Efficacy Of Letrozole Research Articles

Improved clinical and cell cycle response with an mTOR inhibitor, daily oral RAD001 (everolimus) plus letrozole versus placebo plus letrozole in a randomized phase II neoadjuvant trial in ER+ breast cancer

530 Background: Activation of the mTOR pathway is a key adaptive change driving endocrine resistance. RAD001, an oral mTOR inhibitor, and letrozole synergistically inhibit proliferation in breast cancer cells. Methods: 270 postmenopausal women with > T2 ER+ tumors were randomized to receive 4 mo of letrozole 2.5mg QD + RAD001 10mg QD or letrozole 2.5mg plus placebo. The primary endpoint was overall clinical response. Mandatory needle biopsies were collected immediately prior to initial treatment, and at day 15 after treatment initiation. Samples were assessed at baseline for Her2 by FISH and mutation of exons 9 and 20 of PIK3CA and exons 5–8 of TP53, and at baseline and day 15 for Ki67, phospho-Akt S473, phospho-S6, PTEN, CyclinD1, ER, PR, p53, and total Akt and S6 by immunohistochemistry. A total of 207 patients (77%) were primary marker evaluable and clinical outcome evaluable; 186 patients had an evaluable second biopsy. Results: The clinical response rate with RAD001 + letrozole was significantly superior to letrozole alone at the preplanned Alpha of 0.1 (68 vs 59%, p=0.062). This was confirmed by ultrasound (OR 58% vs 47 %, p=0.035). Pharmacodynamic changes in each treatment arm were observed. Marked downregulation in progesterone receptor and cyclin D1 were seen in response to letrozole. Phospho- S6 levels showed dramatic down-regulation only in response to RAD001. Cell cycle response, as defined by either % reduction in Ki67 at day 15 or by proportion of patients with Ki67≤2 at day 15, was also significantly higher in the RAD001 + letrozole arm (57% vs 30% for Ki67≤2 at day 15, p<0.01). The rate of grade 3/4 adverse events (Aes) was 22.6% in the RAD001 + letrozole arm vs 3.8% in the placebo + letrozole arm. Most frequent grade 3/4 Aes with RAD001 + letrozole were hyperglycemia (n=7), stomatitis (3), interstitial lung disease/pneumonitis (3) and infections (3). Conclusions: RAD001 significantly increases the efficacy of letrozole in newly diagnosed ER+ breast cancer, with regard to both clinical and cell cycle response. The increased cell cycle response rate in the RAD001 arm was found in all subsets of tumors, including PTEN-positive, PIK3CA wild-type tumors. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis Novartis

Efficacy of letrozole in the treatment of recurrent platinum- and taxane-resistant high-grade cancer of the ovary or peritoneum

ObjectiveTo evaluate the efficacy and safety of letrozole in patients with recurrent platinum- and taxane-resistant estrogen receptor-positive (ER+) high-grade cancer of the ovary or peritoneum. MethodsA single-institution, phase II study was performed in women with recurrent ER+ epithelial carcinoma of the ovary or peritoneum. All patients had measurable disease. Letrozole was administered at a dose of 2.5 mg orally once daily until disease progression or toxicity occurred. ResultsThirty-three patients were enrolled. The median age was 63 years (range, 38 to 83 years). Twenty-three patients (74%) had received three or more prior chemotherapy regimens. The 31 patients evaluable for response received a total of 81 cycles (4 weeks/cycle) of therapy (range, 1 to 14 cycles/patient). The median treatment duration was 8 weeks (range, 4 to 52 weeks). None of the patients had a complete response (CR), 1 (3%) had a partial response (PR), and 7 (23%) had stable disease (SD). The median duration of clinical benefit (SD and PR) was 9 weeks (range, 7 to 46 weeks). The median follow-up for all patients was 25 weeks. All patients were evaluable for toxicity. The most common adverse effects were fatigue (36%) and diaphoresis (21%). No grade 3 or 4 toxicities were reported, and no patients discontinued treatment owing to adverse effects. Eighteen patients (58%) went on to receive additional therapy with other agents. ConclusionIn patients with ER-positive, platinum- and taxane-resistant high-grade ovarian and primary peritoneal cancer treated with letrozole, 26% derived a clinical benefit (SD and PR).

