Rassegna della letteratura – febbraio 2019

Terapia medica: chemioterapia adjuvante, ormonoterapia, immunoterapia, trattamento malattia metastatica

Han Z, Li L, Kang D e t Al. – Label-free detection of residual breast cancer after neoadjuvant chemotherapy using biomedical multiphoton microscopy. Lasers Med Sci. 2019 Feb 28. .

Neoadjuvant chemotherapy has become a standard treatment for breast cancer as it has been shown to increase the rate of breastpreservation and to improve outcome in patients. However, how to accurately detect residual tumors is still a challenge. In this work, we tried to use multiphoton imaging to look for residual breast tumors after preoperative therapy. Imaging results demonstrate that multiphoton microscopy can identify remaining tumor tissues and can even detect rarely residual tumor cells, which would be helpful for surgeons to accurately assess the surgical margin in real time to confirm negative margins during operation. We also performed a quantification analysis of the nuclear area of tumor cells before and after treatment with neoadjuvant chemotherapy. The measurement data show that the tumor cell nuclei after chemotherapy are significantly larger than those without treatment, and there is a statistically significant difference in the nuclear areas between the pre-treatment and post-treatment mammary carcinoma. Our pilot study indicates the potential utility of multiphoton imaging for detecting residual breast carcinoma tissues in fresh, ex vivo specimens without the use of exogenous contrast agents. We foresee real-time intraoperative applications of multiphoton microscopy in evaluating therapy response, and thereby helping clinicians develop individualized treatment plans.

Deklerck E, Denys H, Kreps EO et Al. -Corneal features in trastuzumab emtansine treatment: not a rare occurrence. Breast Cancer Res Treat. 2019 Feb 28.

Purpose/background Ado-trastuzumab emtansine (T-DM1/Kadcyla®;Genentech) is an antibody-drug conjugate used in the treatment of human epidermal growth factor receptor-2-positive metastasized breast cancer. Few studies report a spectrum of corneal changes in patients treated with this drug. Our aim is to specify the nature and prevalence of corneal features of T-DM1 treatment in order to formulate guidelines as to which findings necessitate systemic treatment cessation or dose reduction.

Methods We performed a cross-sectional, prospective study in all patients currently treated with T-DM1 or recently stopped in Ghent University Hospital, Belgium.

Results A total of 12 patients completed a full ophthalmic workup. Ten patients were currently using T-DM1, and two patients had recently (< 10 weeks) stopped treatment because of clinical non-response. Twenty eyes of 10 patients currently on T-DM1-treatment all exhibited coarse cystoid lesions to the deep corneal epithelial cells, primarily in the midperipheral area, both biomicroscopically and on confocal microscopy. The two patients who stopped treatment, displayed no corneal epithelial changes. Only three patients reported symptoms which were attributed to other ocular factors, likely not to be related to T-DM1 treatment.

Conclusions This case series shows that asymptomatic, low-grade corneal epithelial changes are hallmark features in T-DM1-treatment and should not alarm clinicians. These findings are relatively stationary, reversible and thus do not require ocular treatment or cessation of systemic treatment.

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Travis CG, Peace Kaitlin M, Holmes Jarrod P et Al. – Initial safety analysis of a randomized phase II trial of nelipepimut-S + GM-CSF and trastuzumab compared to trastuzumab alone to prevent recurrence in breast cancer patients with HER2 low-expressing tumors. – Clin Immunol. 2019 Feb 25.

The development of HER2-targeted therapy has decreased recurrence rates and improved survival, transforming the natural history of HER2-positive breast cancer. However only a minority of breast cancer patients benefit as these agents are not used in patients with tumors expressing low levels of HER2. Preclinical data suggests a synergistic action of HER2-targeted vaccination with trastuzumab. We report the initial safety interim analysis of a phase II trial that enrolled patients with HER2 low-expressing (IHC 1+/2+) breast cancer who were clinically disease-free after standard therapy. Patients were randomized to receive the HER2-peptide vaccine nelipepimut-S + GM-CSF with trastuzumab (vaccine arm) or trastuzumab + GM-CSF (control arm) and were followed for recurrence. A planned analysis that occurred after enrollment of 150 patients showed no significant differences in toxicity between the two arms, including cardiac toxicity. The clinical efficacy of this combination will be reported 6 months after the final patient was enrolled.

Jain P, Doval DC et Al. – Ki-67 labeling index as a predictor of response to neoadjuvant chemotherapy in breast cancer. – Jpn J Clin Oncol. 2019 Feb 12.

Purpose/background To investigate Ki-67 index with regard to its ability to predict achievement of pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) in breast cancer patient.

