Incidence of Chemotherapy-Induced Ovarian Failure in Premenopausal Women Undergoing Chemotherapy for Breast Cancer

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1 DOI /s y Incidence of Chemotherapy-Induced Ovarian Failure in Premenopausal Women Undergoing Chemotherapy for Breast Cancer V. Tiong A. M. Rozita N. A. Taib C. H. Yip C. H. Ng Ó Société Internationale de Chirurgie 2014 Abstract Introduction Breast cancer is increasingly reported in young premenopausal women in Asia. Adjuvant chemotherapy improves survival; however, it has a unique consequence of ovarian failure in premenopausal patients. Objective This study s aim was to find the incidence of chemotherapy-induced ovarian failure (CIOF) and reversible amenorrhea in premenopausal non-metastatic breast cancer patients. Method This mixed retrospective and prospective study follows premenopausal breast cancer patients receiving chemotherapy between 2008 and Patients in the prospective arm were followed up with menstrual history and serum ovarian hormones (follicle-stimulating hormone [FSH] and estradiol) until 1 year post-chemotherapy, and patients in the retrospective arm were contacted for their menstrual history. Results The mean age of the 102 subjects was 43.3 years. Of the patients, 93.1 and 77.9 % were amenorrheic at completion of chemotherapy and at 12 months post-chemotherapy, respectively. Of those who developed amenorrhea, 24.6 % regained menstruation, on average after 7.86 (range 1 15) months post-chemotherapy. Age was the only statistically significant risk factor. CIOF and reversible amenorrhea was 57 and 50 % at \35 years, 95 and 31.6 % at years, and 97.9 and 14.9 % at [50 years, respectively. The 33 prospective patients estradiol and V. Tiong (&) N. A. Taib C. H. Yip C. H. Ng Department of Surgery, University Malaya, Kuala Lumpur, Malaysia vune@hotmail.com A. M. Rozita Clinical Oncology Unit, University Malaya, Kuala Lumpur, Malaysia FSH levels seem to correlate well with onset of amenorrhea, with a falling estradiol and rising FSH trend. Tamoxifen use was associated with elevated estradiol levels 1 year post-chemotherapy. Conclusion This study found a high incidence of CIOF, with a relatively low rate of reversible amenorrhea. Premenopausal patients should be counselled prior to treatment and education and support provided. Introduction Breast cancer is the most common cancer and the highest cause of cancer mortality in women worldwide. It is largely a disease in postmenopausal women in the developed Western world; however, it is increasingly reported in young premenopausal women in Asian countries. Agarwal et al. [1], in a multinational collaborative study showed breast cancer patients in developing Asian countries to be younger, on average by a decade, than their counterparts in developed Asian and Western nations, with the proportion of young patients aged \35 years up to 25 %. The difference in age on breast cancer diagnosis between the East and the developed West may be due to the difference in population structure, as developing countries have a younger population, lifestyle, environment, socioeconomic status, and access to healthcare [2]. Younger women tend to present with a worse prognostic picture, warranting a more intensive treatment approach. Multimodal treatment with surgery, chemotherapy, and hormonal treatment has been proven to improve survival; however, it does pose a unique consequence to premenopausal patients in the form of ovarian failure after treatment otherwise not experienced in the typical breast cancer patient who is mostly postmenopausal. Chemotherapy-induced amenorrhea has been