Late Extended Adjuvant Treatment With Letrozole Improves Outcome in Women With Early-Stage Breast Cancer Who Complete 5 Years of Tamoxifen

The National Cancer Institute of Canada Clinical Trials Group MA.17 trial examined the efficacy of letrozole (LET) started within 3 months of 5 years of adjuvant tamoxifen in postmenopausal hormone receptor-positive early-stage breast cancer. When the trial was unblinded, patients who received placebo (PLAC) were offered LET. This cohort analysis describes the outcomes of women assigned PLAC at the initial random assignment after unblinding. Efficacy outcomes of women who chose LET (PLAC-LET group) were compared with those who did not (PLAC-PLAC group) by the hazard ratios and by P values calculated from Cox models that adjusted for imbalances between the groups. Toxicity analyses included only events that occurred after unblinding. There were 1,579 women in the PLAC-LET group (median time from tamoxifen, 2.8 years) and 804 in the PLAC-PLAC group. Patients in the PLAC-LET group were younger; had a better performance status; and were more likely to have had node-positive disease, axillary dissection, and adjuvant chemotherapy than those in the PLAC-PLAC group. At a median follow-up of 5.3 years, disease-free survival (DFS; adjusted hazard ratio [HR], 0.37; 95% CI, 0.23 to 0.61; P < .0001) and distant DFS (HR, 0.39; 95% CI, 0.20 to 0.74; P = .004) were superior in the PLAC-LET group. More self-reported new diagnoses of osteoporosis and significantly more clinical fractures occurred in the women who took LET (5.2% v 3.1%, P = .02). Interpretation of this cohort analysis suggests that LET improves DFS and distant DFS even when there has been a substantial period of time since the discontinuation of prior adjuvant tamoxifen.

Randomized controlled trial comparing superovulation with letrozole versus recombinant follicle-stimulating hormone combined with intrauterine insemination for couples with unexplained infertility who had failed clomiphene citrate stimulation and intrauterine insemination

To compare the efficacy of letrozole to recombinant FSH for ovarian stimulation combined with IUI in a group of patients that had failed to conceive after clomiphene citrate (CC) and IUI. Prospective randomized trial with human subjects. University-based fertility center. Fifty couples with unexplained infertility that failed to conceive after three cycles of CC combined to IUI. Couples were randomized to undergo superovulation either with letrozole or with recombinant FSH combined to IUI. Clinical pregnancy per cycle of treatment and clinical pregnancy per couple. Pregnancy rate (PR) per cycle was 8.9% in the letrozole group as compared with 14% in the gonadotropin IUI group. This resulted in a cumulative PR per couple of 24% versus 36% and a take home baby rate of 20% versus 28%. Endometrial thickness was significantly lower in the letrozole group (7.1 +/- 2.3 vs 8.6 +/- 1.8). Ovarian stimulation with letrozole is associated with acceptable PRs compared with gonadotropin with significant less cost, risks, and patient inconvenience.

Update on the use of letrozole in breast cancer

Endocrine therapy is the mainstay of adjuvant treatment for hormonereceptor-positive early breast cancer. Letrozole is a potent third-generation aromatase inhibitor that suppresses plasma estrogen levels to near-undetectable levels in postmenopausal women. The results of well-controlled clinical trials have demonstrated the efficacy of letrozole over the gold-standard treatment, tamoxifen, in the neoadjuvant and upfront adjuvant settings and over placebo in the extended adjuvant setting (i.e., following 5 years of adjuvant tamoxifen). Important benefits in disease-free survival and especially distant disease-free survival have been demonstrated, in both low- and high-risk subgroups of patients (e.g., node-positive disease, prior chemotherapy). Both the efficacy and safety of letrozole for the adjuvant treatment of breast cancer are reviewed.

Prognostic and Predictive Value of Centrally Reviewed Expression of Estrogen and Progesterone Receptors in a Randomized Trial Comparing Letrozole and Tamoxifen Adjuvant Therapy for Postmenopausal Early Breast Cancer: BIG 1-98