Methods It was a prospective observational study, conducted in Department of Medical Oncology, Rajiv Gandhi CancerInstitute & Research Center (RGCIRC), New Delhi from February 2014 to March 2016. A total of 134 patients with Stage II/III breast cancerwho underwent NACT followed by surgery at our center were enrolled and analyzed. Before starting the treatment, clinical, tumor-related and treatment-related factors were recorded. Response evaluation was done clinically and radiologically after completion of NACT and pathologically on the surgical specimen. We calculated Ki-67 cut-off of 35% to label it as high by area under Receiver operating characteristic curve analysis for prediction of pCR.

Results Clinical complete response (cCR) was observed in 35/134 (26.1%) patients while pCR was observed in 32/134 (23.9%) patients. On univariate analysis, higher grade (III), high Ki-67 index (>35%) and number of chemotherapy cycles (>3) were associated with better CCR rates. On multivariate analysis, number of chemotherapy cycles (>3) and high Ki-67 index (>35%) were independent predictive factors. For the predictive factors of pCR, univariate analysis showed grade (III), estrogen receptor/progesterone receptor negativity, HER-2 positivity, number of chemotherapy cycles (>3), TNBC and high Ki-67 index (>35%) to be associated with higher pCR rates. On multivariate analysis, Ki-67 index >35% and HER-2 positivity were the only independent predictive factors of pCR.

Conclusions We suggest 35% as best cut-off for Ki-67 expression for predicting response to NACT and achievement of pCR. Validation of this cut-off is required in larger studies.

Loi S, Giobbie-Hurder A, Gombos A et Al. – Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. – Lancet Oncol. 2019 Feb 11.

Purpose/background HER2-positive breast cancers usually contain large amounts of T-cell infiltrate. We hypothesised that trastuzumab resistance in HER2-positive breast cancer could be mediated by immune mechanisms. We assessed the safety and anti-tumour activity of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, added to trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer.

Methods We did this single-arm, multicentre, phase 1b-2 trial in 11 centres based in five countries. Eligible participants were women aged 18 years or older, who had advanced, histologically confirmed, HER2-positive breast cancer; documented progression during previous trastuzumab-based therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a formalin-fixed, paraffin-embedded metastatic tumour biopsy for central assessment of programmed cell death 1 ligand 1 (PD-L1) status. In phase 1b, we enrolled patients with PD-L1-positive tumours in a 3 + 3 dose-escalation of intravenous pembrolizumab (2 mg/kg and 10 mg/kg, every 3 weeks) plus 6 mg/kg of intravenous trastuzumab. The primary endpoint of the phase 1b study was the incidence of dose-limiting toxicity and recommended phase 2 dose; however, a protocol amendment on Aug 28, 2015, stipulated a flat dose of pembrolizumab of 200 mg every 3 weeks in all Merck-sponsored trials. In phase 2, patients with PD-L1-positive and PD-L1-negative tumours were enrolled in parallel cohorts and received the flat dose of pembrolizumab plus standard trastuzumab. The primary endpoint of the phase 2 study was the proportion of PD-L1-positive patients achieving an objective response. This trial is registered in ClinicalTrials.gov, number NCT02129556, and with EudraCT, number 2013-004770-10, and is closed

Results Between Feb 2, 2015, and April 5, 2017, six patients were enrolled in phase 1b (n=3 received 2 mg/kg pembrolizumab, n=3 received 10 mg/kg pembrolizumab) and 52 patients in phase 2 (n=40 had PD-L1-positive tumours, n=12 had PD-L1-negative tumours). The data cutoff for this analysis was Aug 7, 2017. During phase 1b, there were no dose-limiting toxicities in the dose cohorts tested. Median follow-up for the phase 2 cohort was 13·6 months (IQR 11·6-18·4) for patients with PD-L1-positive tumours, and 12·2 months (7·9-12·2) for patients with PD-L1-negative tumours. Six (15%, 90% CI 7-29) of 40 PD-L1-positive patients achieved an objective response. There were no objective responders among the PD-L1-negative patients. The most common treatment-related adverse event of any grade was fatigue (12 [21%] of 58 patients). Grade 3-5 adverse events occurred in 29 (50%) of patients, treatment-related grade 3-5 adverse events occurred in 17 (29%), and serious adverse events occurred in 29 (50%) patients. The most commonly occurring serious adverse events were dyspnoea (n=3 [5%]), pneumonitis (n=3 [5%]), pericardial effusion (n=2 [3%]), and upper respiratory infection (n=2 [3%]). There was one treatment-related death due to Lambert-Eaton syndrome in a PD-L1-negative patient during phase 2.

Conclusions Pembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER2-positive breast cancer. Further studies in this breast cancer subtype should focus on a PD-L1-positive population and be done in less heavily pretreated patients.