2 reported in literature ranging from 53 to 89 % [3] with age at diagnosis, chemotherapy use, and hormonal therapy associated with menopausal onset [4]. Treatment-induced amenorrhea may be reversible or permanent, and issues of fertility, contraception practice, and a premature onset of menopause with its long-term risks are of concern and relevant to this group of patients. Chemotherapy-induced ovarian failure (CIOF) may not be adequately addressed and counseled for before cancer treatment commencement, with surveys of premenopausal breast cancer survivors suggesting that half of them did not have a memorable discussion on consequent infertility and premature menopause [5]. As the numbers of young premenopausal breast cancer patients surviving after treatment increases, longterm consequences of ovarian failure and quality of life is important and will have implications in treatment plan and compliance. With the demographics of breast cancer in Asia getting younger, and information on ovarian function after chemotherapy lacking in our region, addressing the incidence of CIOF would be relevant in our local setting to appropriately guide counseling, treatment, and fertility options available. The aim of this study was therefore to find the incidence of CIOF and reversible amenorrhea in premenopausal non-metastatic breast cancer patients. Method This mixed retrospective and prospective study follows premenopausal breast cancer patients who received chemotherapy for breast cancer between 2008 and 2012 in two tertiary hospitals, Hospital Tuanku Jaa far in Negeri Sembilan and University Malaya Medical Center in Kuala Lumpur, Malaysia. The primary endpoints of this study are to determine the incidence of CIOF and the incidence of reversible amenorrhea. The secondary endpoints will look at the serum markers of ovarian function (follicle-stimulating hormone [FSH] and estradiol) at pre-chemotherapy, during chemotherapy, and 1 year after completion of chemotherapy and to determine predictive factors associated with CIOF. For the prospective arm of the study, inclusion criteria were as follows: premenopausal women; defined as having menstruation within the last 6 months at diagnosis and a premenopausal serum ovarian hormone profile; and had stage I, II, or III breast cancer requiring chemotherapy. Patients who were post-menopausal, defined as cessation of menses 6 months prior to diagnosis of breast cancer and/or postmenopausal ovarian markers (FSH and estradiol), or had metastatic cancer at the time of diagnosis or during staging, were excluded from the study. All consecutive patients who fulfilled the inclusion and exclusion criteria were enrolled after informed consent was obtained. Standard of care treatment and follow-up were given to all patients. Staging of breast cancer was done by computed tomography (CT) thorax, abdomen, and pelvis and bone scan. Depending on the staging of the breast cancer, these patients were offered surgery, followed by adjuvant chemotherapy ± radiotherapy ± hormonal therapy or primary systemic therapy followed by surgery ± radiotherapy ± hormonal therapy. The standard chemotherapy regime given to patients was six cycles of 5-fluorouracil mg/m 2, epirubicin mg/m 2, and cyclophosphamide mg/m 2 on day 1 every 3-week cycle (6FEC); or three cycles of FEC followed by three cycles of docetaxel mg/m 2 (3FEC/3T); or four cycles of docetaxel 75 mg/m 2 and cyclophosphamide 600 mg/m 2 (TC 4). Tamoxifen was started in patients with estrogen receptor (ER) disease after the last chemotherapy cycle, irrespective of whether radiotherapy was needed. A clinical history of the patients menstrual cycle was taken, along the course of the patients breast cancer treatment. Ovarian markers FSH and estradiol were taken prechemotherapy, during chemotherapy, and 1 year after the last dose of chemotherapy. Sampling of serum ovarian hormones was taken when patients received treatment in hospital and was not specifically timed to the patient s menses for physiological cyclical variations for logistics reasons. The retrospective arm of the study looked at medical records of all breast cancer cases in the University Malaya Medical Center from 2008 to Patients who fit the inclusion criteria with normal regular menstruation prior to chemotherapy for non-metastatic breast cancer were contacted via telephone and asked about their menstrual history. Amenorrhea for [12 months after the completion of chemotherapy was used as a clinical surrogate for ovarian failure for these patients. Data on age, ethnicity, disease pathology and stage, chemotherapy regime, radiotherapy, and tamoxifen use were collected. Ovarian failure was defined as a cessation of menstruation for C12 months after chemotherapy completion and/or by a postmenopausal serum ovarian hormone profile of estradiol \136 pmol/l and FSH [ 25.8 IU/L. Reversible amenorrhea was defined as the return of regular menstruation. The study is reviewed and registered with the National Medical Research Register of Malaysia (Research ID NMRR ) and has also been approved by the Ethics Committee of the University Malaya Medical Center (IRB ref no ). Results Patient demographics A total of 41 patients were recruited for the prospective arm of the study from 2010 to 2012; however, eight

