Long-term outcome of invasive pure micropapillary breast cancer compared with invasive mixed micropapillary and invasive ductal breast cancer: a matched retrospective study.

PURPOSE: Data on the prognostic impact of the micropapillary component in breast cancer are limited. The purpose of this study was to investigate the clinicopathological characteristics and long-term outcomes of pure and mixed invasive micropapillary breast cancer (IMPC) patients compared to invasive ductal cancer (IDC) patients. METHODS: This retrospective study analysed all IMPC and IDC patients treated at the European Institute of Oncology (IEO) between 1997 and 2019. The overall cohort of IMPC patients was divided in two groups, pure and mixed IMPC. Each patient with mixed or pure IMPC was matched with one patient with IDC, based on year of surgery, age, pT, pN, and molecular subtype. RESULTS: A total of 30,115 IDC, 120 pure IMPC and 150 mixed IMPC patients were considered eligible. Compared to IDC, pure and mixed IMPC patients presented a higher rate of locally advanced disease (pT2-T3, pN2-N3), vascular invasion, and Luminal B subtype. After matching, pure and mixed IMPC showed a significant higher rate of vascular invasion compared to IDC patients (p < 0.001). Invasive disease-free survival was better in IDC compared to pure IMPC patients (p = 0.11). Long-term overall survival was significantly worse in pure IMPC group compared to IDC group (p = 0.004), being instead similar between mixed IMPC vs matched IDC (p = 0.07). CONCLUSION: These real-world data reported the worse prognosis of pure IMPC compared to IDC, highlighting the peculiar prognostic value of the micropapillary subtype itself in the decision-making process of IMPC management. An accurate pre-surgical diagnostic evaluation and a multidisciplinary approach are pivotal to best personalize its treatment.

The Evolving Role of Genomic Testing in Early Breast Cancer: Implications for Diagnosis, Prognosis, and Therapy.

Multigene prognostic genomic assays have become indispensable in managing early breast cancer (EBC), offering crucial information for risk stratification and guiding adjuvant treatment strategies in conjunction with traditional clinicopathological parameters. The American Society of Clinical Oncology (ASCO) guidelines endorse these assays, though some clinical contexts still lack definitive recommendations. The dynamic landscape of EBC management demands further refinement and optimization of genomic assays to streamline their incorporation into clinical practice. The breast cancer community is poised at the brink of transformative advances in enhancing the clinical utility of genomic assays, aiming to significantly improve the precision and effectiveness of both diagnosis and treatment for women with EBC. This article methodically examines the testing methodologies, clinical validity and utility, costs, diagnostic frameworks, and methodologies of the established genomic tests, including the Oncotype Dx Breast Recurrence Score®, MammaPrint, Prosigna®, EndoPredict®, and Breast Cancer Index (BCI). Among these tests, Prosigna and EndoPredict® have at present been validated only on a prognostic level, while Oncotype Dx, MammaPrint, and BCI hold both a prognostic and predictive role. Oncologists and pathologists engaged in the management of EBC will find in this review a thorough comparison of available genomic assays, as well as strategies to optimize the utilization of the information derived from them.

Unlocking the Resistance to Anti-HER2 Treatments in Breast Cancer: The Issue of HER2 Spatial Distribution.

Approximately 15% of breast cancers are classified as HER2-positive, with an amplification of the ERBB2 gene and/or an overexpression of the HER2 protein. Up to 30% of HER2-positive breast cancers shows heterogeneity in HER2 expression and different patterns of spatial distribution, i.e., the variability in the distribution and expression of the HER2 protein within a single tumour. Spatial heterogeneity may potentially affect treatment, response, assessment of HER2 status and consequently, may impact on the best treatment strategy. Understanding this feature can help clinicians to predict response to HER2-targeted therapies and patient outcomes, and to fine tune treatment decisions. This review summarizes the available evidence on HER2 heterogeneity and spatial distribution and how this may affect current available treatment choices, exploring possible opportunities for overcoming this issue, such as novel pharmacological agents, belonging to the group of antibody-drug conjugates.

Ten-year results of hypofractionated whole breast radiotherapy and intraoperative electron boost in premenopausal women.

AIM: To evaluate outcome of intraoperative electron boost (IOERT) and hypofractionated whole breast irradiation (HWBI) for breast cancer (BC) in young women. METHODS AND MATERIALS: Women aged ≤ 48 with pT1-2 N0-1 BC received 12 Gy IOERT boost during conservative surgery followed by 3-dimensional conformal HWBI in 13 fractions (2.85 Gy/die). Local relapses (LR) and survival (disease-free, DFS; specific, BCSS; overall, OS) were analyzed. RESULTS: 481 consecutive BC patients, mostly node negative, with median age of 42 were treated between 2004 and 2014. Median tumor size was 1.48 cm and median IOERT collimator was 4 cm. After 25-day mean interval, HWBI was delivered. At a median follow-up of 9.6 years, there were 23 LRs (4.8 %, 9 of which were in the boost region). Ten-year LR cumulative incidence was 4.1 % (95 %CI, 2.5-6.3). Over time, local control rate decreased for Luminal A and HER2 positive with negative hormonal receptors, while remained steady for triple negative. At multivariate analysis, LR predictors included age < 40, extensive intraductal component and the use of 4-cm IOERT collimator size. Ten-year survival outcomes were as follows: DFS 80.0 % (95 % CI, 75.8-83.5), BCSS 97.5 % (95 % CI, 95.5-98.6 %), OS 96.5 % (95 % CI, 94.3-97.9). Luminal B HER2 negative had the worse survival outcomes. Perioperative complications were uncommon (16.4 %), acute toxicity was mild (<2% Grade 3), but moderate/severe fibrosis was described in 40.8 % of the cases. Cosmesis was scored as excellent/good in 86 % of the cases. CONCLUSIONS: ELIOT boost and HWBI achieved an excellent local control at the cost of tumor bed fibrosis. IOERT boost dose lower than 12 Gy is advisable.

Pegylated Liposomal Doxorubicin (Caelyx®) as Adjuvant Treatment in Early-Stage Luminal B-like Breast Cancer: A Feasibility Phase II Trial.

BACKGROUND: Adjuvant chemotherapy for Luminal B-like breast cancers usually includes anthracycline-based regimens. However, some patients are reluctant to receive chemotherapy because of side-effects, especially alopecia, and ask for a "less intensive" or personalized approach. PATIENTS AND METHODS: We conducted a phase II feasibility trial to evaluate pegylated liposomal doxorubicin (PLD, Caelyx®) as adjuvant chemotherapy. Patients who received surgery for pT1-3, any N, and luminal B-like early-stage breast cancer (EBC) candidates for adjuvant chemotherapy were included. PLD was administered intravenously at 20 mg/m2 biweekly for eight courses. Endocrine therapy was given according to menopausal status. Trastuzumab was administered in HER2-positive disease. The primary endpoint was to evaluate the feasibility of this regimen, defined as the ability of a patient to achieve a relative dose intensity (RDI) of at least 85% of the eight cycles of treatment. Secondary endpoints included adverse events (AEs), tolerability, breast cancer-free survival, disease-free survival, and overall survival. RESULTS: From March 2016 to July 2018, 63 patients were included in the trial. Median age was 49 years (range: 33-76), with mostly pre- and peri-menopausal (65%) and stage I-II (94%). Only 5% of patients had HER2-positive EBC. Median RDI was 100% (range: 12.5-100%; interquartile range, IQR: 87.5-100%). The proportion of patients meeting the primary endpoint was 84% (95% confidence interval, CI: 73-92%). Overall, 55 out of 63 enrolled patients completed treatment (87%, 95% CI: 77-94%). Most common AEs were palmar-plantar erythrodysesthesia (12.2%), fatigue (10.4%), and mucositis (8.5%). Only 13% of patients had G3 AEs. None had alopecia. After a median follow-up of 3.9 years (range: 0.3-4.7) two distant events were observed, and all patients were alive at the date of last visit. CONCLUSIONS: The trial successfully met its primary endpoint: the regimen was feasible and well tolerated and could be considered for further evaluation as a treatment option for patients with contraindications to standard anthracyclines or requiring a personalized, less intensive approach.

Prognosis of selected triple negative apocrine breast cancer patients who did not receive adjuvant chemotherapy.

BACKGROUND: Triple negative breast cancer encompasses several biological entities with different outcomes and is a priority to identify which patients require more treatment to reduce the risk of recurrence and which patients need less treatment. PATIENTS AND METHODS: Among the 210 women with first primary invasive apocrine non metastatic breast cancer operated on between January 1998 and December 2016 at the European Institute Oncology, Milan, we identified 24 patients with a pT1-pT2, node-negative, triple negative subtype and Ki-67 ≤ 20% who did not receive adjuvant chemotherapy (CT). We compared the outcome of this cohort with a similar group of 24 patients with ductal tumors who received adjuvant chemotherapy, matched by pathological stage and biological features and also with a similar group of 12 patients with apocrine tumors who received adjuvant chemotherapy. RESULTS: The median age was 64 and 61 years in the apocrine (w/o CT) and ductal group, respectively. The median value of Ki-67 expression was 12% in the apocrine group (w/o CT) and 16% in the ductal group (p < 0.001). After a median follow-up of 7.5 years, no patients in the apocrine group (w/o CT) experienced a breast cancer related event compared with 4 events in the ductal carcinoma group (Gray test p-value = 0.11). CONCLUSIONS: The outcome of selected apocrine triple negative breast cancer patients who did not received adjuvant chemotherapy is excellent and supports a treatment de-escalation. Multicenter projects focusing on the possibility of avoiding adjuvant chemotherapy in selected subtypes of triple negative breast cancers with favorable outcome are warranted.

Preventing chemotherapy-induced alopecia: a prospective clinical trial on the efficacy and safety of a scalp-cooling system in early breast cancer patients treated with anthracyclines.

BACKGROUND: Chemotherapy-induced alopecia (CIA) is a distressing side effect of cancer therapy. The trial aimed to assess feasibility and effectiveness of scalp-cooling system DigniCap® to prevent CIA in primary breast cancer patients receiving an anthracycline containing adjuvant chemotherapy (CT). METHODS: Hair loss (HL) was evaluated by patient self-assessment and by the physician according to the Dean's scale at baseline and after each cycle of CT. The primary efficacy endpoint was the patient self-assessment HL score evaluated at least 3 weeks after completing CT. A Dean's scale score of 0-2 (i.e. HL ≤50%) was considered a success. RESULTS: From July 2014 to November 2016, 139 consecutive breast cancer patients were enrolled and received at least one treatment with scalp cooling. Fifty-six out of 131 evaluated patients successfully prevented HL (43%, 95% CI: 34-51%). Twenty-four patients (32%) discontinued the scalp cooling because of alopecia or scalp-cooling related AE, three patients had missing information on CIA, and 48 patients (64%) had a HL greater than 50% after CT. No serious AEs were reported. CONCLUSIONS: DigniCap® System resulted as a promising medical device to be safely integrated in supportive care of early breast cancer patients. Longer follow-up is needed to assess long-term safety and feasibility. CLINICAL TRIAL REGISTRATION NUMBER: NCT03712696.

Neoadjuvant Degarelix Versus Triptorelin in Premenopausal Patients Who Receive Letrozole for Locally Advanced Endocrine-Responsive Breast Cancer: A Randomized Phase II Trial.