Ekholm M, Bendahl PO, Fernö M et Al. – Effects of adjuvant tamoxifen over three decades on breast cancer-free and distant recurrence-free interval among premenopausal women with oestrogen receptor-positive breast cancerrandomised in the Swedish SBII:2pre trial. Eur J Cancer. 2019 Feb 12;110:53-61.

Purpose/background The primary aim was to compare 2 years of adjuvant tamoxifen versus no systemic treatment in premenopausal patients with oestrogen receptor (ER)-positive tumours, regarding breast cancer-free interval (BCFi) and distant recurrence-free interval (D-RFi), with 30 years of follow-up and for specified intervals. Moreover, we aimed to investigate the effects of adjuvant tamoxifen on the incidence of secondary malignancies and survival after distant recurrence.

Methods Premenopausal patients with primary breast cancer were randomised to 2 years of tamoxifen (n = 277) or no systemic treatment (n = 287), irrespective of ER status. Information regarding events was collected by a review of medical records and from national registers.

Results The median follow-up for all patients without events was 28 years, and only four of the patients alive had a follow-up of <20 years. With 30 years of follow-up, tamoxifen prolonged BCFi in the intention-to-treat population (hazard ratio [HR] = 0.76, 95% confidence interval (CI) 0.61-0.94, p = 0.011) compared with no treatment. In patients with ER-positive tumours (n = 362), tamoxifen prolonged BCFi (HR = 0.62, 95% CI 0.47-0.82, p = 0.001) and D-RFi (HR = 0.73, 95% CI 0.54-0.99, p = 0.043). The positive effect on BCFi was significant also for the interval >15-30 years (HR = 0.53, 95% CI 0.28-0.98, p = 0.042). For patients with ER-positive tumours who were diagnosed with distant recurrence (n = 165), survival after distant recurrence was shorter among tamoxifen-treated patients (median, 29 months versus 43 months). The incidence of contralateral breast cancer was 42% lower in the tamoxifen group (HR = 0.58, 95% CI 0.35-0.96, p = 0.035), whereas no differences were observed regarding other secondary malignancies.

Conclusions With three decades of follow-up, 2 years of adjuvant tamoxifen reduced the incidence of breast cancer-related events and distant recurrence, and the carryover effect seems to extend beyond 15 years. Moreover, adjuvant tamoxifen seems to be associated with shorter survival after diagnosis of distant recurrence.

Mariani G, Galli G, Cavalieri S et Al. – Single Institution trial of anthracycline- and taxane-based chemotherapy for operable breast cancer: The ASTER study. – Breast J. 2019 Feb 27.

The efficacy of anthracycline- and taxane-based chemotherapy for perioperative treatment of breast cancer (BC) has been established. No superiority of a cytotoxic regimen has been demonstrated, provided that administration of an anthracycline and a taxane is warranted. The ASTER study was designed to investigate the safety of 6 months of perioperative chemotherapy with Doxorubicin and Paclitaxel, followed by Cyclophosphamide, Methotrexate, and 5-Fluorouracil. ASTER enrolled patients with cT2-3 N0-1 or pT1-2 N1-3 BC, from November 2008 to August 2011. Treatment consisted of Doxorubicin 60 mg/sm, Paclitaxel 200 mg/sm q21 (AT) for three cycles followed by Cyclophosphamide 600 mg/sm, Methotrexate 40 mg/sm, 5-Fluorouracil 600 mg/sm d1,8 q28 (CMF) for three cycles, in either neo-adjuvant or adjuvant setting. All HER-positive patients received targeted therapy with Trastuzumab for 1 year. Disease-free and overall survival (DFS and OS, respectively) were estimated according to Kaplan-Meier method. Three hundred and thirty patients were enrolled, where 77.9% of cases were treated in an adjuvant setting; 65.5% received breast conservative surgery, 72.4% axillary dissection. 75.5% of cases presented estrogen receptor positivity, 66.7% progesterone receptor positivity; 18.5% of patients presented HER2-positive BC, 16.1% triple negative disease. Twenty-eight (8.5%) developed grade III-IV hematologic toxicity; nine patients (2.7%) developed grade III neurological toxicity. Loco-regional DFS was 99.6% at 1 year, 97.1% at 5 years, 95.9% at 7 years. Corresponding distant DFS was 98.4%, 90.2%, and 88.8%. One, 5, and 7-year OS was 99.6%, 94.9%, and 91.2%, respectively. Chemotherapy with ATx3→CMFx3 is confirmed safe and effective at 6.7 years follow-up. These results appear comparable to those reported in regulatory trials of most commonly prescribed anthracycline and taxane-based regimens.


Milano MT, Katz AW, Zhang H et Al. – Oligometastatic breast cancer treated with hypofractionated stereotactic radiotherapy: Some patients survive longer than a decade – Radiother Oncol. 2019 Feb;131:45-51.

