+/PgR+/HER2- subgroup presented a 5-year breast cancer-related survival (BCS) of 97% (95% confidence interval (CI), 96-97) and overall survival (OS) of 95% [95% CI, 95-96], the best survivals of the Luminal B subgroups. In the multivariate analysis, the ER+/PgR-/HER2- subgroup was associated with a reduced BCS (HR 1.71; 95%CI, 1.25-2.35) and OS (HR 1.47; 95%CI, 1.10-1.96) when compared with the ER+/PgR+/HER2- subgroup. Also patients within the ER+/PgR-/HER2+ subgroup had a reduced BCS (HR 1.93; 95%CI, 1.32-2.83) and OS (HR 1.62; 95%CI, 1.14-2.30) when compared with ER+/PgR+/HER2- subgroup. On the other hand, no statistically significant differences were found with regard to BCS and OS among patients with ER+/PgR+/HER2+ and patients with ER+/PgR+/HER2- disease. CONCLUSIONS: PgR loss identifies Luminal B breast cancer subgroups at higher risk of relapse and death, both with HER-2-positive and HER-2-negative disease.

Outcome of special types of luminal breast cancer.

BACKGROUND: The identification of special types of breast cancer might be of value in assessing prognosis and predicting response to therapy. METHODS: A total of 7372 consecutive patients with immunohistochemically defined luminal invasive breast cancer operated at the European Institute of Oncology between 1997 and 2005 were included. We then explored patterns of recurrence by histological type. Median follow-up was 5.8 years. RESULTS: Tumors from 5707 patients were classified as invasive ductal cancer (IDC) not otherwise specified (NOS), 851 lobular, 338 mixed ductal and lobular, 250 cribriform, 143 mucinous and 83 tubular carcinomas. Compared with IDC NOS disease-free survival (DFS) was significantly longer in patients with cribriform tumors [5-year DFS 97.9% versus 87.4%; hazard ratio (HR) = 0.48; P = 0.015) and in pooled cribriform plus tubular carcinomas (5-year DFS 98.7% versus 87.4%; HR = 0.45; P = 0.005). Mucinous tumors presented similar DFS if compared with IDC (5-year DFS 93 % versus 87.4%; HR = 1.03; P = 0.91). Conversely, DFS was poorer for patients with lobular carcinoma (5-year DFS 86.8% versus 87.4%; HR = 1.27; P = 0.01). CONCLUSIONS: The diagnosis of tubular, cribriform and lobular carcinomas carry distinct prognostic implications. The identification of these special types has a significant utility in luminal breast cancer and should be considered in therapeutic algorithms.

Prognosis in women with small (T1mic,T1a,T1b) node-negative operable breast cancer by immunohistochemically selected subtypes.

Knowledge is limited about prognostic significance of breast cancer subtypes among women with small invasive node-negative breast tumours. We explored patterns of recurrence in 1691 women with pT1mic/T1a/T1b, pN0 and M0 breast cancer according to four immunohistochemically defined tumour subtypes: (i) Luminal A (ER-positive, PgR-positive, HER2-negative and Ki-67 < 14%); (ii) Luminal B (ER-positive and/or PgR-positive, HER2-positive and/or Ki-67 ≥ 14%); (iii) HER2-positive, both endocrine receptors absent; and (iv) Triple Negative. At multivariate analysis, women with the Triple Negative breast cancer subtype had an increased risk of loco-regional relapse (LRR) (Hazards Ratio (HR) 3.58; 95%CI: 1.40-9.13) and breast cancer related events (HR 2.18; 95%CI: 1.04-4.57). Overall, Luminal B subtype was not associated with a statistically significant increased risk of recurrence compared with Luminal A, while patients with Luminal B subtype tumours overexpressing HER2 had a 2 fold risk of reduced breast cancer related survival (BCS), but not an increased risk of LRR and distant metastases. Women with HER2 breast cancer subtype had a statistically significant increased risk of LRR (HR 4.53; 95%CI: 1.56-13.1), distant metastases and reduced BCS (HR 3.22; 95%CI: 1.44-7.18) and overall survival (HR 2.87; 95%CI: 1.05-7.89) when compared with the Luminal A subtype, at multivariate analysis. In conclusion, women with small size, node-negative, breast cancer are at higher risk of relapse if with HER2-positive endocrine receptor absent or Triple Negative disease.

Oral vinorelbine as first line chemotherapy in unfit elderly patients with hormone-refractory prostate cancer.

Hormone-refractory prostate cancer (HRPC) is a rapidly progressive disease which produces considerable morbidity and involves mostly men over 70, often comorbid and with poor tolerance to chemotherapy. Low-toxicity chemotherapy is a reasonable option in this setting. Vinorelbine and a corticosteroid show activity and clinical benefit responses in HRPC. An oral regimen is preferable for elderly patients. This study aimed to evaluate safety, prostate-specific antigen (PSA) response, clinical benefit and progression-free survival in chemonaive elderly HRPC patients. 33 men, median age 78.2, were treated with oral vinorelbine 60 mg/m2 days 1 and 8 every 3 weeks, escalable to 80 mg/m2 after the first cycle, and prednisone 5 mg b.i.d. The main toxicity was hematopoietic (mild at 60 mg/m2 and moderate at 80 mg/m2). Of 27 evaluable patients, 9 (33%) had PSA responses and 9 had clinical benefit, PSA-correlated in 5 cases (56%). Median progression-free survival was 13.4 weeks, median overall survival 45 weeks. Oral vinorelbine plus prednisone is safe and has moderate activity, with biochemical and clinical responses in about one-third of patients and could be an option in unfit elderly HRPC patients.

Overview and new strategies in metastatic breast cancer (MBC) for treatment of tamoxifen-resistant patients.

The treatment with aromatase inhibitors (AIs) and fulvestrant has been demonstrated to be active in a proportion of tamoxifen-resistant breast cancer patients, obtaining, in some cases, a long-term control of tumor growth. Results from clinical trials indicate that treatment with fulvestrant might either precede or follow AIs. However, the AIs are now replacing tamoxifen as first-line advanced and adjuvant therapies, and thus, other options following tamoxifen failure are required. Fulvestrant may be effective in this setting, even if there is also evidence of a lack of cross-resistance between nonsteroidal and steroidal AIs, resulting in the potential use of steroidal AIs following nonsteroidal AI failure and vice versa. Resistance mechanisms to these therapies appear to be related to a cross talk between estrogen receptor (ER) and growth factor-signaling cascades. Novel therapeutic approaches for ER+ patients, which combine hormonal agents and signal transduction inhibitors, have been developed to overcoming resistance. Several trials are now investigating signal transduction inhibitors combined with endocrine agents. This approach might provide efficient treatments and delay the onset of antihormone resistance, thereby significantly improving patient's survival.