To evaluate locally versus centrally assessed estrogen (ER) and progesterone (PgR) receptor status and the impact of PgR on letrozole adjuvant therapy compared with tamoxifen in postmenopausal women with early breast cancer. Breast International Group (BIG) 1-98 randomly assigned 8,010 patients to four arms comparing letrozole and tamoxifen with sequences of each agent. The Central Pathology Office received material for 6,549 patients (82%), of which 79% were assessable (6,291 patients). Prognostic and predictive value of both local and central hormone receptor expression on disease-free survival (DFS) were evaluated among 3,650 assessable patients assigned to the monotherapy arms. Prognostic value and the treatment effect were estimated for centrally assessed ER and PgR expression levels using the Subpopulation Treatment Effect Pattern Plot. Central review confirmed 97% of tumors as hormone receptor-positive (ER and/or PgR > or =10%). Of 105 tumors locally ER-negative, 73 were found to have more than 10% positive cells, and eight had 1% to 9%. Of 6,100 tumors locally ER positive, 66 were found to have no staining, and 54 had only 1% to 9%. Discordance was more marked for PgR than ER. Patients with tumors reclassified centrally as ER-negative, or as hormone receptor-negative, had poor DFS. Centrally assessed ER and PgR showed prognostic value. Among patients with centrally assessed ER-expressing tumors, letrozole showed better DFS than tamoxifen, irrespective of PgR expression level. Central review changed the assessment of receptor status in a substantial proportion of patients, and should be performed whenever possible in similar trials. PgR expression did not affect the relative efficacy of letrozole over tamoxifen.

Endocrine effects of letrozole + triptoreline compared to tamoxifen + triptoreline as adjuvant treatment of premenopausal patients with early breast cancer

578 Background: Few data have been reported on endocrine effects of combining LHRH-analogues with aromatase inhibitors (AI) in premenopausal patients. However, promising data in postmenopausal patients make this information interesting in view of extending adjuvant AI to premenopausal patients. We are conducting a phase 3 trial (Hormonal adjuvant treatment bone effects (HOBOE)) comparing tamoxifen (Tam), letrozole (L) and L + zoledronate (Z) for the effect on bone mineral density at 1 year. Postmenopausal and premenopausal patients are eligible, the latter also receiving monthly triptorelin (Tr). Methods: This analysis is limited to 76 premenopausal patients with early endocrine-responsive breast cancer, 28 treated with Tam+Tr and 48 with L+Tr±Z, assuming that Z has no endocrine effects. Serum 17-β-estradiol, FSH, LH, Δ4-androstenedione, testosterone, dehydroepiandrosterone-solphate, progesterone, ACTH and cortisol are measured at baseline and after 6 months of treatment. We compared, for each hormone, 6-month values between treatment groups by applying Exact Wilcoxon-Mann-Whitney test. Results: Baseline values for all the hormones were comparable between treatment groups. At 6 months, statistically significant differences were found for estradiol, FSH, LH and cortisol (see table , with median and range values by treatment group). No differences were found in plasma levels of testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups. Conclusions: These data support that letrozole compared to tamoxifen, in combination with triptorelin, induces a more intense estrogen suppression also in premenopausal patients. Such evidence makes reasonable the hypothesis that the higher efficacy of letrozole versus tamoxifen shown in postmenopausal patients could be confirmed also in premenopausal patients. [Table: see text] No significant financial relationships to disclose.

Efficacy of Letrozole Extended Adjuvant Therapy According to Estrogen Receptor and Progesterone Receptor Status of the Primary Tumor: National Cancer Institute of Canada Clinical Trials Group MA.17

Controversy exists regarding estrogen (ER) and progesterone (PgR) receptor expression on efficacy of adjuvant endocrine therapy. In the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, the benefit of anastrozole over tamoxifen was substantially greater in ER+/PgR-than ER+/PgR+ tumors. In BIG 1-98 (Breast International Group), the benefits of letrozole over tamoxifen were the same in ER+ tumors irrespective of PgR. MA.17 randomized postmenopausal women after 5 years of tamoxifen, to letrozole or placebo. We present outcomes according to tumor receptor status. Disease-free survival (DFS) and other outcomes were assessed in subgroups by ER and PgR status using Cox's proportional hazards model, adjusting for nodal status and prior adjuvant chemotherapy. The DFS hazard ratio (HR) for letrozole versus placebo in ER+/PgR+ tumors (N = 3,809) was 0.49 (95% CI, 0.36 to 0.67) versus 1.21 (95% CI, 0.63 to 2.34) in ER+/PgR-tumors (n = 636). ER+/PgR+ letrozole patients experienced significant benefit in distant DFS (DDFS; HR = 0.53; 95% CI, 0.35 to 0.80) and overall survival (OS; HR = 0.58; 95% CI, 0.37 to 0.90). A statistically significant difference in treatment effect between ER+/PgR+ and ER+/PgR-subgroups for DFS was observed (P = .02), but not for DDFS (P = .06) or OS (P = .09). These results suggest greater benefit for letrozole in DFS, DDFS, and OS in patients with ER+/PgR+ tumors, implying greater activity of letrozole in tumors with a functional ER. However, because this is a subset analysis and receptors were not measured centrally, we caution against using these results for clinical decision making.