Purpose/background The clinical state of oligometastases describes metastases limited in number and extent, amenable to metastasis-directed therapy. We sought to analyze long-term outcomes and characterize potential prognostic factors, in women with breast cancer (BC) oligometastases treated with hypofractionated stereotactic radiation (HSRT) therapy on a prospective phase II protocol

Methods Forty-eight women with 1-5 extracranial BC oligometastases received HSRT to all radiographically apparent sites of disease. Various dose-fractionation schedules were used. Most (n = 27) received 10 daily fractions, typically ≥50 Gy (n = 17).

Results BC patients with bone-only oligometastases (BO, n = 12) vs. all other patients (non-BO; n = 36) were significantly younger, more likely to present with oligometastases at the time of primary BC diagnosis (i.e., synchronous), and significantly more likely to have had hormone receptor-positive disease. The 5-year and 10-year overall survival (OS) rates after HSRT were 83% and 75%, respectively, for BO patients vs. 31% and 17%, respectively, for non-BO patients (p = 0.002). BO patients experienced a significantly (p = 0.018) greater freedom from widespread metastases (FFWM). Among non-BO patients, net oligometastatic GTV >25 cc (reflecting disease burden) was a significant factor for freedom from local recurrence (p = 0.047) and FFWM (p = 0.028). The number of oligometastatic lesions (p = 0.007) and organs (p = 0.001) involved were also significant factors for FFWM in non-BO patients.

Conclusions Some patients with BC oligometastases treated with HSRT can survive >10 years. Tumor burden (volume and number of lesions) appears to impact risk of recurrence. Further research is needed to help better identify BC patients most likely to benefit from metastasis-directed radiotherapy.

Stuart-Harris R, Dahlstrom JE et Al. – Recurrence in early breast cancer: Analysis of data from 3,765 Australian women treated between 1997 and 2015. – Breast. 2019 Feb 11;44:153-159.

Purpose/background Evidence suggests recent improvements in outcome in early breast cancer (EBC). To analyse recurrence in women with EBC from our region from 1997 to 2015.

Methods We analysed recurrence in 3,765 women with EBC. Median follow up was 83·0 months. 62·5% had a symptomatic presentation. 81·8% were hormone receptor positive and 38·5% were node positive. Lymphovascular invasion (LVI) was present in 24·3%. Of the 2,686 women entered from 2002 onwards tested for HER2 status, 72·7% had a luminal tumour, 15·2% had a HER2+ tumour and 12·1% had a triple negative (TN) tumour.

Results Recurrence occurred in 459 (12·2%), predominantly in distant sites (71·7%). In women entered from 2002 onwards, the five and 10 year recurrence rates were significantly lower in the luminal group than the HER2+ and the TN groups. Few recurrences occurred in HER2+ and TN cancers after 36 months. On multivariate analysis the following were associated with a significantly increased risk of recurrence: nodal involvement (p < 0·0001), tumour grade (p < 0·0001), symptomatic presentation (p < 0·0001), presence of LVI (p = 0·001), non-luminal tumour type (p < 0·0001) and tumour size >50 mm (p = 0·02).

Conclusions The recurrence rate in this series was much lower than in previous older series. Lymph node involvement, tumour grade, symptomatic presentation, presence of LVI, non-luminal tumour type and tumour size (>50 mm) were associated with an increased risk of recurrence. We strongly recommend that clinicians include the presence of LVI and symptomatic presentation as well as the other established tumour factors, when assessing the risk of recurrence in women with EBC.

Aghili M , Zare M, Mousavi N – Efficacy of gabapentin for the prevention of paclitaxel induced peripheral neuropathy: A randomized placebo controlled clinical trial. – Breast J. 2019 Feb 17.

Neuropathy is a dose limiting side effect of taxanes which may impact the quality of life and treatment outcomes. This randomized placebo-controlled double-blinded clinical trial was carried out to assess the efficacy of gabapentin in preventing chemotherapy induced neuropathy. Women with breast cancer were randomized into two groups of paclitaxel chemotherapy with gabapentin 300 mg/three times a day orally or placebo for 2 weeks started at day 1 of each paclitaxel cycle. Two groups were compared based on the relative frequency of neuropathy and change in nerve conducting velocity (NCV). Twenty women were assigned to each study arm. The majority of the neuropathy in gabapentin group was grade 1 in all of the four cycles with no event of ≥grade 3 neuropathy in this group. Compared to the placebo, the rate of 2nd and 3rd grade neuropathy was significantly lower in the gabapentin group (P = 0.000). The change in NCV after four cycles of paclitaxel was significantly lower in the gabapentin group compared to the placebo group (17.7% vs 61.0% decline in NCV for sural and 21.9% vs 62.5% declines in NCV for peroneal nerve). Gabapentin given with paclitaxel is effective in the prevention of intermediate and high grade neuropathies both objectively and subjectively