PURPOSE: To evaluate endocrine activity in terms of ovarian function suppression (OFS) of degarelix (a gonadotropin-releasing hormone [GnRH] antagonist) versus triptorelin (a GnRH agonist) in premenopausal patients receiving letrozole as neoadjuvant endocrine therapy for breast cancer. PATIENTS AND METHODS: Premenopausal women with stage cT2 to 4b, any N, M0; estrogen receptor and progesterone receptor greater than 50%; human epidermal growth factor receptor 2-negative breast cancer were randomly assigned to triptorelin 3.75 mg administered intramuscularly on day 1 of every cycle or degarelix 240 mg administered subcutaneously (SC) on day 1 of cycle 1 then 80 mg SC on day 1 of cycles 2 through 6, both with letrozole 2.5 mg/day for six 28-day cycles. Surgery was performed 2 to 3 weeks after the last injection. Serum was collected at baseline, after 24 and 72 hours, at 7 and 14 days, and then before injections on cycles 2 through 6. The primary end point was time to optimal OFS (time from the first injection to first assessment of centrally assessed estradiol level ≤ 2.72 pg/mL [≤ 10 pmol/L] during neoadjuvant therapy). The trial had 90% power to detect a difference using a log-rank test with a two-sided α of .05. Secondary end points included response, tolerability, and patient-reported endocrine symptoms. RESULTS: Between February 2014 and January 2017, 51 patients were enrolled (n = 26 received triptorelin plus letrozole; n = 25 received degarelix plus letrozole). Time to optimal OFS was three times faster for patients assigned to degarelix and letrozole than to triptorelin and letrozole (median, 3 v 14 days; hazard ratio, 3.05; 95% CI, 1.65 to 5.65; P < .001). Furthermore, OFS was maintained during subsequent cycles for all patients assigned to receive degarelix and letrozole, whereas 15.4% of patients assigned to receive triptorelin and letrozole had suboptimal OFS after cycle 1 (six events during 127 measurements). Adverse events as a result of both degarelix plus letrozole and triptorelin plus letrozole were as expected. CONCLUSION: In premenopausal women receiving letrozole for neoadjuvant endocrine therapy, OFS was achieved more quickly and maintained more effectively with degarelix than with triptorelin.

Metronomic Chemotherapy for First-Line Treatment of Metastatic Triple-Negative Breast Cancer: A Phase II Trial.

BACKGROUND: Few data are available on the benefit of metronomic cyclophosphamide, capecitabine, and vinorelbine as first-line therapy in patients with metastatic triple-negative breast cancer. METHODS: This phase II study assessed the safety and efficacy of metronomic oral chemotherapy with vinorelbine 40 mg orally 3 times a week, cyclophosphamide 50 mg daily, and capecitabine 500 mg 3 times a day (VEX regimen) in untreated metastatic triple-negative breast cancer patients. The biopsy of the metastatic site had to be triple-negative, independent of the hormone receptor expression of the primary tumor. The primary endpoint was time to progression (TTP). Secondary endpoints included assessment of safety and clinical benefit (objective response rate plus stable disease rate at ≥24 weeks). RESULTS: 25 patients were included, and 22 were evaluable for both efficacy and toxicities (median age, 66 years). Median TTP was 6.4 months (95% confidence interval 3.6-12.6). The most common grade 1-2 toxicities were nausea, diarrhea, leuko-/neutropenia, and reversible liver enzyme alteration. Grade 3 events included hand and foot syndrome (9%). CONCLUSION: The VEX regimen demonstrated activity and was relatively well tolerated when given as first-line therapy in selected metastatic breast cancer patients with triple-negative disease.

Phase II Trial of Bevacizumab Plus Weekly Paclitaxel, Carboplatin, and Metronomic Cyclophosphamide With or Without Trastuzumab and Endocrine Therapy as Preoperative Treatment of Inflammatory Breast Cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare and highly aggressive disease. A neoadjuvant regimen with chemotherapy and an antiangiogenic strategy was investigated. PATIENTS AND METHODS: Patients with primary or recurrent IBC who were candidates for neoadjuvant treatment received weekly carboplatin and paclitaxel plus bevacizumab every 3 weeks and oral metronomic cyclophosphamide for 6 months. Trastuzumab was added for patients with HER2+ tumors and endocrine therapy was added for patients with estrogen receptor and/or progesterone receptor ≥ 10% tumors. Oral metronomic capecitabine and cyclophosphamide was continued for 6 months after surgery in those patients with a response. The primary efficacy endpoints were pathologic complete remission (pCR) and the objective response. RESULTS: From July 2010 to December 2013, 34 patients with IBC were included. The surrogate intrinsic tumor subtypes were as follows: luminal B-like (HER2-), 10 (29%); luminal B-like (HER2+), 8 (24%); HER2+ (nonluminal), 6 (18%); and triple negative, 10 (29%). An objective response was obtained in 30 patients (88%; 95% confidence interval, 73%-97%) and a pCR in 10 patients (29%; 95% confidence interval, 15%-48%). The proportion of pCR was significantly greater in the patients with HER2+ tumors (57%) than in patients with triple-negative (20%) or luminal B-like (HER2-) tumors (0%; P = .019). After a median follow-up of 4.4 years, the 5-year disease-free survival and overall survival was 58% and 72%, respectively. The achievement of pCR was associated with longer disease-free (P = .12) and overall (P = .029) survival. CONCLUSION: In patients with IBC, neoadjuvant treatment with the investigated regimen was successful and well tolerated. Further studies evaluating the potential benefit of an antiangiogenic strategy in this setting are awaited.

Intermittent Letrozole Administration as Adjuvant Endocrine Therapy for Postmenopausal Women With Hormone Receptor-Positive Early Breast Cancer: A Biologic Study.

BACKGROUND: Letrozole withdrawal for 3 months might permit estrogenic stimulation in residual resistant breast cancer disease susceptible to letrozole reintroduction. We investigated the impact of a 3-month letrozole-free interval on serum estradiol levels in patients with early stage breast cancer. PATIENTS AND METHODS: Postmenopausal women with estrogen receptor- and/or progesterone receptor-positive (> 10% of immunoreactive cells), node-negative early breast cancer were eligible. Patients received letrozole for 5 years with a 3-month treatment-free interval after the first year of therapy. The primary end point was to evaluate the increase in serum estradiol levels after a 3-month treatment-free interval. The secondary end points were the evaluations of other biologic markers (eg, follicle-stimulating hormone, luteinizing hormone, cholesterol, high-density lipoprotein, triglycerides, osteocalcin). RESULTS: From November 2007 to February 2012, 130 evaluable patients were enrolled. The median age was 61 years. Mean values of estradiol levels at time of discontinuation were 5.6 pg/mL (standard deviation 1.7). Estradiol levels increased after a 3-month treatment-free interval by a mean of 3.3 pg/mL (66%; P < .0001). Follicle-stimulating hormone and luteinizing hormone levels decreased from baseline by a mean of 7.5 mU/mL (P < .0001), and 1.4 mU/mL (P = .0062), respectively. Triglycerides decreased from baseline by a mean of 8.6 mg/dL (P = .036), and osteocalcin increased by a mean of 2.8 ng/mL (P = .013). CONCLUSION: Intermittent letrozole significantly affects estradiol levels.

Phase II Study With Epirubicin, Cisplatin, and Infusional Fluorouracil Followed by Weekly Paclitaxel With Metronomic Cyclophosphamide as a Preoperative Treatment of Triple-Negative Breast Cancer.

BACKGROUND: The aggressive biological behavior and the lack of target therapy prompts the search for new therapeutic approaches for triple-negative breast cancers. PATIENTS AND METHODS: We evaluated the efficacy in terms of Ki-67 variation and clinical response but also the toxicity of a neoadjuvant regimen based on metronomic principles including ECF (epidoxorubicin with cisplatin on day 1 with low-dose 5-fluorouracil in continuous infusion every 21 days for 4 courses) followed by paclitaxel (90 mg/m(2)) on day 1, 8, and 15 every 28 days for 3 courses in combination with metronomic oral cyclophosphamide 50 mg/d for 12 weeks in patients with HER2-negative breast cancer (T2-T4a-d, N0-3, M0) with estrogen receptor and progesterone receptor < 10%. RESULTS: We enrolled 34 patients from June 2009 to May 2013. All were considered evaluable on an intention-to treat basis. The mean difference between the percentage of Ki-67 positive cells evaluated in surgical resection specimens and in pretreatment tumor core biopsy was 41% (95% confidence interval [CI], 30-51; P < .0001) for the entire population, and 22% (95% CI, 7-38; P = .0097) in patients who did not achieve pathological complete response (pCR). Responses to the treatment were obtained in 31 patients [91%] of the patients, and 19 patients (56%; 95% CI, 35-70) had a pCR. Stable disease was observed in 3 patients and none had progressive disease. Grade ≥ 3 hematologic adverse events included leukopenia in 9% (3 of 34), neutropenia in 38% (13 of 34), and anemia in 3% (1 of 34) of patients. Nonhematologic Grade ≥ 3 toxicities included only stomatitis in 1 patient. CONCLUSION: A neoadjuvant program with an ECF regimen followed by weekly paclitaxel with metronomic cyclophosphamide proved to be very effective, with high pCR rates, reduction of Ki-67, and it was associated with a low toxicity profile.

Metronomic therapy and breast cancer: a systematic review.

Metronomic therapy (MT) refers to repetitive, low doses of chemotherapy drugs. MT exerts an effect not only on tumour cells, but also on their microenvironment. In particular, the low-dose schedule compromises the repairing process of endothelial cells, leading to an anti-angiogenic effect. In addition to the anti-angiogenic effect, MT could have an immunological action through the restoration of the anticancer effect of the immune system and induction of tumour dormancy. Consequently the association of targeted therapy with anti-angiogenic properties or specific immunologic drugs could enhance the efficacy of MT. During the past 15 years, several studies have been published evaluating the metronomic strategy in breast cancer. We conducted a systematic review of the results of phase I, II and III studies testing MT in breast cancer patients. The analyses included the efficacy and toxicity data of MT, and the future development of this strategy in breast cancer are also discussed. The systematic review presented here suggests that MT is a treatment option for breast cancer patients, has a low toxicity profile, efficacy in most patients and has potentially significant cost-effective advantages for public health.

Proposed new clinicopathological surrogate definitions of luminal A and luminal B (HER2-negative) intrinsic breast cancer subtypes.

INTRODUCTION: The St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 recognized substantial progress in the pathological characterization of breast cancer subtypes. A useful surrogate definition was developed to distinguish luminal A-like breast cancer from luminal B-like disease based on a combination of estrogen receptor (ER), progesterone receptor (PgR) and Ki-67 status, without a requirement for molecular diagnostics. Differences depend upon the choice of the threshold value for Ki-67 and the requirement for substantial PgR positivity. We aimed to verify the suitability of the new surrogate definitions of luminal subtypes in terms of distant disease control in a large series of patients. METHODS: We studied 9,415 women with a median follow-up of 8.1 years who (1) had ER-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer and (2) had undergone surgery at the European Institute of Oncology between 1994 and 2006. We evaluated distant disease-free survival of patients with "low" (<14%), "intermediate" (14% to 19%) or "high" (≥20%) Ki-67 positivity stratified by PgR expression (negative or low versus high). We calculated the cumulative incidence of distant events, considered competing events and performed multivariable analysis adjusted for pathologic tumor stage, pathologic node stage, tumor grade, peritumoral vascular invasion and menopausal status. RESULTS: Lack of substantial PgR positivity was associated with poorer outcomes only for patients with an intermediate Ki-67 level (P<0.001). The 4,890 patients (51.9%) with low Ki-67 level (any PgR expression level) or with intermediate Ki-67 level but substantial PgR positivity had comparably good outcomes and thus may represent a most advantageous grouping of those with luminal A-like disease. CONCLUSIONS: The updated pathological definition of intrinsic molecular subtypes may maximize the number of patients classified as having the luminal A-like intrinsic subtype of breast cancer and for whom the use of cytotoxic drugs could mostly be avoided.

Outcomes of patients with breast cancer who present with ipsilateral supraclavicular or internal mammary lymph node metastases.

BACKGROUND: The prognostic implications of internal mammary (IM) and supraclavicular (SC) node involvement in locally advanced breast cancer is still unclear. PATIENTS AND METHODS: We evaluated 107 patients with IM (n = 65) or SC (n = 42) node involvement who underwent operation at the European Institute of Oncology between 1997 and 2009 to assess their prognostic features. We subsequently analyzed matched cohorts, using the 107 patients as cases and another group of patients as a control cohort, to evaluate prognostic differences between patients with and those without IM or SC node involvement. RESULTS: Five-year disease-free survival (DFS) was 84% in IM vs. 38.8% in SC node involvement (P < .0001), and 5-year overall survival (OS) was 96.9% in IM node vs. 57.1% in SC node involvement (P < .0001). No difference in outcome was found between patients with and controls without IM node involvement. Conversely, a statistically significant difference in DFS and locoregional recurrence was observed in patients with SC node involvement compared with controls without SC node involvement. CONCLUSION: SC node involvement correlated with a significantly poorer outcome in patients with locally advanced breast cancer. Adequate staging, including biopsy of suspicious locoregional ipsilateral lymph nodes, is mandatory in these patients. Patients with IM or SC node involvement should be treated with curative intent using combined-modality treatments.

Survival outcomes in breast cancer patients with low estrogen/progesterone receptor expression.

INTRODUCTION: The prognostic value of low estrogen and progesterone receptors expression (ER/PgR 1%-10%) in early breast cancer patients is still unclear. PATIENTS AND METHODS: We retrospectively analyzed 1424 consecutive patients with HER2/neu-negative and low endocrine receptors expression early breast cancer, submitted to surgery at the European Institute of Oncology between January 1995 and December 2009. Patients were classified according to the percentage of ER/PgR expression using immunohistochemistry. Group 1 with ER/PgR < 1%, and group 2 with ER/PgR 1% to 10%. RESULTS: Group 1 (ER/PgR < 1%) included 1300 patients, and group 2 (ER/PgR 1%-10%) 124 patients. Median follow-up time was 74 months (range, 3-192 months). The 5-year disease-free survival (DFS) rate was 74% (95% confidence interval [CI], 72%-77%) for group 1, and 79% (95% CI, 70%-86%) for group 2 (P = .16). The 5-year overall survival (OS) rate was 86% (95% CI, 84%-88%) in group 1 and 90% (95% CI, 83%-95%) in group 2 (P = .13). In patients without lymph node involvement, the 5-year OS rate was 92% (95% CI, 89.5%-93.6%) for group 1 and 98% (95% CI, 90.2%-99.8%) for group 2 (P = .061). One hundred ten patients received endocrine therapy with no significant effect on DFS (P = .36) and OS (P = .30). CONCLUSION: The ER/PgR 1%-10% group had a slight, but not statistically significant, better prognosis than the ER/PgR <1% group. Further studies are needed to identify the appropriate clinical approach in this subset of patients with low ER/PgR expression (ER/PgR 1%-10%), HER2-negative early breast cancer.

Adjuvant pegylated liposomal doxorubicin for older women with endocrine nonresponsive breast cancer who are NOT suitable for a "standard chemotherapy regimen": the CASA randomized trial.

There is no optimal treatment for breast cancers lacking estrogen (ER) and progesterone (PgR) receptors in elderly women with co-morbidities that prevent use of "standard chemotherapy regimens" such as AC or CMF. The CASA trial studied pegylated liposomal doxorubicin (PLD) and low dose, metronomic cyclophosphamide + methotrexate (CM) for older (>65), vulnerable women with operable, ER and PgR-negative breast cancer. After two years the trial closed early, due to slow and inadequate accrual, with 77 patients (38:PLD, 36:CM, 3:nil). Sixty-eight percent completed PLD; 83% completed CM (both 16 weeks). Patients on PLD reported worse quality of life, cognitive and physical functioning than non-PLD regimens (primarily CM). At a median follow-up of 42 months, 81% of randomized patients remained free of any breast cancer recurrence. Based on our limited experience, PLD and CM may be reasonable options for further study for elderly vulnerable patients with endocrine nonresponsive breast cancer.

Immunohistochemically defined subtypes and outcome of apocrine breast cancer.

BACKGROUND: Conflicting data are available in the literature on the outcome of invasive apocrine carcinoma (IAC), possibly related to a heterogeneous classification of these tumors. PATIENTS AND METHODS: A series of 6899 consecutive patients with invasive ductal carcinoma (IDC) not otherwise specified and 72 patients with immunohistochemically defined IAC who received surgery at the European Institute of Oncology between 1997 and 2005 were included. We then explored patterns of recurrence of IAC according to 2 immunohistochemically defined tumor subtypes: pure apocrine carcinoma (estrogen [ER] and progesterone [PgR] receptor negative, and AR positive) and apocrine-like carcinoma (ER or PgR positive and AR negative). RESULTS: The diagnosis of pure apocrine carcinoma was correlated with a worse outcome in terms of DFS (hazard ratio [HR] 1.7; 95% confidence interval [CI], 1.01-2.86; P = .0010) if compared with IDC, whereas IDC and apocrine-like breast cancers showed a similar outcome in terms of DFS and overall survival. Patients with pure apocrine carcinoma had an increased risk in contralateral breast cancer (HR, 4.12; 95% CI, 1.22-14; P = .02). CONCLUSION: Pure apocrine carcinoma represents a distinct subtype of breast cancer with a significantly worse DFS as compared with IDC. AR determination might have an important prognostic implication in IAC. Moreover, AR-targeted therapy should be further explored within these tumors.

A risk score based on histopathological features predicts higher risk of distant recurrence in premenopausal patients with lymph node-negative endocrine-responsive breast cancer.

PURPOSE: To develop a Risk Score (RS) to predict distant recurrence among premenopausal women with node-negative endocrine-responsive early breast cancer. METHODS: The Cox model was used to develop the RS using clinical and histopathological features from 378 women participating in the IBCSG Trial VIII who received endocrine therapy alone or following chemotherapy. The performance of the resulting model was validated on a cohort of 1005 patients from a single institution who received endocrine therapy alone. RESULTS: In a multivariable analysis, the risk of distant recurrence was associated with tumor size, ER, Ki-67 and peritumoral vascular invasion. In the validation cohort, patients with high RS were at greater risk of distant recurrence compared to patients with low RS (HR, 17.41; 95% CI, 5.72-52.95). CONCLUSION: In premenopausal women with node-negative endocrine-responsive early breast cancer, the RS identifies patients at higher risk of distant recurrence.

Metronomic chemotherapy combined with bevacizumab and erlotinib in patients with metastatic HER2-negative breast cancer: clinical and biological activity.

UNLABELLED: The aim of this study was to determine the safety and efficacy of metronomic chemotherapy combined with targeted drugs in patients with metastatic breast cancer (MBC). We included 26 untreated patients with HER2-negative (HER-) MBC and poor hormone receptor expression. The analysis of the results suggests that the metronomic chemotherapy combined with bevacizumab and erlotinib is effective and well tolerated. BACKGROUND: The object of this study was to evaluate the safety and efficacy of metronomic chemotherapy in combination with bevacizumab and erlotinib in patients with HER2-negative (HER2(-)) metastatic breast cancer (MBC) and poor hormone receptor expression. PATIENTS AND METHODS: Patients with untreated MBC were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (15 mg/kg every 3 weeks) and erlotinib (100 mg daily). RESULTS: Of 24 patients assessable for response, we observed 1 complete response (CR, 4%), 14 partial responses (58%), 5 patients with stable disease greater than 9 weeks' duration (SD, 21%), and 1 patient (4%) with early progression of disease. The overall clinical benefit (CB) (CR + partial response + SD > 24 weeks) was 75% (95% confidence interval [CI], 53%-90%). Median time to progression was 43 weeks (95% CI, 21-69). Patients with low levels of circulating endothelial progenitors (CEPs) at baseline had a significantly improved progression-free survival (PFS). Toxicity was generally mild. Grade 3 toxicity included diarrhea (n = 1), thrombosis (n = 1), and hypertension (n = 2). Grade 2 adverse events included diarrhea (n = 5), hand-foot syndrome (n = 13), and hypertension (n = 4). CONCLUSION: Treatment with metronomic chemotherapy in combination with bevacizumab and erlotinib was effective in HER2(-), estrogen receptor (ER)- and progesterone receptor (PR)-poor advanced breast cancer.