Letrozole and norethisterone acetate in rectovaginal endometriosis

This open-label prospective study evaluated the efficacy of letrozole (2.5 mg/day) combined with norethisterone acetate (2.5 mg/day) in the treatment of pain symptoms related to the presence of rectovaginal endometriosis. The treatment significantly and quickly decreased the intensity of symptoms, but pain recurred at 3-month follow-up; five women underwent surgery during the follow-up, and histologic examination of rectovaginal nodules revealed the presence of active endometriotic lesions.

Continuing with letrozole offers greater benefits

Tamoxifen has been at the foundation of adjuvant treatment to prevent disease recurrence in postmenopausal women with hormone-responsive early breast cancer. After 5 years of adjuvant tamoxifen therapy, however, options for further treatment are limited. Additional tamoxifen is not indicated, as no further benefit in disease-free survival (DFS) has been observed. The aromatase inhibitor letrozole significantly improves DFS over placebo in postmenopausal women who have completed 4.5-6.0 years of adjuvant tamoxifen. This article reviews the data supporting extended adjuvant letrozole therapy. Extended adjuvant letrozole has been shown to be particularly effective in patients with node-positive disease, who are at a higher risk for disease recurrence, improving both DFS and overall survival. Extended adjuvant letrozole is associated with a significant increase in self-reported osteoporosis, but no significant increases in fracture, endometrial malignancies, hypercholesterolemia, or cardiovascular events and no worsening of quality of life, making it suitable for long-term use. The ASCO treatment guidelines recommend at least 2.5 years of extended adjuvant letrozole for patients completing tamoxifen therapy, based upon the MA.17 trial follow-up period. A recent cohort analysis now suggests that extended adjuvant letrozole treatment for at least 48 months is associated with greater benefit. The efficacy of letrozole for up to 10 years following tamoxifen is also being investigated.

Management of Cancer-Treatment–Induced Bone Loss in Postmenopausal Women Undergoing Adjuvant Breast Cancer Therapy: A Z-FAST Update

The prevention of cancer-treatment-induced bone loss (CTIBL) in long-term adjuvant breast cancer therapy is a high priority. Postmenopausal women with cancer, already at increased risk of bone loss because of age-related estrogen deficiency, face accelerated bone loss with the use of estrogen-depleting therapies such as third-generation aromatase inhibitors (AIs). Although effective in reducing cancer recurrence rates in the adjuvant setting, AIs are associated with bone loss and an increased risk of fractures. Bisphosphonates, which act by inhibiting osteoclastic bone resorption, have been shown to increase bone mineral density (BMD) and reduce fracture risk in postmenopausal women with established osteoporosis. Furthermore, the potent bisphosphonate zoledronic acid has been shown to be efficacious in reducing bone loss in premenopausal women receiving combination adjuvant hormone therapy (goserelin, a gonadotropin-releasing hormone agonist, plus either an AI or tamoxifen). The use of zoledronic acid to prevent CTIBL in postmenopausal women receiving adjuvant AI therapy with letrozole is currently being investigated in the Zometa/Femara Adjuvant Synergy Trial (Z-FAST). Postmenopausal women with stage I-IIIa estrogen-receptor-positive and/or progesterone-receptor-positive breast cancer starting letrozole are randomized to receive either upfront zoledronic acid or delayed zoledronic acid. At 6 months, assessable women in the upfront group showed a mean increase of 1.55% in lumbar spine (L1 - L4) BMD, compared with a mean decrease of 1.78% in women in the delayed group, resulting in a difference of 3.33% between groups; moreover, women in the former group showed a mean increase of 1.02% in total hip BMD, compared with a mean decrease of 1.40% in those in the latter group, resulting in a significant difference of 2.42% between groups (P <.001). Thus, the Z-FAST BMD results show that upfront zoledronic acid prevents CTIBL in postmenopausal women receiving adjuvant letrozole therapy for early breast cancer. Combining the anticancer efficacy of letrozole with the bone-protective effect of zoledronic acid may be a successful treatment in this setting.

Review of the development of letrozole and its use in advanced breast cancer and in the neoadjuvant setting

Five years of adjuvant endocrine therapy with the antiestrogen tamoxifen has been shown to significantly reduce the risk of recurrence in women with early breast cancer and has thus been the standard of adjuvant therapy for this malignancy over the last two decades. Tamoxifen has also been used for the first-line treatment of advanced or metastatic breast cancer, and it was studied in the neoadjuvant setting to promote breast-conserving surgery in those patients who may be otherwise ineligible. However, comparative clinical trials involving the more recently approved third-generation aromatase inhibitor drugs (anastrozole, letrozole, and exemestane) have challenged tamoxifen as first-line therapy in advanced/metastatic breast cancer as well as in the neoadjuvant setting. Although trials with other AIs have shown improved efficacy and better tolerability over tamoxifen, letrozole has consistently demonstrated superiority over tamoxifen when used as first-line treatment for advanced/metastatic breast cancer or as neoadjuvant therapy. The efficacy of letrozole in the neoadjuvant setting further extends to those tumors with positive human epidermal growth factor receptor (HER1) and/or HER2 expression, which are often less responsive to tamoxifen. The encouraging results of such trials identify letrozole as a better alternative to tamoxifen in improving responses rates in the treatment of advanced breast cancer and as neoadjuvant therapy, which allows breast-conserving surgery in women with inoperable breast cancer or who were not candidates for breast-conserving surgery.

Letrozole induction of ovulation in women with clomiphene citrate–resistant polycystic ovary syndrome may not depend on the period of infertility, the body mass index, or the luteinizing hormone/follicle-stimulating hormone ratio

Letrozole induction of ovulation in clomiphene citrate-resistant women with polycystic ovary syndrome is associated with an ovulation rate of 54.6% and pregnancy rate of 25%. There was no significant difference between letrozole responders and nonresponders in age, period of infertility, body mass index, waist circumference, LH, FSH, or LH/FSH ratio.

Aromatase Inhibitors in Adjuvant Therapy of Breast Cancer: Before, Instead of, or Beyond Tamoxifen

The trial by Boccardo et al, which is published in this issue of the Journal of Clinical Oncology, represents the fourth published randomized trial of an adjuvant aromatase inhibitor used either instead of or after 2 to 3 or 5 years of tamoxifen. Before these data became available, 5 years of adjuvant tamoxifen had been considered standard based on the results of individual trials and the Early Breast Cancer Trialists’ Collaborative Group Overview. These trials showed that 5 years of tamoxifen therapy, compared with either 2 years of tamoxifen or none, was associated with greatly improved relapse-free and overall survival. Several trials of 5 years compared with indefinite tamoxifen or 5 years compared with 10 years of tamoxifen therapy subsequently suggested that longer therapy might be less beneficial, whereas one small trial suggested the opposite conclusion. The Oxford Overview Database, including data from the ongoing randomized ATOM (Adjuvant Tamoxifen or More) and ATLAS (Adjuvant Tamoxifen Longer Against Shorter; C. Davies, personal communication, April 2004) trials of 5 compared with 10 years of tamoxifen, has not yet shown any clear significant difference between 5 years of tamoxifen therapy and more prolonged tamoxifen (http://www.ctsu.ox.ac.uk/ ebctcg/). Based on these aggregate data, most clinicians around the world have adopted 5 years of tamoxifen therapy as the optimal duration. However, it is well known that women with a previous diagnosis of breast cancer have a long-term ongoing risk of breast cancer recurrence. Data from the long-term follow-up of a group of Eastern Cooperative Oncology Group trials and from the Oxford Overview have shown that there are as many recurrences during years 6 through 15 after primary surgery as between years 1 through 5 in both women treated with tamoxifen and controls. The estimated recurrence risk beyond year 5 is approximately 4% per year for women with node-positive disease at the time of primary surgery and approximately 2% per year for women with node-negative disease. Consideration of these data before the design of the current group of adjuvant endocrine trials strongly suggested that additional therapy beyond 5 years of tamoxifen could prove useful. Now, for women nearing completion of 5 years of tamoxifen, the decision to consider additional years of endocrine therapy with an aromatase inhibitor seems fairly straightforward. Issues for discussion should include the risk of recurrence over the next 5 years based on prior nodal status and other risk factors. Patients should be informed of the efficacy of letrozole in reducing recurrence risk and, in the subset of node-positive women, in increasing overall survival. This information, together with a review of the potential short-, intermediate-, and long-term side effects of this aromatase inhibitor, should allow clinicians and patients to make a relatively informed choice regarding the desirability of this treatment. Although the MA-17 trial of 5 years of letrozole compared with placebo after tamoxifen for 5 years has, to date, a median follow-up of only 2.5 years, more data will be forthcoming. Such data should be available before the women we are currently starting on letrozole after 5 years of tamoxifen reach that 2.5-year point. Thus, more mature information regarding efficacy and longer term side effects can be provided as patients move through these phases of treatment. Currently, it seems that the added benefit of letrozole year by year, compared with the previous year, remains constant, at least through the first 3 to 4 years of therapy. Furthermore, women from the MA-17 trial who have completed 5 years of letrozole will be offered the opportunity to undergo another random assignment between a further 5 years of letrozole or placebo, thus JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 22 AUGUST 1 2005

Neoadjuvant Endocrine Therapy for Breast Cancer: More Questions Than Answers

Neoadjuvant endocrine therapy studies for breast cancer are a great opportunity to develop insights into the biologic basis for the efficacy of estrogen receptor–targeting agents. Neoadjuvant endocrine treatment is also appealing from the drug development perspective. Theoretically, a promising new adjuvant endocrine strategy could be first tested as a short-term neoadjuvant treatment against a standard medication. Improvements in tumor response rate, surgical outcomes, and evidence for enhanced efficacy at the cellular level, for example in terms of the effect on proliferation, would provide a sound basis for taking the new approach forward into the resource-demanding setting of a phase III adjuvant trial. The potential of randomized phase III neoadjuvant endocrine treatment trials was first emphasized by the results of a double-blind study by Eiermann et al (Letrozole P024) that compared 4 months of the aromatase inhibitor letrozole with tamoxifen as neoadjuvant treatment for women with hormone-receptor–positive tumors who were ineligible for breast-conserving surgery. Letrozole outperformed tamoxifen in terms of clinical and radiologic response rates as well as in the incidence of subsequent breast-conserving surgery. Interestingly, the advantage of letrozole appeared to be particularly evident in a subpopulation of tumors with estrogen-receptor–positive (ER ) and human epidermal growth factor receptor (HER) 1 and/or HER2-positive tumors, indicating that the comparison of endocrine agents in the neoadjuvant setting could provide insights into the molecular basis for differences in efficacy between endocrine agents. The enhanced efficacy of letrozole was also apparent at the level of the cell cycle, since letrozole suppressed tumor Ki67 immunohistochemical staining to a greater extent than tamoxifen. These results were consistent with the advantages of third generation aromatase inhibitors over tamoxifen in other disease settings. The Immediate Preoperative Anastrozole, tamoxifen or Combined with Tamoxifen study (IMPACT) is only the second phase III neoadjuvant endocrine trial to be reported in the peer-reviewed literature. The primary hypothesis focused on a drug development question: would the results of the neoadjuvant endocrine trial (IMPACT) mirror those of a much larger adjuvant study (the Arimidex, Tamoxifen, Alone or in Combination trial; ATAC)? In particular, the investigators wanted to prove that negative preliminary data for enhanced efficacy of anastrozole and tamoxifen in combination compared with tamoxifen alone in the preoperative setting would theoretically have prevented ATAC investigators from randomly assigning 3,000 women to the combination arm. With these primary aims in mind, 330 patients with ER breast cancer were randomly assigned to 3 months of treatment with either anastrozole, tamoxifen, or the combination of the two in a multicenter trial in the United Kingdom and Germany. Response was monitored by caliper measurements (“clinical response”) and by ultrasound. Final surgical outcomes were compared with the surgical approach that would have been initially chosen for the patient if she had not received primary systemic therapy. Unfortunately, none of these clinical end points showed any difference among the three arms and the efficacy of anastrozole was lower than postulated in the statistical design. Given these negative results, this editorial was solicited to consider whether the hypothesis regarding the neoadjuvant-adjuvant link is in jeopardy for neoadjuvant endocrine trials, or whether the IMPACT study was a valiant but flawed test of the postulate. A comparison of the conduct of the IMPACT trial versus the Letrozole P024 trial reveals some straightforward issues that support the latter conclusion. First is the question of sample size. Whereas the IMPACT and Letrozole P024 trial sizes were similar, the IMPACT study involved a three-way randomization. With fewer patients in each treatment group than the Letrozole JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 22 AUGUST 1 2005

Letrozole efficacy is related to human aromatase CYP19 single nucleotide polymorphisms (SNPs) in metastatic breast cancer

The efficacy of aromatase inhibitors varies widely among postmenopausal breast cancer patients, but it is not associated with aromatase gene expression. We evaluated whether polymorphisms of the aromatase gene CYP19 are related to the efficacy of the aromatase inhibitor letrozole.

Aromatase inhibitors in advanced breast cancer: there are efficacy differences

Sir, In the recently published review, ‘Aromatase inhibition in the treatment of advanced breast cancer: is there a relationship between potency and clinical efficacy?' (Sainsbury, 2004), the author claims that differences in the potency of aromatase inhibition and oestrogen suppression among the modern aromatase inhibitors do not translate into differences in efficacy benefits. The clinical trial results listed within the article, however, contradict the author's conclusion. Furthermore, some of the more general statements within this review must be challenged. Dr Sainsbury claims to see no efficacy differences between letrozole and anastrozole, despite the former being associated with higher potency in aromatase inhibition and oestrogen suppression (Geisler et al, 2002). The author makes a number of indirect comparisons of different trials to support his point: the first-line advanced breast cancer trials of anastrozole or letrozole vs tamoxifen demonstrated ‘anastrozole to be at least as effective as tamoxifen' (Bonneterre et al, 2001; Nabholtz et al, 2003), whereas ‘letrozole was found to be superior to tamoxifen' in all end points including a prospectively planned survival analysis at 1- and 2-year follow-up, which is not mentioned in this review (Mouridsen et al, 2003). In a head-to-head comparison of anastrozole vs letrozole in second-line advanced breast cancer, results were comparable in all end points except overall response rate (ORR), which was more than 50% higher in patients treated with letrozole (Rose et al, 2003). While ORR was a secondary rather than primary end point of the trial, the higher likelihood of responding to endocrine therapy is inarguably highly relevant for women with advanced stage breast cancer, as response implies both personal relief as well as delay of more aggressive, usually cytotoxic, therapies. Dr Sainsbury uses a subgroup analysis to challenge the results of this 713-patient trial, citing a significant superiority for letrozole only in the group of patients with undetermined hormone receptor status. Letrozole response rates in this group of patients were similar to those in the overall trial collective, not surprisingly so, as at least two-thirds of these patients are likely to bear oestrogen receptor (ER)- and/or progesterone receptor (PgR)-positive tumours. In view of the size of the ER/PgR-unknown subgroup (n=340), the well-balanced demographics in the two trial arms overall, and the high chance of a tumour of undetermined hormone receptor status being positive renders statistical imbalance of ER/PgR status in favour of letrozole, a very unlikely explanation for the 2.5-fold increased response rate achieved with letrozole. In fact, the high efficacy of letrozole in ER/PgR-unknown tumours in this second-line study is consistent with results of the phase III first-line comparison of letrozole vs tamoxifen, in which the superiority of letrozole over tamoxifen was consistent among both ER/PgR-positive and -unknown patients – in contrast to the anastrozole trials that demonstrated superiority only in the ER/PgR-positive subgroup. While hard to explain, it seems that while letrozole may be effectively used in both hormone receptor-positive and -unknown patients, the efficacy of anastrozole appears limited to only those patients with a distinct expression of ER/PgR. The efficacy of an endocrine agent in ER/PgR-unknown patients remains clinically relevant, as even today there is a pool of patients with advanced breast cancer of undetermined ER/PgR status. While Dr Sainsbury maintains that ‘…they [AIs] are used in this [hormone receptor-positive] group of patients', this is, in fact, not entirely true for advanced breast cancer: endocrine therapy is still widely recommended for these women with receptor-unknown advanced breast cancer, based on the fact that the majority will be endocrine responsive and a response to endocrine therapy would delay chemotherapy (National Cancer Institute, 2004). Within the summary of this review, the author introduces the notion that while the degree of oestrogen suppression beyond a certain threshold does not translate into increased antitumour efficacy, it might well result in different toxicity profiles. This statement is purely speculative and is not supported by any data available so far. We are not aware of any research demonstrating that endocrine-sensitive normal tissues, such as bone, would be more sensitive to small changes in oestrogen levels than breast cancer cells, which are well recognised for their ability to develop a pronounced hypersensitivity to small levels of oestrogen (Masamura et al, 1995). Using bone metabolism as an example, we may point out that the less potent aromatase inhibitor anastrozole has been associated with a marked increase in fracture rates when used in early breast cancer (Baum et al, 2002, 2003), whereas letrozole has not (Goss et al, 2003). The author of this letter is a consultant to Novartis Oncology. It would seem advisable that future reviews of the kind published by Dr Sainsbury include disclosure of the author's potential conflicts of interest as well.

The Effect of Letrozole on Bone Age Progression, Predicted Adult Height, and Adrenal Gland Function

A common problem in pediatric endocrinology is limited growth potential resulting from advancing skeletal maturation. We determined the efficacy of letrozole, an aromatase inhibitor, on delaying bone age advancement in adolescent males with limited growth potential. Twenty-four patients met the study inclusion criteria. Six patients treated with androgen were analyzed separately. Low-dose ACTH stimulation tests were performed to ascertain the effect of letrozole on adrenal gland function. In patients not on androgen, bone age progression decelerated from 1.51+/-0.57 (deltabone age/deltachronological age) before treatment to 0.68+/-0.66 on therapy (mean duration 12.4 months; p <0.0005). Predicted adult height standard deviation scores (SDS) increased from -1.41+/-0.54 to -0.64+/-0.65 on treatment (p <0.0005). Similar results were noted in androgen-treated patients. Approximately one-fourth of patients displayed subnormal responsiveness to ACTH. In summary: 1) letrozole decelerates skeletal maturation, resulting in significant increases in predicted adult height, and 2) letrozole causes mild adrenal suppression.

Preliminary experience comparing the efficiency of inhibitors of aromatase (Letrozole™) and clomiphene citrate (Serophene™) in controlled ovarian stimulation (COH) in a prospective clinical trial

To compare the efficacy of Letrozole and Serophene as adjuvants to gonadotropins in COH cycles combined with intrauterine insemination (IUI) therapy. Prospective cohort study in a tertiary teaching center. Twenty-eight patients undergoing IUI therapy received from day 3 to day 7 of the cycle either letrozole 2.5 mg/day (n=12) or Serophene 100 mg/day (n=16). All patients received 75 IU of recombinant follicle stimulating hormone (rFSH) starting on day 7 on stimulation until the day of hCG administration. Ovulation was triggered with recombinant hCG (250 mcg) when the leading follicle(s) reached 18 mm in diameter. A single IUI was performed 36 hours thereafter using a soft-pass insemination catheter (Cook™, Indiana, USA) in a 500 μL volume following wash/centrifugation in isolate medium. Only patients with over a 1-year unexplained infertility were included. Tubal patency was confirmed with hysterosalpingography and pelvis normality ascertained by laparoscopy. Couples with abnormal semen parameters were excluded from the study. There were no differences in demographic characteristics between groups. A very significantly lower peak serum estradiol level was observed in the group receiving letrozole + rFSH compared with Serophene + rFSH (914 ± 187 vs 1207 ± 309 pg/mL, respectively, P< 0.007). There was no differences in number of follicles (range of 1–5) There was no difference in endometrial thickness at the time of hCG administration among groups. The clinical pregnancy rate was similar between groups (23.2% vs 22.1% respectively). Inhibitors of aromatase appear to constitute a good alternative to clomiphene citrate in patients with unexplained infertility undergoing gonadotropin-stimulated COH cycles combined with IUI therapy.

Letrozole efficacy is related to human aromatase CYP19 single nucleotide polymorphisms (SNPs) in metastatic breast cancer patients

507 Background: We have previously reported a prospective cohort study of patients with ER+ and/or PR+ metastatic breast cancer treated with the aromatase inhibitor letrozole (SABCS 2001), in which the efficacy of letrozole, measured with time to treatment progression (TTP), correlated with the levels of circulating HER2 ECD. We have now evaluated in tumor tissue samples whether SNPs of the CYP19 aromatase gene had a predictive value. CYP19 is located on chromosome 15q and encodes a steroid aromatase that catalyzes the conversion of C19 androgens to estrogens. Methods: PCR allelic discrimination (ABI prism 7700 sequence detector) was used to examine SNPs in DNA obtained from 67 breast cancer patients accrued from 04/1999 to 11/2000. Two regions of the aromatase CYP19 gene were examined, one localized in the 3' untranslated region (UTR) and one in the intronic region. Presence of wild-type gene (WT) or SNPs was recorded. All patients in the study had documented disease progression and had been treated previously with a SERM. Sixty-five patients are evaluable for efficacy. Results: Median age was 62 years, median number of metastatic sites was 2. Percentage of cases with SNP variation of CYP19 UTR was 46% and of CYP19 intronic region was 63%, respectively. Time to treatment progression was longer in patients with SNPs of CYP19 UTR when compared with CYP19 UTR WT (525 vs. 196 days, p=0.02). This relationship was not observed for CYP19 intronic region (459 vs 510 days, p=0.9). Conclusions: In hormone receptor-positive metastatic breast cancer patients treated with the aromatase inhibitor letrozole, the presence of single nucleotide polymorphisms on the 3'UTR of the CYP19 aromatase gene is associated with improved treatment efficacy, and may help in selecting patients for letrozole therapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis