Andrea Rocca

Response to primary chemotherapy in breast cancer patients with tumors not expressing estrogen and progesterone receptors

BACKGROUND We recently demonstrated that in premenopausal patients with estrogen receptors (ER)-absent tumors, early initiation of systemic chemotherapy after primary surgery might improve outcome. These data indicate a different responsiveness to chemotherapy for tumors not expressing hormone receptors. To test this hypothesis we evaluated the responsiveness to preoperative chemotherapy in patients with ER and progesterone receptors (PgR)-absent tumors. PATIENTS AND METHODS Patients with biopsy-proven T2-T3, N0-2 breast cancer treated at a single institution from January 1995 to August 1999 with preoperative chemotherapy were retrospectively evaluated. ER and PgR were determined immunohistochemically and classified for this purpose as absent (0% of the cells positive) or positive (> or = 1% of the cells). RESULTS On 117 evaluable patients 72 had an objective response (61%). A significant difference in response was observed for patients with ER and PgR absent compared with those with ER and/or PgR-positive tumors (82% vs. 57%, P = 0.03 Fisherss exact test). Pathological complete remission rates were also significantly different in the two groups (23% vs. 7%, respectively; P = 0.04). CONCLUSIONS The different degree of response according to hormone receptors expression supports the hypothesis that tumors not expressing both ER and PgR might represent a different clinical entity in terms of chemotherapy responsiveness.

Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer

BackgroundHER2/neu overexpression is linked to promotion of angiogenesis in breast cancer. We therefore tested the activity of the combination of Trastuzumab with metronomic, low dose chemotherapy with cyclophosphamide (CTX) and methotrexate (MTX) in metastatic breast cancer (MBC).MethodsBetween April 2002 and June 2005, twenty-two patients with metastatic breast cancer with the presence of overexpression or amplification of HER2-/neu, all pre-treated with trastuzumab plus other cytotoxics, were treated with trastuzumab (6 mg/kg every three weeks) in combination with metronomic chemotherapy (MTX 2.5 mg, bid on Day 1 and Day 4 every week) and CTX (50 mg daily) (CM).ResultsThe 22 enrolled patients are evaluable: most had an ECOG performance status of 0 (17 pts), and all were pre-treated with chemotherapy for metastatic disease; 14 had progressive disease at study entry, and 11 had progressive disease during the last trastuzumab therapy. Metastatic sites included: lung (5 pts), liver (14 pts), bone (12 pts), lymph nodes (8 pts), central nervous system (CNS) (9 pts). We observed 4 partial remission (PR) (18%, 95% CI 5–40%), 10 stable disease (SD) (46%, 95% CI 24–68%), and 8 PD (36%, CI 17–59%). The clinical benefit (RP plus RC plus SD for ≥ 24 weeks) in all pts and in pts with disease resistant to previous trastuzumab therapy were 46% (95% CI, 24–68%) and 27% (95% CI, 6–61%), respectively. Median time to progression was 6 months and median duration of treatment was 5 months (range, 0,7 to 18.4 months and range, 1 to 18 months, respectively). Overall clinical toxicity was generally mild. Grade ≥2 reversible liver toxicity and leukopenia were reported in 5 and 3 pts, respectively.ConclusionThe combination of trastuzumab and metronomic chemotherapy is effective and minimally toxic in advanced breast cancer patients. The efficacy observed in patients with disease resistant to trastuzumab supports the need of larger trial to confirm a role of this combination to delay acquired trastuzumab resistance.

Cisplatin in advanced salivary gland carcinoma. A phase II study of 25 patients.

A prospective Phase II study was carried out to test cisplatin (CDDP) as a single agent in salivary gland carcinomas. CDDP was administered (100 mg/m2) every 3 weeks to 25 consecutive patients with either recurrent or locally advanced salivary gland carcinoma. Six patients had received prior chemotherapy, and the other patients had had only surgery or radiation therapy or no treatment at all. The response rate was 18% (95% confidence interval [CI], 6% to 41%). Response duration was between 5 and 9 months. Median overall survival time was 14 months. CDDP is a moderately active drug in salivary gland carcinomas. It should be included in multidrug regimens to be tested in prospective studies, which are difficult to carry out due to the rarity of these tumors.

Reverting estrogen-receptor-negative phenotype in HER-2-overexpressing advanced breast cancer patients exposed to trastuzumab plus chemotherapy

IntroductionThe amounts of estrogen receptor (ER) and progesterone receptor (PgR) in a primary tumor are predictive of the response to endocrine therapies of breast cancer. Several patients with ER-positive primary tumors relapse after adjuvant endocrine therapy with no ER expression in the recurrent tissue; much fewer with a recurrent disease after an ER-negative primary tumor may become endocrine responsive. These sequences of events indicate that a phenotype based on ER expression may not be a permanent feature of breast cancer.MethodsTen patients with advanced breast cancer whose tumors overexpressed HER-2, but not ER or PgR, were treated with weekly trastuzumab at standard doses with or without chemotherapy.ResultsThree out of 10 patients showed overexpression of ERs first appearing after 9, 12 and 37 weeks, respectively, from the initiation of trastuzumab. Two of these patients were subsequently treated with endocrine therapy alone: one of them received letrozole for 3 years without evidence of progression.ConclusionTherapeutic targets enabling the appearance of an endocrine responsive disease may increase treatment options for patients with breast cancer. Furthermore, these clinical data suggest that an ER-negative phenotype is a multi-step process with a reversible repression modality, and that some ER-negative tumors may either revert to an ER-positive phenotype, allowing an endocrine treatment to be effective.

Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors

Objective Although adjuvant trastuzumab improves survival in patients with HER2-positive early breast cancer, there is growing concern about the long-term effect of trastuzumab-induced cardiotoxicity (TIC). We retrospectively assessed the incidence of TIC and heart failure (HF) to identify possible risk and protective factors. Design Retrospective study. Setting Institute for Cancer Research and Treatment, Medical Oncology Department. Patients Consecutive patients who started adjuvant trastuzumab between 2007 and 2010. Main outcome Measures TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease ≥15 points from baseline or a LVEF<50%. Logistic regression was used to estimate OR and their 95% CI in order to evaluate the risk of TIC, considering potential cardiac risk factors (hypertension, hypercholesterolaemia, diabetes mellitus, smoke, cardiac ischaemia and previous chest radiotherapy) and protective factors (β-blockers, ACE inhibitors and/or angiotensin receptor blockers). Results Among 179 patients, 78 cases of TIC (44%, 95% CI 37% to 51%) and four cases of HF (2%, 95% CI 0% to 4%) were reported. 14 patients stopped trastuzumab as a result of TIC. None of the cardiac risk factors or concomitant cardiovascular medications altered the risk of TIC. A previous cumulative dose >240 mg/m2 of doxorubicin or >500 mg/m2 of epirubicin increased the risk of TIC compared with lower doses (OR 3.07; 95% CI 1.29 to 7.27, p=0.0011). Conclusions TIC is a frequent, albeit generally mild, adverse event in clinical practice. Further studies are warranted to better define the risk of and protective factors for TIC.

Palbociclib (PD 0332991) : targeting the cell cycle machinery in breast cancer.

Introduction: The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway, governing the cell cycle restriction point, is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy. Palbociclib (PD 0332991), a potent and selective inhibitor of CDK4 and CDK6, inhibits proliferation of several Rb-positive cancer cell lines and xenograft models. Areas covered: The basic features and abnormalities of the cell cycle in breast cancer are described, along with their involvement in estrogen signaling and endocrine resistance. The pharmacological features of palbociclib, its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated, and its clinical development in breast cancer described. A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years. Expert opinion: The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy. Further, potentially useful combinations are those with drugs targeting mitogenic signaling pathways, such as HER2- and PI3K-inhibitors. Combination with chemotherapy seems more problematic, as antagonism has been reported in preclinical models. The identification of predictive factors, already explored in preclinical studies, must be further refined and validated in clinical trials.

Perfusion computed tomography for monitoring induction chemotherapy in patients with squamous cell carcinoma of the upper aerodigestive tract: correlation between changes in tumor perfusion and tumor volume.

Objective: The aim of this study was to assess the potential of perfusion computed tomography (CTp) for monitoring induction chemotherapy in patients with squamous cell carcinoma (SCCA) of the upper aerodigestive tract. Materials and Methods: Twenty-five patients with advanced SCCA underwent CTp and volumetric CT before and after induction chemotherapy. Perfusion CT parameters were calculated in the tumor, normal tissue, and muscles and correlated with tumor volume. Results: The blood flow (BF), blood volume (BV), and permeability surface were significantly higher, and the mean transit time was significantly lower in the tumor than in the normal tissue. The tumor BF and BV significantly decreased, and the mean transit time significantly increased after the therapy; decrease in BF and BV correlated with tumor volume reduction after chemotherapy. The baseline tumor BV was significantly lower in nonresponders compared with that in responders. Conclusions: In patients with SCCA, CTp showed potential for monitoring induction chemotherapy, reduction in tumor BF and BV correlated with reduction of tumor volume after chemotherapy, and baseline tumor BV may predict response to chemotherapy.

Serum EGFR and Serum HER-2/neu Are Useful Predictive and Prognostic Markers in Metastatic Breast Cancer Patients Treated With Metronomic Chemotherapy

Metronomic chemotherapy has been demonstrated to be of value in patients with advanced breast cancer. No reliable markers of response are available. In breast tumor, HER‐2/neu is a prognostic factor, whereas no definite data exist for EGFR. The aim of the study was to evaluate the prognostic and predictive role of serum HER‐2/neu and serum EGFR in breast cancer patients treated with low‐dose chemotherapy.

Multicentric/multifocal breast cancer with a single histotype: is the biological characterization of all individual foci justified?

BACKGROUND Invasive multiple breast cancers with a single histological feature (MBCSH) are routinely assessed for biological parameters to indicate adjuvant treatments only in the largest invasive carcinomas. However, the heterogeneity of individual foci in multiple carcinomas has not been widely studied. We analyzed whether such biological features are differently expressed in different MBCSH foci. PATIENT AND METHODS One hundred and thirteen invasive MBCSH were tested over a 5-year period. The expression of estrogen (ER) and progesterone (PgR) receptors, Ki-67 proliferative index, expression of HER2 and tumor grading were prospectively determined in each tumor focus, and mismatches among foci were recorded. RESULTS Mismatches in ER status were present in 5 (4.4%) cases and PgR in 18 (15.9%) cases. Mismatches in tumor grading were present in 21 cases (18.6%), proliferative index (Ki-67) in 17 (15%) cases and HER2 status in 11 (9.7%) cases. CONCLUSIONS In our experience, invasive MBCSH showed heterogeneity among foci. In our clinical practice, such assessment led to 14 (12.4%) patients receiving different adjuvant treatments compared with what would have been indicated if we had only taken into account the biologic status of the primary tumor.BACKGROUND Invasive multiple breast cancers with a single histological feature (MBCSH) are routinely assessed for biological parameters to indicate adjuvant treatments only in the largest invasive carcinomas. However, the heterogeneity of individual foci in multiple carcinomas has not been widely studied. We analyzed whether such biological features are differently expressed in different MBCSH foci. PATIENT AND METHODS One hundred and thirteen invasive MBCSH were tested over a 5-year period. The expression of estrogen (ER) and progesterone (PgR) receptors, Ki-67 proliferative index, expression of HER2 and tumor grading were prospectively determined in each tumor focus, and mismatches among foci were recorded. RESULTS Mismatches in ER status were present in 5 (4.4%) cases and PgR in 18 (15.9%) cases. Mismatches in tumor grading were present in 21 cases (18.6%), proliferative index (Ki-67) in 17 (15%) cases and HER2 status in 11 (9.7%) cases. CONCLUSIONS In our experience, invasive MBCSH showed heterogeneity among foci. In our clinical practice, such assessment led to 14 (12.4%) patients receiving different adjuvant treatments compared with what would have been indicated if we had only taken into account the biologic status of the primary tumor.

Androgen receptor signaling pathways as a target for breast cancer treatment

The androgen receptor (AR) is a ligand-dependent transcription factor, and its effects on breast range from physiological pubertal development and age-related modifications to cancer onset and proliferation. The prevalence of AR in early breast cancer is around 60%, and AR is more frequently expressed in ER-positive than in ER-negative tumors. We offer an overview of AR signaling pathways in different breast cancer subtypes, providing evidence that its oncogenic role is likely to be different in distinct biological and clinical scenarios. In particular, in ER-positive breast cancer, AR signaling often antagonizes the growth stimulatory effect of ER signaling; in triple-negative breast cancer (TNBC), AR seems to drive tumor progression (at least in luminal AR subtype of TNBC with a gene expression profile mimicking luminal subtypes despite being negative to ER and enriched in AR expression); in HER2-positive breast cancer, in the absence of ER expression, AR signaling has a proliferative role. These data represent the rationale for AR-targeting treatment as a potentially new target therapy in breast cancer subset using androgen agonists in some AR-positive/ER-positive tumors, AR antagonists in triple-negative/AR-positive tumors and in combination with anti-HER2 agents or with other signaling pathways inhibitors (including PI3K/MYC/ERK) in HER2-positive/AR-positive tumors. Only the ongoing and future prospective clinical trials will allow us to establish which agents are the best option in every specific condition, keeping in mind that there is evidence of opposite androgens and AR agonist/antagonist drug effects on cell proliferation particularly in AR-positive/ER-positive tumors.