Philippe Piette

Incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel

BackgroundTo determine the incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel.MethodsWe studied the incidence and duration of amenorrhea induced by two chemotherapy regimens: (i) 6 cycles of 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 every 3 weeks (6FEC) and (ii) 3 cycles of FEC 100 followed by 3 cycles of docetaxel 100 mg/m2 on day 1 every 3 weeks (3FEC/3D). Reversible amenorrhea was defined as recovery of regular menses and, where available (101 patients), premenopausal hormone values (luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol) in the year following the end of chemotherapy.ResultsOne hundred and fifty-four premenopausal patients were included: 84 treated with 6FEC and 70 with 3FEC/3D. The median age was 43.5 years (range: 28–58) in the 6FEC arm and 44 years (range: 29–53) in the 3FEC/3D arm. Seventy-eight percent of patients were treated in the context of the PACS 01 trial. The incidence of chemotherapy-induced amenorrhea at the end of chemotherapy was similar in the two groups: 93 % in the 6FEC arm and 92.8 % in the 3FEC/3D arm. However, in the year following the end of chemotherapy, more patients recovered menses in the 3FEC/3D arm than in the 6FEC arm: 35.5 % versus 23.7 % (p = 0.019). Among the 101 patients for whom hormone values were available, 43 % in the 3FEC/3D arm and 29 % in the 6FEC arm showed premenopausal levels one year after the end of chemotherapy (p < 0.01). In the 3FEC/3D group, there was a statistically significant advantage in disease-free survival (DFS) for patients who were still amenorrheic after one year, compared to patients who had recovered regular menses (p = 0.0017).ConclusionOur study suggests that 3FEC/3D treatment induces more reversible amenorrhea than 6FEC. The clinical relevance of these findings needs to be investigated further.

Tamoxifen and ovarian function.

Background Some studies suggest that the clinical parameter “amenorrhea” is insufficient to define the menopausal status of women treated with chemotherapy or tamoxifen. In this study, we investigated and compared the ovarian function defined either by clinical or biological parameters in pre-menopausal breast cancer patients treated with tamoxifen administered as adjuvant therapy. Materials and Methods Between 1999 and 2003, 138 premenopausal patients consecutively treated for early breast cancer were included. Sixty-eight received tamoxifen in monotherapy as the only adjuvant systemic treatment (Group I) and 70 were treated with tamoxifen after adjuvant chemotherapy (Group II). All patients had a confirmed premenopausal status based on clinical parameters and hormonal values at study entry. They were followed prospectively every 3 months for 3 years: menses data, physical examination and blood tests (LH, FSH, 17-beta-estradiol). Vaginal ultrasonography was carried out every 6 months. After 3 years, prospective evaluation was completed and monitoring of ovarian function was performed as usual in our institution (1x/year). All data were retrospectively evaluated in 2011. Results Three patients were excluded from the study in group I and 2 were excluded in group II. Patients were divided into 4 subgroups according to clinical data, i.e. menses patterns. These patterns were assessed by questionnaires. a: Regular menses (>10 cycles/year) b: Oligomenorrhea (5 to 9 cycles/year) c: Severe oligomenorrhea (1 to 4 cycles/year) d: Complete amenorrhea Estrogen levels did not appear to have any impact on disease-free survival rates after 3 or 8 years. FSH values were also documented and analyzed. They exhibited the same profile as estradiol values. Conclusions Amenorrhea is an insufficient parameter to define menopausal status in patients receiving tamoxifen. Low estradiol levels must be coupled with other biological parameters to characterize endocrine status. These data are very important for the choice of endocrine therapy.

The Place of Extensive Surgery in Locoregional Recurrence and Limited Metastatic Disease of Breast Cancer: Preliminary Results

The aims of this study were first to clearly define two different entities: locoregional recurrences and limited metastatic disease and secondly to evaluate the place of extensive surgery in these two types of recurrence. Material and Methods. Twenty-four patients were followed from June 2004 until May 2014. All patients underwent surgery but for 1 patient this surgery was stopped because the tumour was unresectable. Results. The median interval between surgery for the primary tumour and the locoregional recurrence or metastatic evolution was 129 months. Eight patients had pure nodal recurrences, 4 had nodal and muscular recurrences, 5 had muscular + skin recurrences, and 8 had metastatic evolution. Currently, all patients are still alive but 2 have liver metastases. Disease free survival was measured at 2 years and extrapolated at 5 years and was 92% at these two time points. No difference was observed for young or older women; limited metastatic evolution and locoregional recurrence exhibited the same disease free survival. Conclusion. Extensive surgery has a place in locoregional and limited metastatic breast cancer recurrences but this option must absolutely be integrated in the multidisciplinary strategy of therapeutic options and needs to be planned with a curative intent.

Abstract P3-13-19: Isolated sternal metastases: The place of surgical resection

Background: Solitary sternal metastases from breast cancer are found in approximately 1.9 to 2.5 % of all advanced breast cancer cases. According to the latest AJCC classification, they are still considered as stage IV disease, but their prognosis is better in the absence of other foci of metastatic disease. Their treatment still remains controversial. Material and methods: This is a monocentric retrospective study performed in our breast clinic and approved by our ethics committee. Twelve patients were included in this study between 2010 and 2015; 11 had a metachronous solitary sternal metastasis and 1 had a synchronous metastatic sternal lesion. Complete restaging was negative in all patients for other metastatic lesions. The extent of resection (different parts of the sternum and frequently also adjacent rib cartilages) necessary to obtain free margins was estimated preoperatively on MRI images focused with adequate sequences. All the patients underwent a large sternal resection and a chest wall reconstruction integrated in a multimodal approach. Characteristics of the patients and of the tumors were studied. The major outcomes studied were disease-free (DFS) and overall survival (OS). Results: The mean interval between the initial diagnosis of breast cancer and the discovery of sternal metastasis was 115 months. After surgical resection, free margins were obtained in 10 patients. No post-operative complications were observed except for persistent thoracic pain in one patient with a medical history of chronic pain. Excellent cosmetic and functional outcomes were obtained without significant impairment of respiratory function. Ten patients received chemotherapy pre- or postoperatively. All the tumors expressed ER and /or PgR receptors, and endocrine therapy was administered in all patients. Mean duration of follow-up was 25 months (9-51 months). Three patients presented distant recurrences: 2 liver lesions and 1 cervical nodal recurrence with pericardic effusion. Out of these 3 patients, 1 died after 51 months. Currently the DFS of this small study is 75 % and the OS is 91.6 %. Conclusion: Treatment of isolated sternal metastases of breast cancer must be based on a multidisciplinary strategy. Sternectomy and multilayered chest wall reconstruction (with different types of meshes and flaps) could be a curative approach in highly selected patients with no other metastatic lesions. In this group of patients, the good prognosis observed could be due to a different mechanism of dissemination, based on lymphatic rather than hematogenic diffusion. Longer follow-up and prospective studies are needed to confirm these encouraging results. Citation Format: Berliere M, Taburiaux L, Lacroix V, Gerday A, Coyette M, Lecouvet F, Piette P, Galant C, Duhoux F, Lengele B. Isolated sternal metastases: The place of surgical resection [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-13-19.

Abstract P2-12-04: Is there any benefit to perform extensive nodal dissection in primary or recurrent aggressive form of breast cancer?

Background: Breast oncologic surgery and especially nodal surgery has become ever more minimally invasive. However, some aggressive breast cancers exhibit at their primary or recurrent presentation extensive nodal invasion at the axillary, retropectoralis and sometimes supraclavicular and cervical levels. Surgical treatment of these tumors is not standardized. Material and methods: Between January 2012 and April 2015, 7 primary breast cancer patients (group I) and 7 recurrent breast cancer patients (group II) were included in a prospective, non randomized study approved by our local ethics committee. All the patients had cytologically proven retropectoralis and infraclavicular lymph node invasion and 7 of them had cytologically proven cervical lymph node invasion (5 in the group of primary tumors and 2 in the group of recurrences). Four of the 7 primary tumors were triple negative and 3 were HER2 positive tumors, while 4 out of the 7 recurrent tumors were triple negative and 3were HER2 positive. All the patients underwent PET/CT and breast MRI at baseline. Visceral metastases were absent in all cases. In the group of primary tumors, all the patients were treated with neoadjuvant chemotherapy (plus trastuzumab for the 3 HER2 positive tumors); in the group of recurrent tumors, neoadjuvant chemotherapy associated with trastuzumab was administered in 3 patients, while the 4 other patients underwent complementary mastectomy plus extensive nodal surgery followed by chemotherapy. Radiotherapy was administered in all primary breast cancer patients and cervical radiotherapy was administered in 3 of the 7 recurrent diseases. The following parameters were assessed: disease-free survival, overall survival and adverse events of surgical treatment. Results: All the patients are still alive after a relatively short mean duration of follow-up [24 months in group I (6 to 40 months) and 29 months in group II (3 to 39 months)]. Six of the 7 patients in group I have no signs of recurrence, one has metastatic evolution (bilateral cervical and mediastinal node evolution) and is currently receiving chemotherapy in combination with a PARP inhibitor. In group II, 6 of the 7 patients have no signs of recurrence and one has metastatic evolution (inguinal nodes and bone metastases), treated with chemotherapy and HER2-targeted therapy. The major adverse event is arm lymphedema, affecting 4 out of 14 patients (28%). No persistent pain nor motor troubles are noted. Discussion: Patients with nodal metastases outside the axilla seem to benefit from extensive surgery integrated in a multidisciplinary therapeutic approach. Some studies have demonstrated survival benefits for patients undergoing surgical resection of these nodes. Conclusion: In aggressive breast tumors (HER2 positive or triple negative tumors) presenting with extensive nodal invasion, surgical excision of these nodal metastases must be integrated in the multidisciplinary treatment and patients need to be followed prospectively for a long time to confirm survival benefits. Citation Format: Berliere M, Duhoux F, Nardai P, Schmitz S, Taburiaux L, Galant C, Leconte I, Piette P, Lengele B. Is there any benefit to perform extensive nodal dissection in primary or recurrent aggressive form of breast cancer?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-12-04.

Abstract P2-18-03: Potential benefits of hypnosis sedation on different modalities of breast cancer treatment

Background: In oncology, hypnosis has been used for pain relief in metastatic patients but rarely for induction of anaesthesia. Material and methods: Between January 2010 and February 2014, 220 patients from our breast clinic (Cancer Center - Cliniques universitaires Saint-Luc - Universite catholique de Louvain) were included in an observational, non randomized study approved by our local ethics committee. 110 consecutive patients underwent breast surgery (lumpectomy or mastectomy +/- axillary lymph node dissection or sentinel lymph node biopsy) while on general anaesthesia (group I) and 110 consecutive patients underwent the same surgical procedures while on hypnosis sedation (group II). The stages and the tumor characteristics were well balanced between the two groups. After surgery, 28 patients received chemotherapy in group I and 27 patients in group II. Radiotherapy was administered to 96 patients of group I and 95 patients of group II. Currently, 83 patients of group I and 82 patients of group II are receiving endocrine therapy. Different parameters were studied for each treatment modality. Results: Duration of hospitalization was statistically significantly reduced in group II vs. group I (3.3 days vs. 4.4 days) (CI 95% range: -1.48 -0,72, p=0,0000000578) for all surgical procedures. The same results were observed for mastectomies alone (3.1 vs. 5.3 days) (CI 95 % range: -3,19 -1,31, p=0,0002 ) and for lumpectomies (3.1 vs. 4.3 days) (CI 95 % range: -1,024 -0,364, p=0,00065). The number of post-mastectomy lymph punctures was reduced in group II (1 to 3 (median value n=1.6) vs. group I (2 to 5 (median value n=3.1, p=0.01), as was the quantity of lymph removed (103 ml versus 462.7 ml) (p=0,0297) in the group of mastectomies. Concerning chemotherapy, the incidence of asthenia was statistically decreased (p=0.015) in group II. There was a statistically non significant trend towards a decrease in the incidence of nausea/vomiting and muscle pain in group II (respectively p=0.1 and p=0.2). The frequencey of severe radiodermitis (p=0.01) and post-radiotherapy asthenia (p=0.01) were significantly reduced in group II. Finally, compliance to endocrine therapy was improved in group II (p=0.05), while incidence of hot flashes (p=0,00029), joint or muscle pain (p=0,000139) and asthenia (p=0,00002) were statistically significantly decreased in group II. Discussion: Hypnosis sedation exerts beneficial effects on nearly all modalities of breast cancer treatment. The absence of a significant benefit for chemotherapy-induced nausea/vomiting and muscle pain observed is probably due to the small number of patients receiving chemotherapy in our study. Conclusion: Benefits of hypnosis sedation on breast cancer treatment are very encouraging and further promote the concept of integrative oncology. Citation Format: Martine Berliere, Sarah Lamerant, Philippe Piette, Aurore Lafosse, Laurence Delle Vigne, Fabienne Roelants, Christine Watremez, Marie-Agnes Docquier, Lafita Fellah, Isabelle Leconte, Francois Duhoux. Potential benefits of hypnosis sedation on different modalities of breast cancer treatment [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-18-03.

Chemotherapy-Related Amenorrhea in Breast Cancer: Review of the Main Published Studies, Biomarkers of Ovarian Function and Mechanisms Involved in Ovarian Toxicity

Breast carcinoma is the most common cancer in women of reproductive age. In Europe and in the United States, approximately 30% of all breast cancers occur before menopause and 15% of women are diagnosed in the reproductive age (age of 45 or younger). Adjuvant chemotherapy prolongs disease-free survival (DFS) and overall survival (OS), especially in young women, but also induces long-term and severe side effects such as temporary or definitive ovarian function suppression which results in potential loss of fertility and premature exposure to the risks of menopause including cardiovascular diseases, osteoporosis, hot flashes and genitourinary dysfunctions Bines et al. (1996). The probability of menopause with chemotherapy depends on the type of regimen used and on the age of the patient. In the literature, the estimated risk of amenorrhea varies between 0% and 60% in women younger than 40 years and between 40% and 100% in women older than 40 years. Beyond age and the type of regimen used, important variations reflect different durations of follow-up and variable definitions of menopause and of chemotherapy-related amenorrhea Bines et al. (1996).