3 patients were excluded (two were found to be post-menopausal on baseline serum ovarian hormonal profile, one had lung metastasis on staging, one had chemotherapy contraindicated for heart failure, one patient refused chemotherapy treatment, and three were not given chemotherapy). For the retrospective arm, there were 874 cases of breast cancer from 2008 to 2010, with 278 of them premenopausal. Of these 278 patients, 176 were excluded (131 not given chemotherapy, 30 had metastatic disease, 16 patients had passed away). Of the remaining 102 patients, 69 (67.7 %) were contactable via phone for a clinical menstrual history. The demographics of the total 102 patients (33 prospective and 69 retrospective) in this study are as shown in Table 1. The average age of the patients was 43.3 years (range 22 56). One patient defaulted treatment after the third cycle of chemotherapy. Incidence of amenorrhea and subsequent return of menstruation The overall incidence of amenorrhea was 93.1 % (94 of 101 patients) at chemotherapy completion and 77.9 % (67 of 86 patients) at 12 months after completion of chemotherapy, with 68.6 % (70 of 102 patients) and 76.5 % (78 of 102 patients) amenorrhic after the second and third cycle of chemotherapy, respectively (Fig. 1). Of the 94 patients who became amenorrhic after chemotherapy completion, 23 (24.6 %) subsequently regained menstruation, on average after 7.86 months (range 1 15). Four of the patients who regained menstruation after chemotherapy-induced amenorrhea later became amenorrhic again after an average of 8.25 months after return of menstruation. Only seven patients did not experience amenorrhea with chemotherapy and were still menstruating 1 year after chemotherapy completion. Figures 2, 3, 4 show the trend of clinical menstruation during and after chemotherapy according to the following age groups: \35, 35 45, and [45 years. CIOF and reversible amenorrhea were 57 % (8/14) and 50 % (4/8) at \35 years, 95 % (38/40) and 31.6 % (12/38) at years, 97.9 % (47/ 48) and 14.9 % (7/47) at [50 years, respectively. Ovarian hormone profile Serum ovarian hormones FSH and estradiol were taken for the prospective arm patients at baseline before chemotherapy, during chemotherapy, and at 12 months after completion of chemotherapy. The results are as shown in Fig. 5. Based on serum ovarian hormone markers, FSH started to rise steadily after the first cycle of chemotherapy, and patients on average become perimenopausal after the third cycle and had a postmenopausal ovarian hormone profile after the fifth cycle. Results at 1 year after completion of Table 1 Study population Patient demographics No. of patients (n = 102) Percentage Ethnicity Malay Chinese Indian Others Age (years) \ [ Pathology Invasive ductal carcinoma Mucinous Medullary Apocrine Metaplastic Invasive cribiform Stage I II III Unknown Chemotherapy regime a 6FEC FEC/3T TC TAC Gemcitabine/cisplatin FEC 2/EC Radiotherapy Yes No Tamoxifen Yes No a Refer to text for chemotherapy regimens chemotherapy showed an elevated FSH as well as high estradiol levels, which may be due in part to hormonal therapy as most patients were on tamoxifen. Figure 6 shows the breakdown of mean estradiol levels dependent on tamoxifen use; patients on hormonal therapy had higher estradiol levels than those who were not on tamoxifen. Associated factors for chemotherapy-induced ovarian failure Risk factors associated with CIOF were analyzed. Only age was found to be statistically significantly associated with chemotherapy-induced amenorrhea (Table 2).

4 b Fig. 1 Menstruation during and after chemotherapy (n = 102) (seven patients in the retrospective arm who became amenorrheic after chemotherapy were not able to recall the onset of amenorrhea in relation to their chemotherapy cycle). a overall, b prospective arm, c retrospective arm Fig. 2 Menstruation during and after chemotherapy in patients aged \35 years (two patients who became amenorrheic after chemotherapy were not able to recall the onset of amenorrhea in relation to their chemotherapy cycle) Fig. 3 Menstruation during and after chemotherapy in patients aged years (one patient who became amenorrheic after chemotherapy was not able to recall the onset of amenorrhea in relation to her chemotherapy cycle)

5 Fig. 4 Menstruation during and after chemotherapy in patients aged [45 years (three patients who became amenorrheic after chemotherapy were not able to recall the onset of amenorrhea in relation to their chemotherapy cycle) Fig. 6 Mean estradiol levels with tamoxifen use in the prospective arm Fig. 5 Mean serum estradiol and follicle-stimulating hormone levels pre-chemotherapy, during chemotherapy, and after chemotherapy in the prospective arm. FSH follicle-stimulating hormone Discussion Demographics In Malaysia, breast cancer is the most common cancer in women, with an overall age standardized rate of 39.3 per 100,000 [6]. A regional breast cancer database from Malaysia and Singapore found that 51 % of the 2,545 patients were diagnosed before 50 years of age, with 56 % of them receiving chemotherapy and 60 % receiving hormonal therapy [7]. The incidence of chemotherapy-induced amenorrhea in this study was 93.1 % upon completion of chemotherapy; 77.9 % of the patients were still amenorrhic 1 year later. This correlates to the higher range of reported rates of chemotherapy-induced amenorrhea. Age is a significant factor in chemotherapy-associated amenorrhea, with increasing age prone to developing amenorrhea. The majority of patients in the study were in their 40 s; 40 % were aged between 45 and 49 years, and the next biggest group (21 %) in the year group. The mean age of menopausal onset in Malaysian women is 50.7 years [8]. It may be difficult to differentiate whether the onset of ovarian failure was induced or hastened prematurely by chemotherapy treatment or if it was due to natural progression of ageing by virtue of breast cancer diagnosed at a perimenopausal age. However, looking at the 14 young breast cancer patients aged \35 years in the study, the incidence of amenorrhea after chemotherapy was lower in this age group, with eight (57 %) developing amenorrhea while six (43 %) continued to experience menstruation. Of these eight patients, there was a relatively higher percentage of reversal of amenorrhea, with four (50 %) having return of menses, on average after 8.25 months. Correlation of clinical menstrual history with ovarian hormones Assessment of ovarian function after breast cancer treatment can be imprecise, with chemotherapy and hormonal

6 Table 2 Factors associated with chemotherapy-induced amenorrhea Variables Incidence of amenorrhea (n/102) p value Age (years) \35 8/ /40 [45 47/48 Ethnicity Chinese 41/43 Malay 35/40 Indian 15/17 Others 2/2 Pathology IDC 87/95 Medullary 1/2 Metastatic 1/1 Mucinous 2/2 Apocrine 1/1 Invasive cribiform 1/1 Stage of disease I 10/11 II 58/63 III 24/27 Chemotherapy regime FEC 53/57 3FEC/3T 22/24 TC4 11/14 TAC4 4/4 Gemsa/cisplatin 1/1 FEC4/T2 1/1 FEC2/EC4 1/1 Radiotherapy 56/ Tamoxifen 58/ IDC invasive ductal carcinoma treatment affecting menstruation and serum ovarian hormone levels; clinical and biochemical markers, respectively, are usually used to assess ovarian function. Currently, there is no universally accepted definition of the constituents of CIOF, with definitions used by studies in literature varying from using clinical menstrual history as a surrogate for ovarian failure to measurement of serum ovarian hormone levels, with varying qualitative and duration limits used. Prospectively validated and predictive markers of ovarian function have not been established [9]. Menopause is defined by the World Health Organization (WHO) as the permanent cessation of menstruation resulting from the loss of ovarian follicular activity [10], and amenorrhea is the last event to happen in the scheme of menopausal transition. However, as many patients with reduced ovarian reserve still have regular menses, studies may be underestimating the extent of damage [11]. Reh et al. [12] investigated the effect of taxane chemotherapy regime on ovarian function of 45 patients and found that, when ovarian markers were included, eight menstruating patients had abnormally elevated FSH or estradiol levels. Conversely, it is also important to understand that return of menses is not directly representative of fertility or ovarian function. Hormonal therapy may also affect ovarian hormone levels, with estradiol four to five times greater and FSH markedly suppressed while on tamoxifen [13]. Of the patients in this study, 59.8 % were receiving adjuvant hormonal treatment; we also found that patients in this study who were receiving tamoxifen had elevated estradiol levels (5.5 times higher than in patients who were not on hormonal therapy) at 1 year after completion of chemotherapy. The pathophysiology of this event is currently not known. Another point of interest to note is that serum ovarian hormone levels have natural variations in different ethnic groups, which may be relevant to a multiethnic population such as Malaysia; the Pan Asian Menopause (PAM) study looked at serum ovarian hormone levels in postmenopausal women from nine different Asian ethnicities and showed a significant variance in postmenopausal women between ethnicities even after adjustments for age and body mass index the mean estradiol level was 50 pmol/l in Chinese women and 76.9 pmol/l in Malay women, while FSH levels were 84.9 IU/L in Chinese and 90.8 IU/L in Malay women [14]. Other hormones used in studies to reflect ovarian follicular reserve include inhibin A, inhibin B, and antimullerian hormone (AMH). Inhibin decreases as a woman approaches menopause [15]. AMH level is nearly undetectable at birth, rises during puberty, remains stable throughout adulthood and decreases at menopause. There is no reported ethnic differences in AMH in women of comparable age [13]. AMH level does not change significantly during the menstrual cycle, unlike luteinizing hormone (LH), FSH, estradiol, or inhibin B [9]. A decline in AMH may be the first indication of a decline in ovarian follicular reserve, even prior to elevation of FSH. AMH has been shown to have a greater sensitivity than FSH and estradiol in predicting ovarian follicular reserve [13] and may prove to be useful, especially in fertility preservation in young cancer patients. Swain et al. [13] prospectively investigated the relationship between established ovarian markers of FSH and estradiol and more recent markers, namely AMH and inhibin A and B. Their results showed that pre-chemotherapy inhibin B and AMH levels were statistically significantly lower in patients who became amenorrhic than in patients who resumed menstruation. They concluded that lower baseline values in a premenopausal patient is a risk factor for the development of amenorrhea with chemotherapy [9]. Unfortunately, inhibin

7 and AMH levels were not used in this study as it is not routinely available in our public hospitals. Based on serum estradiol and FSH levels, patients in this study undergoing chemotherapy developed a perimenopausal mean ovarian hormone profile after the third cycle and subsequently a postmenopausal profile after the fifth cycle. Clinically, 76.5 and 90.1 % of the patients were amenorrheic after the third and fifth cycle, respectively. Menstruation and ovarian hormones, FSH and estradiol, seem to correlate quite well, albeit not completely, in this series with patients who were still clinically menstruating after chemotherapy, having premenopausal ovarian hormone levels except for one patient who had a postmenopausal profile. Those who developed amenorrhea either had perimenopausal or postmenopausal ovarian hormone profiles. Four patients who were amenorrheic 1 year after completion of chemotherapy still had a perimenopausal serum ovarian hormone profile. Five patients were regularly menstruating on recruitment into the study, but the baseline ovarian hormone profile had lower (perimenopausal) estradiol levels four of them developed persistent amenorrhea post-chemotherapy, and serum ovarian markers then showed persistently low estradiol with elevated FSH (postmenopausal profile). This may suggest that perimenopausal women undergoing chemotherapy will be tipped into menopause. The remaining patient continued to have regular menses at 1 year post-chemotherapy completion; however, she unfortunately refused to allow the taking of blood to assess ovarian hormones at 1 year after completion of therapy. Factors associated with chemotherapy-induced ovarian failure The Early Breast Cancer Trialists Collaborative Group states that patients aged \50 years derived the greatest benefit from chemotherapy [9]. Age has been shown to be an independent factor associated with ovarian failure after chemotherapy. This study found age to be strongly associated with CIOF. Goodwin et al. [4], in their risk model, found that menopause onset was significantly increased with chemotherapy (as opposed to hormonal therapy use only) after the age of 35 years: use of chemotherapy increased the menopausal risk for a 40-year-old woman from \5 to[40 %, and for a 50-year-old woman from 20 to close to 100 % [4]. Younger women are also reported to have higher rates of reversible amenorrhea after chemotherapy. Similarly in this study, young age was a significant factor in the return of menses: amenorrhea was reversible in 50 % of patients aged \35 years, 31.6 % of patients aged years, and 14.9 % of patients aged [45 years. Chemotherapy depletes the ovaries reserve of primordial follicles in a cumulative dose-dependent fashion. Polychemotherapy regimes, compared with single agents and higher cumulative doses, pose a greater risk on subsequent ovarian function: amenorrhea rates for 6 months of CMF (cyclophosphamide methotrexate fluorouracil) were reported as 69 % compared with 34 % for 12 weeks of an AC (cyclophosphamide, doxorubicin) regime [9]. In this study, we found that patients receiving six cycles of chemotherapy had a higher amenorrhea rate (6FE 100 C93% and 3FE 100 C/3T %) than patients who received four cycles of chemotherapy (4TC 79 %). Taxane-containing regimes have been reported as having rates of induced amenorrhea in the first year of chemotherapy that are similar to or higher than those of anthracycline-based regimens; however, taxane-based regimens have a higher rate of recovery of menses in the second year after completion of chemotherapy than non-taxane-based regimes [3, 16]. Clinical application When a young woman is diagnosed with breast cancer, she will be more likely than her older counterpart to face an adverse prognosis, which may translate to more aggressive treatment. She faces unique issues brought on with cancer therapy due to her young age and premenopausal status, like hormonal dysfunction, resulting in impaired fertility and earlier onset of menopause. For some young women, cessation of menses may be welcomed and may improve outcomes for women; a study with data from the National Cancer Institute of Canada Clinical Trials Group showed amenorrhea at 1 year was significantly associated with both relapse-free and overall survival in patients with receptor-positive breast cancer [3]. However for many, the threat or experience of infertility may be devastating. Amongst premenopausal breast cancer patients, more than 50 % wished to retain fertility [5]. In general, chemotherapy appears to add 10 years to ovarian age in terms of reproductive function [17]. For the significant proportion of patients who are premenopausal at diagnosis, issues regarding fertility, pregnancy, and premature menopause are concerns [17]. Patients are also generally advised to delay pregnancy till 2 years after diagnosis, as most recurrence will develop during this time, and if hormonal therapy is indicated, continues for at least 5 years, during which pregnancy is advised against for teratogenicity risks, after which fertility may be further impaired because of age-related decline [17]. Coupled with a common practice of delaying childbirth until after 35 years of age, a larger proportion of young breast cancer patients face infertility [18]. Even if patients resume menstruation after completion of chemotherapy, ovarian reserve is negatively impacted. Because of the interactive relationship of breast cancer and hormones, fertility and reproductive issues in a young

8 breast cancer patient are complex, with hormonal manipulation being a significant part of breast cancer treatment. Some patients opt to forego pregnancy for fears of triggering a cancer recurrence or having a child with birth defects, even though breast cancer recurrence is not proven to be associated with pregnancy, and neither are congenital abnormalities associated in cancer survivor pregnancies [19]. Advances in fertility preservation options are available: biological interventions to reduce the impact of chemotherapy on ovarian reserves, e.g. with gonadotropicreleasing hormone (GnRH) agonists, or removal and preservation of ovarian tissue/mature oocytes/embryos for fertility treatment after breast cancer treatment, or some patients may opt for adoption. However, equally important is the physician s and patient s awareness of available options of fertility preservation as an integral part of cancer care, balancing life-preserving therapy with fertility options. In clinical practice, clinical menstrual history and ovarian hormonal profiles serve as a practical surrogate of ovarian reserve after completion of chemotherapy; however, it may not be an absolute reflection of ovarian function, especially with adjuvant hormonal therapy. Contraceptive advice should be given appropriately. Similarly, a return of menstruation may not result in fertility. Timely referral to a fertility specialist should be made if pregnancy is a priority for the patient. The risk of ovarian failure associated with treatment must be understood so that the patient can weigh the risk to benefit ratio of her treatment options; some patients may not want to take personal risks and may consider alternatives such as adoption. The initial step in counselling breast cancer patients regarding fertility is to determine their intentions in terms of having children. For breast cancer patients, strategies for fertility preservation have little information on efficacy and safety, which may affect discussion and utilization of available options. Younger patients prefer a greater involvement in decision making regarding their cancer treatment plan, and their information needs may differ from those of older patients. Issues of self-image and fertility are of substantially more importance than for older patients, and information for these concerns is lacking compared with that for older patients, contributing to greater psychosocial distress [20]. In a study of over 1,000 premenopausal breast cancer patients, 75 % of young breast cancer patients had major concerns regarding future fertility, and 30 % reported that it affected their decisions around cancer treatment [9]. In another survey of 104 premenopausal cancer patients, onefifth of the patients, including some women aged [40 - years, desired fertility preservation. The frequency with which the effects of treatment on sexual health are discussed has also been found to be low, even though 77 % of patients had severe sexual dysfunction at 1 year follow-up [21]. Menopausal symptoms are common and troublesome in breast cancer treatment in all ages. Most common are vasomotor symptoms (e.g. flushing, palpitations, sweating, anxiety, panic, and irritability) and urogenital symptoms (e.g. vaginal dryness, dyspareunia, and recurrent urinary tract infection). Up to 20 % of patients have considered or actually stopped hormonal therapy due to menopausal symptoms [17]. As such, the effects of chemotherapy on ovarian function can potentially affect breast cancer survivors in terms of treatment choice, quality of life, and survival. The results of this study will have practical clinical implications for the decision-making process and on the counselling of premenopausal breast cancer patients regarding the possible outcomes and consequences of premature ovarian failure, and will assist in making tradeoffs between possible benefits of adjuvant therapy and its side effects. Treatment should be tailored and individualized, balancing the potential effects of treatment and the possible side effects and future risks of ovarian failure. When absolute benefits are low (e.g. in low-risk, nodenegative disease), it may tip the decision away from chemotherapy; however, if the absolute risk is high (e.g. nodepositive disease), the effects of chemotherapy on disease recurrence and survival will outweigh the menopausal effect [4]. It is also important to consider the patient s concerns. For instance, a patient aged \35 years, with lowrisk breast cancer and for whom pregnancy is a priority, may prefer chemotherapy with its relatively shorter duration and low risk of (permanent) amenorrhea over receiving tamoxifen for 5 years, which would mean a deferral of pregnancy. In contrast, a patient in her 40 s, who will have an increased risk of permanent ovarian failure of up to 40 % post-chemotherapy, must weigh the risk of premature menopause and its sequelae and cancer recurrence. When pregnancy is not a concern, onset of premature menopause and its consequences, e.g. vasomotor symptoms, increased risk of osteoporosis and heart disease, may play a role in decision making. In a young 35-year-old woman, it may be reassuring that her risk is relatively low; however, a 45-year-old woman with a risk for cardiac disease may conclude that the risk brought on by chemotherapy-induced premature menopause may outweigh the benefits of chemotherapy and decide for hormonal therapy only. Early discussion would lead to more realistic expectations and better psychosocial outcomes for young breast cancer patients. CIOF is very common, and its consequences can be profound, physically, emotionally, and socially. Proper early counselling at the start of treatment is essential; patients desires for children, and expectations and acceptability of menopausal outcomes, should be

9 discussed. The patient should be guided in deciding on her best possible treatment plan, balancing the potential benefits of chemotherapy against its possible adverse effects and future risks. Accurate predictors of CIOF will rely on multiple parameters, including hormonal status, age at diagnosis, and chemotherapy treatment. Conclusion Chemotherapy is a crucial part of treatment for breast cancer and has been shown to improve survival. However, it does come with certain consequences such as ovarian failure, which may be temporary or permanent. This has implications for fertility and the (premature) onset of menopause, which consequently may affect the patient s decisions regarding treatment regime and compliance with treatment. Acknowledgments This study is supported by research grants from the Ministry of Science, Technology and Innovation and the Ministry of Higher Education, Malaysia (UM.C/HIR/MOHE/06). References 1. Agarwal G, Pradeep PV, Aggarwal V et al (2007) Spectrum of breast cancer in Asian women. World J Surg 31: doi: /s Yip CH, Taib NAM, Mohamed I (2006) Epidemiology of breast cancer in Malaysia. Asian Pac J Cancer Prev 7: Han H-S, Ro J, Lee KS et al (2009) Analysis of chemotherapyinduced amenorrhea rates by three different anthracycline and taxane containing regimen for early breast cancer. Breast Cancer Res Treat 115: Goodwin PJ, Ennis M, Pritchard KI et al (1999) Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 17: Bakkum-Gamez JN, Laughlin SK, Jensen JR et al (2011) Challenges in the gynecologic care of premenopausal women with breast cancer. Mayo Clin Proc 86: Omar ZA, Ali ZM, Tamin NSI (eds) (2006) Malaysian cancer statistics: data and figure peninsular Malaysia National Cancer Registry, Ministry of Health, Putrajaya 7. Pathy NB, Yip CH, Taib NA et al (2011) Breast cancer in a multiethnic Asian setting: results from the Singapore-Malaysia hospital-based breast cancer registry. Breast 20(Suppl 2):S75 S80 8. Ismael NN (1994) A study on the menopause in Malaysia. Maturitas 19: Anders C, Marcom PK, Peterson B et al (2008) A pilot study of predictive markers of chemotherapy related amenorrhea among premenopausal women with early stage breast cancer. Cancer Invest 26: Burger HG, Dudley EC, Robertson DM et al (2002) Hormonal changes in the menopause transition. Recent Prog Horm Res 57: Sonmezer M, Oktay K (2006) Fertility preservation in young women undergoing breast cancer treatment. Oncology 111: Reh A, Oktem O, Oktay K (2008) Impact of breast cancer chemotherapy on ovarian reserve: a prospective observational analysis by menstrual history and ovarian reserve markers. Fertil Steril 90: Karkanaki A, Vosnakis C, Panidis D (2011) The clinical significance of anti-mullerian hormone evaluation in gynecological endocrinology. Hormones 10: Ausmanas MK, Tan DA, Jaisamrarn U et al (2007) Estradiol, FSH and LH profiles in nine ethnic groups of postmenopausal Asian women: the Pan-Asia Menopause (PAM) study. Climacteric 10: Swain S, Jeong J, Geyer C et al (2010) Longer Therapy, iatrogenic amenorrhea and survival in early breast cancer. New Engl J Med 362: Berliere M, Dalenc F, Malingret N et al (2008) Incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel. BMC Cancer 8: Hickey M, Peate M, Saunders CM et al (2009) Breast cancer in young women and its impact on reproductive function. Hum Reprod Update 15: Hulvat MC, Jeruss JS (2009) Maintaining fertility in young women with breast cancer. Curr Treat Options Oncol 10: Canada AL, Schover LR (2012) The psychosocial impact of interrupted childbearing in long-term female cancer survivors. Psychooncology 21(2): Partridge AH, Goldhirsch A, Gelber S et al (2010) Breast cancer in younger women. In: Harris JR, Lippman ME, Morrow M, Osborne CK (eds) Diseases of the breast, 4th edn. Lippincott Williams & Wilkins, Phildelphia 21. Scanlon M, Blaes A, Gellar M et al (2012) Patient satisfaction with physician discussions of treatment impact on fertility, menopause and sexual health among pre-menopausal women with cancer. J Cancer 3: