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Evidence-based Breast Cancer Treatment Guidance - The State of the Art
Compiled by: Constantine Kaniklidis, medical researcher
[ Breast Cancer Watch is a member of the Evidencewatch portal of evidence-based medicine sites ]


Breast Cancer Watch is a unique service providing the latest best evidence-based guidance on state-of-the-art breast cancer therapies, annotated with critical commentaries, and clinical practice recommendations. Critical appraisal and systematic review is undertaken aggressively with major updates monthly, and at least weekly revisions for high-impact findings. The series addresses two problems: (1) the lack of any timely single-source evidence-based systematic review of breast cancer treatment research findings for both healthcare professionals and informed patients, and (2) the rapid aging of breast cancer guidelines issued on less timely schedules (e.g., NCCN, ASCO and other guidelines).       [updated: 12/07/07]



Suppression of Ovarian Function: Ovarian Ablation and Ovarian Suppression


New Findings on Premenopausal OS + AI Therapy [new: 6/20/07]

Arimidex-Zoladex Trial
Robert Carlson at Stanford and coresearchers recently presented further findings at ASCO 2007, after completion of accrual, from the Arimidex-Zoladex Trial, a phase II study evaluating a combination endocrine therapy regimen of ovarian suppression via the LHRH/GnRH agent goserelin (Zoladex), every 4 weeks subcutaneous (4qwk SQ), plus aromatase inhibitor (AI) therapy via anastrozole (Arimidex), 1mg./daily, in 32 endocrine-responsive (ER and/or PR positive) premenopausal women with measurable recurrent or metastatic breast cancer [Carlson RW, Shurman CM, Rivera C, et al. Goserelin plus anastrozole in the treatment of premenopausal hormone receptor positive, recurrent or metastatic breast cancer. J Clin Oncol. 2007 ASCO Annual Meeting Proceedings 45(18S Jun 20 suppl):1030].

This OS + AI regimen was highly active, resulting in 13% complete response (CR), 34% partial response (PR), and 34% stable disease of 6+ months (SD) in 11(34%), and a 72% clinical benefit, and with rapid, near-complete suppression of ovarian estrogen production even as earlier as one month, maintained at three and six months (a median reduction of estradiol levels from 75 pg/ml at baseline to 21 at 1 months, 19 at 3 months, and 15 at 6 months), and with one patient with a durable complete response at 5+ years. Treatment was highly tolerability, with only grade 1 - 2 toxicity, except a single grade 3 weight loss.

Breast Cancer Watch notes that in contrast to the official protocol schedule of goserelin every 3 months, the Arimidex-Zoladex trial uses a monthly schedule. This addresses the problem of ovary-level breakthrough (circulating) estrogen production observed with the 3-month schedule - namely, effective estrogen suppression within the first month or two, followed by a rise in a latter interval. And although it is unknown whether this is actually of clinical significance, as it is possible that aromatase inhibition targets intratumoral aromatase in which case complete estrogen production suppression in the ovaries may not be necessary for clinical benefit, nonetheless absent more definitive determination, the breakthrough estrogen is disconcerting to the clinician and could represent a treatment compromise. Therefore, the deployment of aromatase inhibitory therapy in a functionally premenopausal women needs robust suppression of ovarian function, something that every three month administration appears unable to reliably assure, and this dictates ovarian suppression via LHRH/GnRH agonists on a monthly basis.

The Future of the STP (SOFT, TEXT, PERCHE) Ovarian Suppression Trials - PERCHE Trial Closed [new: 6/20/07]

A suite of three trials - the STP Trials (SOFT, TEXT, PERCHE) - have been designed by the International Breast Cancer Study Group (IBCSG) to assess various aspects of ovarian suppression in endocrine-responsive premenopausal women:

  • SOFT (Suppression of Ovarian Function Trial) - assesses tamoxifen monotherapy to
    (1) ovarian (function) suppression (OS) + tamoxifen and (2) OS + exemestane (Aromasin);
  • TEXT (Tamoxifen and Exemestane Trial) - compares OS + tamoxifen to OS + exemestane (Aromasin);
  • PERCHE (Premenopausal Endocrine Responsive Chemotherapy Trial) - evaluates the necessity of adjutant chemotherapy for premenopausal women with endocrine responsive breast cancer who receive endocrine therapy in the form of either OS + tamoxifen or OS + exemestane (Aromasin).
On October 17, 2006, the STP Data and Safety Monitoring Committee (DSMC) recommended the closure of the PERCHE trial by the IBCSG, stating that there was no evidence that the trial would ever reach its target accrual. PERCHE opened for enrollment on August 4, 2003, with an accrual target of 1750, although it was not until June 1, 2004 that the first patient was randomized. The accrual goal for the study was 1750 patients (250 per year for 7 years with 2.4 years additional follow-up). Furthermore, although 46 centers had activated PERCHE, only 10 had accrued patients as of August 31, 2006, and a total of 26 patients accrued and randomized by October 17, 2006 when the STP DSMC met, with an average of 20 patients accrued annually. Based on this accrual history, the Committee noted that at the observed rate, the target accrual of 1750 patients would be reached by PERCHE in approximately 85 more years, somewhere around 2091 or later, despite the trial's protocol (as with SOFT and TEXT also) having been amended in October of 2005 to facilitate increased recruitment, and therefore that an answer to the research questions the PERCHE trial was designed to answer was unlikely to be forthcoming in realistic time. Upon this recommendation of the STP DSMC to the IBCSG, the STP Steering Committee and the IBCSG Foundation Council agreed to close PERCHE as of December 31, 2006.

Breast Cancer Watch notes in this connection that the SOFT trial was activated in August of 2003 with an accrual target of 3000. Our research shows that as of November 30, 2006 total accrued patients stands at 291 (and 334 as of Feb. 28, 2007)*, and so it would appear that accrual is proceeding at a rate of 153 patients annually, suggesting that the target accrual might require an additional 17+ years, out to around 2023. Applying similar considerations, it strikes Breast Cancer Watch as unlikely that the research questions SOFT was designed to addressed will remain open or sufficiently opaque out to this duration to fully justify trial continuation, and we would be unsurprised if the STP DSMC and IBSCG at some point reconsider whether on the balance the continuation of this trial is adequately and clearly compelling. It further strikes us that only the TEXT trial may escape potential closure given accrual velocity: this trial, also activated in August of 2003 with an accrual target of 1845, has accumulated 796 patients as of November 30, 2006 (and 929 as of Feb. 28, 2007), a rate of approximately 239 patients annually, in this case suggesting achievement of target accrual is approximately 4+ years, somewhere out to 2011.

* We have used figures and statistics provided by SAKK (Swiss Group for Clinical Cancer Research), an IBSCG and BIG partner, and from official IBSCG publications; latest data from SAKK Newsletter, March 29, 2007, Issue 2 - Accruals as of February 28, 2007).


Suppression of Ovarian Function
may be induced via

    (a) surgery (surgical ovarian ablation, via oophorectomy (OO)),
    (b) radiotherapy (irradiation ovarian ablation), or
    (c) ovarian suppression (OS) via LHRH/GnRH analogs

    [updated] Ovarian Suppression and LHRH/GnRH Agonists

    Suppression of ovarian function (SOF), sometimes also known as ovarian ablation/suppression (OA/OS), refers the induction of ovarian failure - namely, the reduction or elimination of estrogen production - without regard to technique used to accomplish that. The first adjuvant treatment for breast cancer studied in clinical trials involving premenopausal women was exactly this suppression of ovarian function. The term ovarian ablation typically refers specifically either to oophorectomy (surgical) or ovarian irradiation (radiotherapeutic). The term medical ovarian suppression indicates the use of certain agents to suppress estrogen production, the most widely used (see below) called LHRH (Luteinizing Hormone-Releasing Hormone) analogs like goserelin (Zoladex), leuprolide (Lupron), triptorelin (Trelstar), and buserelin (Suprefact).

  • However, medical ovarian suppression can also be a consequence - intended or not - of systemic cytotoxic chemotherapy which may result in primary ovarian failure. It is well established now that chemotherapy can unpredictably induces amenorrhea and ovarian failure as a side effect of toxicity on the ovaries in a drug-, dose-, and patient age-dependent fashion, and is called CRA (Chemotherapy-Related Amenorrhea). CRA on an average affects about 68% of women treated with CMF cyclophosphamide/methotrexate/5-fluorouracil) chemotherapy, where 10%–33% of such CMF treated women get CRA after a single cycle, 33%–81% after six cycles, and 61%–95% after 12 cycles (Prowell & Davidson, Oncologist (2004): What Is the Role of Ovarian Ablation in the Management of Primary and Metastatic Breast Cancer Today?). And even though such induced amenorrhea is seen most often with CMF chemotherapy, other regimens can and do produce it in lesser percentages. So it is known that the AC regimen (doxorubicin/cyclophosphamide) causes CRA in 43% of women (again in a dose- and age-dependent fashion). And we also know that the addition of a taxane (paclitaxel, docetaxel) to the regimen increases the likelihood of developing such chemotherapy-induced amenorrhea.

    El-Saghir et al. (Anticancer Drugs (2006): Combined ovarian ablation and aromatase inhibition as first-line therapy for hormone receptor-positive metastatic breast cancer in premenopausal women: report of three cases), noting that addition of aromatase inhibitors to LHRH analogs has been reported to significantly decrease circulating estrogens and produce tumor responses, treated three premenopausal patients with hormone receptor-positive MBC (metastatic breast cancer) with combined oophorectomy or ovarian irradiation and anastrozole (Arimidex), with patients remaining free of progression for between 3 and 5 years, with monthly zoledronic acid (Zometa) for 4 years producing sclerosis of vertebral body metastasis; they concluded that combined ovarian ablation and aromatase inhibition is a feasible treatment modality deserving more attention and further investigation in premenopausal MBC context.

    Beginning with the observation that patients with hormone receptor-positive tumors show a pathological complete response (pCR) less often than those with hormone receptor-negative tumors, Rosalba Torrisi and colleagues at the European Institute of Oncology (Breast (2006): Primary therapy with ECF in combination with a GnRH analog in premenopausal women with hormone receptor-positive T2–T4 breast cancer) explored whether the addition of endocrine therapies may improve the clinical benefits of primary therapies in such patients by testing the efficacy of continuous infusion ECF (epirubicin + cisplatin + fluorouracil regimen combined with a gonadotropin-releasing hormone (GnRH) analog in 36 premenopausal women with ER and/or PgR-positive breast cancer, observing clinical response (complete or partial) in 27 out of 36 patients, with a pCR observed in four patients, and with nine patients having stable disease and no progression, and concluding that the combination of ECF + OS (ovarian suppression via GnRH analog) is associated with a high response rate in the primary treatment of breast cancer.

    The ZIPP study (Zoladex In Pre-menopausal Patients) recently reported by Baum et al. (Eur J Cancer (2006): Adjuvant goserelin in pre-menopausal patients with early breast cancer: Results from the ZIPP study) study sought to determine whether addition of goserelin ‘Zoladex) and/or tamoxifen to adjuvant therapy (radiotherapy and/or chemotherapy), provided benefit to pre- or perimenopausal women with operable, early breast cancer, using a combined analysis of four randomised trials (RCTs) in a 2×2 factorial trial design, showing that TAM + OS (via goserelin) provided a significant benefit for event-free survival and overall survival, yielding a 20% reduction in risk of event and a 19% reduction in risk of death, and being more effective than standard therapy (radio and/or chemotherapy) alone in pre-menopausal women with early breast cancer (EBC), and with benefits seen in ER–positive and ER-negative patients, except ER-negative patients with prior chemotherapy, although greatest benefit may be for ER-positive patients.

    And in the Danish Breast Cancer Cooperative Group (DBCG) Trial 89B, the European research team of Bent Ejlertsen and colleagues (J Clin Oncol (2006): Similar Efficacy for Ovarian Ablation Compared With Cyclophosphamide, Methotrexate, and Fluorouracil: From a Randomized Comparison of Premenopausal Patients With Node-Positive, Hormone Receptor–Positive Breast Cancer) conducted an open, randomized, multicenter trial of premenopausal breast cancer patients with hormone receptor–positive tumors and either axillary lymph node metastases or tumors with a size of 5 cm or more, with patients randomly assigned to ovarian ablation (OA) by irradiation or to nine courses of chemotherapy with intravenous CMF administered every 3 weeks, finding that ablation of ovarian function in premenopausal women with hormone receptor–positive breast cancer had a similar effect to CMF on disease-free survival (DFS) and overall survival (OS).

    With reference to the DBCG Trial, in the accompanying editorial by Antonio Wolff and Nancy Davidson (J Clin Oncol (2006): Still Waiting After 110 Years: The Optimal Use of Ovarian Ablation As Adjuvant Therapy for Breast Cancer) of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, the authors note:

"By the 1960s, many considered OA to be an effective adjuvant modality in breast cancer, but interest subsided with the demonstration of the efficacy of adjuvant chemotherapy and the belief that OA failed to alter survival in premenopausal women. This view was challenged by the serial reports of the Early Breast Cancer Trialists' Collaborative Group showing that OA or ovarian suppression (OS) offered an unequivocal survival benefit compared with no therapy for women under 50 years of age . . . This study joins four other published studies comparing OA/OS by surgery, goserelin, or leuprolide with variations of CMF that have shown similar results for women with hormone-responsive disease".

And the authors conclude with a plea that the exploration of the optimal use and benefits of ovarian suppression / ablation not be further delayed in history:

"It is both exhilarating and sobering to compare the pace of clinical development of two different strategies of estrogen-deprivation therapy, OA/OS for premenopausal women and aromatase inhibitors for postmenopausal women. In the latter case, improvements in our understanding of breast cancer biology, use of more sophisticated trial design, and freedom from bias about the value of chemotherapy led to a rapid and ongoing evaluation of the rightful role for aromatase inhibitors. In the former case, our failure to capitalize optimally on Dr Beatson's observations was hampered by our inability to recognize OA/OS as the first targeted therapy, the use of primitive trial designs by modern standards, and fundamental misconceptions about the effectiveness of endocrine therapy in premenopausal women. With the advantage of hindsight, let us hope that it will not take another 100+ years to right these errors and that these lessons will inform our evaluation of biologically based therapy in the future".



Chemotherapy-induced Premature Menopause / Amenorrhea
There is some evidence that giving the LHRH analog goserelin before and during chemotherapy may prevent premature menopause in the majority of patients, although the success rate is sensitive to age, with the highest success associated with women under 40 years of age (Del Mastro et al. Ann Oncol (2005): Prevention of chemotherapy-induced menopause by temporary ovarian suppression with goserelin in young, early breast cancer patients), and Cheer et al. (Drugs (2005): Goserelin: A Review of its Use in the Treatment of Early Breast Cancer in Premenopausal and Perimenopausal Women) similarly found that the addition of goserelin to adjuvant chemotherapy appeared to offer an advantage over chemotherapy alone in younger patients, as fewer patients remained amenorrheic after goserelin therapy than after chemotherapy, a valuable benefit for women wishing to regain ovarian function after treatment.

Luteinizing hormone-releasing hormone (LHRH) analogs offer an alternative form of ovarian estrogen suppression for premenopausal women, producing reliable, targeted suppression of ovarian estrogen production which is potentially reversible on therapy cessation, thus avoiding the long-term morbidity commonly associated with permanent ovarian suppression. Goserelin (Zoladex) - also referred to as a gonadotropin-releasing hormone agonist - is the most widely used LHRH treatment. Early clinical trials have shown goserelin to be effective for the treatment of advanced breast cancer in premenopausal patients, exhibiting a response rate similar to that of surgical oophorectomy or ovarian irradiation (Taylor et al., J Clin Oncol (1998): Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study).

Similarly, the recent IBCSG findings (International Breast Cancer Study Group, J Natl Cancer Inst (2003): Adjuvant Chemotherapy Followed by Goserelin Versus Either Modality Alone for Premenopausal Lymph Node–Negative Breast Cancer: A Randomized Trial) found that for patients with ER-positive disease, chemotherapy alone and goserelin alone provided similar outcomes, while for patients with ER-negative tumors, CMF achieved better disease-free survival); a possible exception was noted for those women under 39 years of age where the combination of chemotherapy followed by goserelin resulted in superior disease-free survival.


that "the combination of an LHRH/GnRH analog and tamoxifen may be superior to endocrine monotherapy in premenopausal HR+ women with advanced breast cancer".

[updated] Reviewing the same four randomized trials (the three above of Boccardo (1994), Jonat (1995), Klijn (2000), along with Klijn (1996) [Klign et al, Eur J Cancer (1996): Combined estrogen suppression and receptor (ER) blockade by buserelin (LHRH-A) and tamoxifen (TAM) in premenopausal metastatic breast cancer: Preliminary results of a 3-arm randomized study (EORTC 10881)]), as analyzed in the meta-analysis of Klijn (2001) above, Kathleen Pritchard of the Toronto Sunnybrook Regional Cancer Centre, although noting that there are some questions to be considered in the interpretation of these data, goes on to conclude that "Nonetheless, the available data suggest that the use of an LHRH agonist plus tamoxifen could result in an improved clinical outcome, in comparison to the use of an LHRH agonist alone followed by tamoxifen, in the premenopausal metastatic setting" (K Pritchard, Translating Advances in hormonal therapies for breast cancer into clinical practice [A continuing education monograph for oncology professionals, Meniscus/Novartis (2006)]: Management of Hormone Receptor–Positive Advanced Breast Cancer [pdf]).

Finally, the guidelines of the St Gallen's Consensus (Goldhirsch et a;, Ann Oncol (2005): Meeting Highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005) concluded that that TAM + OS (tamoxifen plus ovarian suppression) may be accepted as reasonable for very young patients, especially in intermediate- and high-risk groups, and for premenopausal patients of any age at high risk (especially if chemotherapy did not itself induce ovarian failure).




  • [updated] OS (Ovarian Suppression via LHRH/GnRH) + AI (Aromatase Inhibitor)

    In addition to the ADAGIO trial discussed above combining goserelin (Zoladex) + exemestane (Aromasin), Forward et al. (Br J Cancer (2004): Clinical and endocrine data for goserelin plus anastrozole as second-line endocrine therapy for premenopausal advanced breast cancer) examined premenopausal women with metastatic or locally advanced primary breast cancer treated as second line endocrine therapy with a combination of the LHRH agonist goserelin and the aromatase inhibitor anastrozole (Arimidex), finding the LHRH + AI combination to yield significant clinical response of worthwhile duration, with demonstrable endocrine changes, therefore offering another therapeutic option for the premenopausal MBC setting.

    And the Nottingham team of Cheung et al. (J Clin Oncol, ASCO Annual Meeting (2005): Goserelin plus anastrozole as first-line endocrine therapy for premenopausal women with oestrogen receptor (ER) positive advanced breast cancer (ABC)) studied OS + AI in the form of ovarian suppression (via goserelin) + anastrozole in the first-line endocrine therapy setting for premenopausal women, finding that the OS + AI regimen yielded significant clinical benefit with long duration (20+ months) in a significant proportion of premenopausal women (60%) with ER+ ABC (advanced breast cancer), extending their previously reported findings on the use of the same OS + AI regimen as second-line endocrine therapy for premenopausal women with ER+ ABC (Cheung et al., J Clin Oncol, ASCO Annual Meeting (2004): Primary endocrine therapy with anastrozole for early operable primary breast cancer in the elderly: Early clinical and biological data).

    In addition, Jannuzzo (J Clin Oncol, ASCO Annual Meeting (2004): Estrogen suppression of 8-week treatment with exemestane combined with triptorelin versus triptorelin alone in healthy premenopausal women) observed that OS (via + triptorelin (Trelstar) + AI (as exemestane (Aromasin)) induced greater estrogen suppression in premenopausal subjects compared to those on OS alone, with equivalent tolerability.

    The Italian research team of Francesco Recchia and colleagues (Cancer (2005): Gonadotropin-releasing hormone analogues added to adjuvant chemotherapy protect ovarian function and improve clinical outcomes in young women with early breast carcinoma) examined women who were high-risk with early breast carcinoma (EBC) (Stage II and Stage III, both ER+ and ER-) and who received a gonadotropin-releasing hormone (GnRH/LHRH) analog as ovarian protection during adjuvant chemotherapy (varying over CMF, anthracycline-based regimens, high-dose chemotherapy with autologous peripheral blood progenitor cell transplantation, and a taxane in cases of HER2+). During ovarian suppression therapy via GnRH analog, serum estradiol suppressed to values < 40 pg/mL for all patients, and patients remaining ER + after chemotherapy received an aromatase inhibitor (AI). The projected recurrence-free survival (RFS) rates at 5 years and 10 years were 84% and 76%, respectively; and the projected overall survival rates at 5 years and 10 years were 96% and 91%, respectively, supporting the conclusion that that, in premenopausal women with early breast carcinoma (EBC), the addition of a GnRH/LHRH analog to adjuvant therapy and the temporary total estrogen suppression in patients with ER+ disease protected long-term ovarian function, and improved the expected clinical outcome.

    [new] Finally, another recent study was conducted by the Korean research team of Jong Ro (Ro et al., 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition): Aromatase inhibitors (AIs) with or without GnRH agonist as first-line hormone therapy in pre- and post-menopausal Korean women with metastatic breast cancer (MBC): Clinical outcomes in correlation with tumor ER/PR/HER2 status) from the National Cancer Center (NCC) who examined 111 pre- and post-menopausal patients on either letrozole or anastrozole as first-line AI endocrine therapy, with or without a LHRH/ GnRH agonist, for metastatic breast cancer (MBC) at NCC Hospital between Nov. 2001 and Aug. 2005. In this population, the combination of AI + LHRH/GnRH agonist was used whenever hormonal levels were not postmenopausal and significant clinical benefit (CB) was for all MBC patients with ER+/PR+/HER2- tumors regardless of ages or menopausal status; in addition, the investigators found (1) more CB with ER+/PR+ tumors vs. ER+/PR- tumors, (2) more CB with HER2- tumors vs. HER2+ tumors, and (3) HER2-positivity was associated with less CB / shorter TTP in ER+/PR+ tumors vs. having no influence on CB / TTP in ER+/PR- tumors.

    Thus we have to date experience of OS + AI in the deployments for premenopausal women of goserelin (Zoladex) combined with either exemestane (Aromasin) or anastrozole (Arimidex), across the spectrum of low-to-intermediate risk and from EBC (early breast cancer) through LABC (locally advanced breast cancer) and MBC (metastatic Breast cancer).

  • Preliminary Preview of the Arimidex-Zoladex Trial (Stanford)
    Unpublished interview (available in audio only) with Robert Carlson, Principal Investigator, Stanford University Medical Center:
    Estradiol Suppression for the Treatment of Metastatic Breast Cancer in Premenopausal Women
    (ClinicalTrials: A Phase II Trial of Arimidex Plus Zoladex in the Treatment of Hormone Receptor Positive, Metastatic Carcinoma of the Breast in Premenopausal Women):

    • "My expectation is that such a strategy is going to be highly effective. If you look at the studies that have looked at ovarian suppression and aromatase inhibition in metastatic premenopausal breast cancer with positive hormone receptors, like the trial that we are doing at Stanford with MD Anderson, the clinical benefit rate is very high, it's in the 80% range . . . It's a study designed for premenopausal women with hormone receptor positive measurable metastatic breast cancer who have not received prior aromatase inhibitor. It's a straight phase II trial, and we're seeing quite surprisingly high rates of clinical benefit and very long durations of disease control. Clinical benefit rate is about 75 - 80%, the time to progression is well beyond six months. One of our earlier patients that was enrolled in the trial is still in a clinical complete response at four and a half years. She had disease in bone and pleaura and lung and she actually presented with hypercalemia and was quite ill, had a performance status of probably 60 - 70% and declining. She is in her mid-forties. She got this therapy without chemotherapy . . . and she is now four and a half years down the road working full-time with long black hair; actually I saw her just recently, she swam 128 miles last month . . . Most of them tolerated it remarkably well; they do have hot flashes that improve with time, and of some interest - and I don't know exactly what to make of it - the arthralgia syndrome that we see with the aromatase inhibitors does not appear to be as frequent".
    (Breast Cancer Update, V 5, Issue 7 (2006): Ovarian suppression plus an aromatase inhibitor in premenopausal women [mp3]).

  • [new] OS + Trastuzumab (Herceptin) + TAM as Rescue Therapy
    Italian researchers Martoni and colleagues (Anticancer Res (2006): Trastuzumab plus estrogen suppression as salvage treatment in a case of liver failure due to metastatic breast cancer) present the case of a triple positive (ER+/PR+/HER2+) 45-year-old premenopausal woman with jaundice from extensive metastatic liver involvement of IDC (infiltrating ductal carcinoma) of the right breast, and with a high proliferative index (Ki-67 60%) who was treated with with trastuzumab (Herceptin) weekly (2 mg/kg, after loading dose of 4 mg/kg), along with an estrogen suppression regimen of ovarian suppression via the LHRH/GnRH agent leuprolide (Lupron) monthly (3.75 mg intramuscularly) plus daily tamoxifen (20 mg daily). patient presented a rapid and progressive improvement in her clinical conditions and in liver tests. Jaundice was resolved after 1.5 months, normal liver function tests and an objective partial response after 4 months, at which point paclitaxel (Taxol) (80 mg/m2 weekly) was added, yielding an objective remission of all the tumor masses after 10 months.

  • OS + AI for Male Breast Cancer
    Although tumors positive for estrogen and/or progesterone are more common in male patients with breast cancer than in their female counterparts, the precise role of aromatase inhibitors in male patients remains relatively unclear, with some preclinical data suggesting that AIs may be less effective in men. In human clinical studies (Nelly Mauras et al., J Clin Endocrinol Metab (2000): Estrogen Suppression in Males: Metabolic Effects) using healthy male volunteers, AIs decrease estradiol by 50% decrease in estradiol but with an increase in testosterone levels. Reasoning that the combination of OS (ovarian suppression) + AI could inhibit the feedback loop to the hypothalamus and pituitary glands to achieve superior estrogen suppression , Sharon Giardano and Garbriel Hortobagyi at MD Anderson Cancer Center (J Clin Oncol (2006): Leuprolide Acetate Plus Aromatase Inhibition for Male Breast Cancer) recently reported two cases of male patients treated with a combination of leuprolide acetate (Lupron) + AI via the aromatase inhibitors letrozole (Femara) or anastrozole (Arimidex), one of which had failed to respond to either agent as a single agent, and finding that the OS + AI combination halted disease progression, even with involved metastases to the lung, concluding therefore that this combination deserves further investigation. Related to this, OS + AI in the form of goserelin (Zoladex) + anastrozole (Arimidex) is currently in clinical trial under SWOG S0511 (Clinical Trials (2006): Goserelin and Anastrozole in Treating Men With Recurrent or Metastatic Breast Cancer), which evaluates the combination of anastrozole and goserelin in men with hormone-receptor–positive metastatic breast cancer; see also Sharon Giordano, Oncologist (2005): A Review of the Diagnosis and Management of Male Breast Cancer).


  • OS (Ovarian Suppression via LHRH/GnRH) + Trastuzumab (Herceptin) Anti-HER-2 Therapy
    Besides OS + endocrine therapy (tamoxifen / aromatase inhibitors / fulvestrant), few studies have explored the value of combining OS + biological therapies, but Italian researchers Martoni et al. (Anticancer Res (2006): Trastuzumab plus estrogen suppression as salvage treatment in a case of liver failure due to metastatic breast cancer) have recently described the case study of a premenopausal woman with ER+ /PR+ / HER2+ tumors and extensive metastatic liver, as well as lymph node and lung, involvement from IDC (infiltrating ductal carcinoma) and a high proliferative index, who was successfully treated with a combination H + TAM + OS + TAX regimen consisting of trastuzumab (at a loading dose of 4 mg/kg, followed by weekly doses of 2 mg/kg), tamoxifen (20 mg daily) and leuprolide (Lupron) (at 3.75 mg intramuscularly monthly), yielding rapid and progressive clinical improvement; normal liver function tests and an objective partial response was evident after 4 months, and after the addition of paclitaxel (Taxol) (80 mg/m2 weekly), objective remission of all the tumor masses has achieved at 10 months. From this, the authors concluded that trastuzumab plus ovarian suppression can be an effective salvage therapy in patients with liver failure due to metastatic HER2 and ER/PgR-positive breast cancer.


  • LHRH/GnRH in the EBC (Early Breast Cancer) Setting

    In addition to its documented use in MBC (metastatic breast cancer) settings, ovarian suppression via LHRH/GnRH analogs has also been found to be a valuable additional available option for treating pre- or perimenopausal women with hormone therapy-responsive early breast cancer (EBC), particularly for women wishing to recover ovarian function as fertility preservation upon termination of treatment (Cheer et al., Drugs (2005): Goserelin: A Review of its Use in the Treatment of Early Breast Cancer in Premenopausal and Perimenopausal Women), in keeping with the earlier results of Boccardo et al. in their Italian Breast Cancer Adjuvant Study Group 02 trial (J Clin Oncol (2000): Cyclophosphamide, Methotrexate, and Fluorouracil Versus Tamoxifen Plus Ovarian Suppression as Adjuvant Treatment of Estrogen Receptor–Positive Pre-/Perimenopausal Breast Cancer Patients: Results of the Italian Breast Cancer Adjuvant Study Group 02 Randomized Trial) who compared the efficacy of chemotherapy versus that tamoxifen (TAM) + OS (ovarian suppression) via goserelin (Zoladex) in premenopausal and perimenopausal ER+ patients with early breast cancer (EBC), who found the TAM + OS combination to be safe and to yield comparable results relative to standard CMF chemotherapy.

    These findings themselves were based on the early EBCTCG (Early Breast Cancer Trialists’ Collaborative Group) trials (Lancet (1996): Early Breast Cancer Trialists’ Collaborative Group: Ovarian ablation in early breast cancer: Overview of the randomized trials) and (Lancet (1998): Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials) where it was suggested that ovarian suppression or tamoxifen can achieve comparable efficacy results, especially in patients with ER+ tumors, leading to the hypothesis tested successfully by Boccardo in the Italian Breast Cancer Adjuvant Study Group 02 trial (cited above) that the combination of tamoxifen with some form of ovarian suppression is probably the best option for premenopausal women who are candidates for adjuvant endocrine therapy, where this option is expected to be more effective than either modality alone, and where in addition, the suppression of ovarian function could help to avoid the gynecologic changes secondary to the hyperstimulatory effects induced by tamoxifen monotherapy, while the weak estrogenic effects of tamoxifen could themselves help to overcome the harmful effects on bone density and blood lipids commonly induced by the suppression of ovarian function, and finally that since a significant decrease in contralateral breast primaries has also been demonstrated in women treated with goserelin. a synergistic effect with tamoxifen can be anticipated.

    The recent systematic review of Rohini Sharma and colleagues (Breast (2005): Systematic review of LHRH agonists for the adjuvant treatment of early breast cancer) identified three mature trials that demonstrated compellingly that adjuvant OS (ovarian suppression) using LHRH/GnRH agonists, with or without tamoxifen, had similar benefits at 5–6 years follow-up in terms of disease-free survival (DFS) and overall survival (OS) to the same outcome endpoints of adjuvant CMF chemotherapy.



  • Ovarian Ablation versus Chemotherapy

    The obvious clinical query arises here: should ovarian ablation be substituted for chemotherapy for patients with hormone receptor–positive disease who are candidates for CMF or adriamycin and cyclophosphamide (AC) chemotherapy? The clinician needs to discuss and elicit patient preference regarding typical side effects of chemotherapy versus those of premature menopause. Note however that there is no compelling data suggesting the efficacy of ovarian ablation over the newer regimens shown to be superior to CMF or AC (such as anthracycline-containing or taxane-containing regimens), and for this reason, ovarian ablation should not be recommended routinely to premenopausal patients who would otherwise be treatment candidates for such newer regimens (Pater & Parulekar, J Natl Cancer Inst (2003): Ovarian Ablation as Adjuvant Therapy for Premenopausal Women With Breast Cancer—Another Step Forward); see also Harrison et al., Endocr. Relat. Cancer (2004): Gonadotropin-releasing hormone and its receptor in normal and malignant cells), and especially Prowell & Davidson, Oncologist (2004): What Is the Role of Ovarian Ablation in the Management of Primary and Metastatic Breast Cancer Today?).

    Ovarian Suppression versus Chemotherapy

    On the matter of CMF versus OS (ovarian suppression) via the LHRH analog goserelin (Zoladex) in premenopausal non-metastatic breast cancer, the watershed study has been the international, multicenter, open randomized ZEBRA (Zoladex Early Breast Cancer Research Association) Trial (Jonat et al., J Clin Oncol (2002): Goserelin Versus Cyclophosphamide, Methotrexate, and Fluorouracil as Adjuvant Therapy in Premenopausal Patients With Node-Positive Breast Cancer: The Zoladex Early Breast Cancer Research Association Study). The central finding concerns the subgroup of patients with ER+ tumors, where goserelin was equivalent to the CMF regimen in terms of DFS (disease free survival); as expected, goserelin was inferior to CMF for DFS in ER-negative patients.

    Breast Cancer Watch     notes that this trial was also one of the first to show that the interplay of amenorrhea is more complex than often assumed: although amenorrhea occurred by 6 months in only 58.6% of CMF patients, it occurred in more than 95% of goserelin patients, yet menstruation returned in most of the goserelin patients after cessation of therapy, in contrast to amenorrhea being generally permanent in CMF patients.

    Roche and colleagues reporting for the French Adjuvant Study Group (FASG) (Ann Oncol (2006): Complete hormonal blockade versus epirubicin-based chemotherapy in premenopausal, one to three node-positive, and hormone-receptor positive, early breast cancer patients: 7-year follow-up results of French Adjuvant Study Group 06 randomised trial) sought to determine optimal adjuvant therapy between complete hormonal blockade induced via LHRH agonist triptorelin (Trelstar), 3.75 mg i.m., monthly, plus tamoxifen (30 mg/day for 3 years) in intermediate risk premenopausal patients with hormone receptor positive breast cancer and one to three positive nodes, compared against a FEC50 chemotherapy regimen (fluorouracil 500 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 21 days for six cycles); they found 7-year disease-free survival (DFS) to be 76% with TAM + OS (ovarian suppression via the LHRH agent triptorelin) versus 72% with FEC50 and 7-year overall survival (OS) to be 91% on TAM + OS versus 88% on FEC50, demonstrating that complete hormonal blockade via TAM + OS and chemotherapy provide similar outcomes.

    Extending the original research comparing OS (ovarian suppression) against the CMF chemotherapy regimen, Von Minchwitz et al. (Eur J Cancer (2006): CMF versus goserelin as adjuvant therapy for node-negative, hormone-receptor-positive breast cancer in premenopausal patients: A randomised trial (GABG trial IV-A-93)) randomized premenopausal patients with node-negative breast cancer to either three cycles of CMF chemotherapy or OS via goserelin (Zoladex) every 28 days for 2 years, finding comparable benefits on ipsilateral locoregional recurrence, contralateral breast cancer, distant failure and death without recurrence.


  • [new] The LHRH-Agonist Overview Group Meta-Analysis of Adjuvant Ovarian Suppression
    This has been further confirmed in the recently reported findings of the LHRH-Agonist Overview Group's meta-analysis of 13 randomized studies on adjuvant LHRH agonists in premenopausal patients with hormone receptor-positive breast cancer (LHRH-agonists in Early Breast Cancer Overview group, Cuzick J, Ambroisine L, Davidson N, et al. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet. 2007 May 19;369(9574):1711-23).  The LHRH-Agonist Overview Group meta-analysis found:

    (1) That in terms of women receiving an LHRH agonist versus no treatment, there was approximately a 30% reduction of recurrence and mortality.

    (2) In terms of LHRH agonist versus chemotherapy, where most of the chemotherapy was CMF, with some anthracycline-based regimens also evaluated, the evidence suggested the two modalities were essentially equally effective, and although it is commonly objected that the chemotherapy like CMF is representative of an older generation of agents, in fact, the investigators were unable to find any real difference between anthracycline-based and CMF-based chemotherapy; this suggests that in women with low-risk disease LHRH agonists can be a reasonable alternative to chemotherapy, but in women with higher-risk disease, many clinicians would maintain that chemotherapy followed by tamoxifen should continue as the standard approach, with the addition of an LHRH agonist a reasonable option for those who remain premenopausal, as observed in an accompanying editorial by Nicholas Wilcken and Martin Stockler at the University of Sydney.
     
    (3) One novel finding highlighted by the LHRH-Agonist Overview Group is the benefit of LHRH agonists after chemotherapy in premenopausal women younger than 40 years, but not in older premenopausal women, where in this group of younger than 40 women, chemotherapy is known to be less likely to induce permanent amenorrhea than in older women, and it must also be remembered that with modern non-CMF chemotherapy permanent amenorrhea occurs far less often.

    (4) This leaves open the important question whether the addition of an LHRH agonist is clinical benefit only when amenorrhea is not induced by chemotherapy, given that some previous trials found worse outcomes after chemotherapy in such non-amenorrheic women, suggesting that this  would be the group who would benefit most from adding an LHRH agonist.

    (5) in terms of the addition of an LHRH agonist to either chemotherapy, tamoxifen, or both, there was a modest effect of 12.7% improvement in recurrence and 15.1% in mortality, and effect that held whether the LHRH agonist was added to tamoxifen, chemotherapy or both. 



  • Ovarian Suppression (OS) and Ablation (OA): Breast Cancer Watch Summary

    Role of Ovarian Suppression (OS) in Current Endocrine Therapy
    In their review of over 60+ seminal studies on ovarian suppression, Prowell & Davidson (Oncologist (2004): What Is the Role of Ovarian Ablation in the Management of Primary and Metastatic Breast Cancer Today?) put forward guidance on the role of OS in premenopausal endocrine (hormone)-responsive women: "For women who receive either agent alone, crossover to the alternate therapy should be considered at the time of progression, before introduction of chemotherapy, except in women who have rapidly progressive or visceral disease", in agreement with the earlier review of Kathleen Pritchard of the Sunnybrook Regional Cancer Centre (Cancer (2000): Current and future directions in medical therapy for breast carcinom Endocrine treatment).

  • Motivations for Ovarian Suppression

    • From our own systematic review, Breast Cancer Watch observes that part of the motivation for OS deployment in premenopausal women is the recognition of the differential devalued comparative prognosis (trend toward higher proliferation index and poorer differentiation, and associated inferior outcome, confirmed in many population-based studies and cancer registries) of the premenopausal context against the postmenopausal context, and hence the imperative to enhance outcome by inducing the more prognostically favorable postmenopausal state.

    A second motivation we observe is the expansion of clinical therapeutic options: premenopausal endocrine-responsive patients face a narrow range of options, given that it is indisputable that chemotherapy in this context is of deprecated value, leaving the best option of endocrine therapy; however, since aromatase inhibitors (AIs) are not available to premenopausal women regardless of receptor status, that leaves a menu of one choice, namely only tamoxifen as a viable therapeutic endocrine therapy, despite the fact of its well-established inferior efficacy to the class of AIs, so OS offers by virtue of an induced postmenopausal state, the full panoply of endocrine therapy options: tamoxifen, AIs, and fulvestrant (Faslodex).

    • Overall Survival Benefit of OS/OA
      A systematic review and meta-analysis of the EBCTCG trials has demonstrated that both ovarian suppression (OS) and ovarian ablation (OA, via surgical oophorectomy) produces in women <50 years old significantly longer survival, with an absolute (not relative) reduction of 9.8%, as well as a lower rate of breast carcinoma recurrence, significantly at an absolute reduction of 8.5%, both clinical benefits being independent of age and nodal status, and with greater benefit in women with ER+ tumors (review of Colozza et al., Oncologist (2006): Breast Cancer: Achievements in Adjuvant Systemic Therapies in the Pre-Genomic Era), and furthermore indirect comparisons finds the magnitude of benefit obtained from ovarian suppression (OS) is comparable to that derived from adjuvant chemotherapy or tamoxifen alone (Colozza review, cited above, and also priorly established by Rivkin et al., (J Clin Oncol (1996): Adjuvant CMFVP versus adjuvant CMFVP plus ovariectomy for premenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study)), in essential agreement with the results of the international trial of Andrea Eisen and colleagues (J Clin Oncol (2005): Breast Cancer Risk Following Bilateral Oophorectomy in BRCA1 and BRCA2 Mutation Carriers: An International Case-Control Study) that oophorectomy is associated with a significant reduction in breast cancer risk: a 56% breast cancer risk reduction for BRCA1 carriers and a 46% breast cancer risk reduction for BRCA2 carriers, with the risk reduction being greater if the oophorectomy was performed before age 40 than after age 40, and with the protective effect evident for 15 years post-oophorectomy.

    • OS/OA Survival Benefit in the BRCA1/BRCA2 Context
      In the special context of BRCA1/BRCA2-associated breast carcinoma, Deborah Schrag and colleagues at the Dana-Farber Cancer Institute (JAMA (2000): Life Expectancy Gains From Cancer Prevention Strategies for Women With Breast Cancer and BRCA1 or BRCA2 Mutations) used a sophisticated decision analysis model to estimate the magnitude of benefit of various defensive strategies, including ovarian ablation in the form of prophylactic oophorectomy (OO), finding that for a 30-year-old early-stage breast cancer patient with BRCA mutations, the gain in life expectancy from OO was comparable to or slightly greater than that conferred by five years of tamoxifen therapy (range of 0.2 to 1.8 years from OO compared to 0.4 to 1.3 years for tamoxifen (and note that since the benefit from PCM (prophylactic contralateral mastectomy) was higher still at 0.6 to 2.1 years, additive benefit of dual or multiple modalities can be anticipated).

      These findings have been recently updated by the invaluable simulated cohort modeling study of Victor Grann and colleagues at the Herbert Irving Comprehensive Cancer Center of Columbia University (J Clin Oncol (2002): Effect of Prevention Strategies on Survival and Quality-Adjusted Survival of Women With BRCA1/2 Mutations: An Updated Decision Analysis) who determined that for the same 30-year-old premenopausal patients, survival could be prolonged beyond that associated with surveillance alone by use of preventive measures: 1.8 years with tamoxifen (TAM), 2.6 years with prophylactic oophorectomy (OO), 4.6 years with both tamoxifen and prophylactic oophorectomy (TAM + OO), 3.5 years with prophylactic mastectomy (PCM), and 4.9 years with both surgeries (OO + PCM); furthermore, quality-adjusted survival could be prolonged by 2.8 years with TAM, 4.4 years with OO, 6.3 years with TAM + OO, and 2.6 years with PCM or with both surgeries (OO + PCM). (Benefits decrease with later age initiation).

      Notice that for overall survival prolongation, (1) TAM + OO was superior to TAM alone, (2) TAM + OO was superior to PCM (prophylactic contralateral mastectomy), and (3) TAM + OO was comparable in efficacy of prolongation of survival to the combined surgical interventions of OO + PCM, and even more tellingly, TAM + OO was far superior to all other interventions when considering quality-of-life patient preferences in the quality-adjusted survival metric, TAM + OO being more than twice that of TAM alone, and more than twice that of the combined surgeries (OO + PCM).

      And it should not be forgotten that ovarian ablation via prophylactic oophorectomy (OO) not only reduces the risk of breast cancer, but also of ovarian cancer (Rebbeck et al., J Natl Cancer Inst (1999): Breast Cancer Risk After Bilateral Prophylactic Oophorectomy in BRCA1 Mutation Carriers), confirmed additional by Lori Pierce et al. (J Clin Oncol (2006): Ten-Year Multi-Institutional Results of Breast-Conserving Surgery and Radiotherapy in BRCA1/2-Associated Stage I/II Breast Cancer) who found that the incidence of in-breast tumor recurrence in BRCA1/BRCA2 carriers who had undergone oophorectomy was not significantly different from that in sporadic controls.

      And OO is known to reduce the breast cancer penetrance in BRCA1 mutation carriers, as found by Joan Kramer and colleagues at NCI (J Clin Oncol (2005): Prophylactic Oophorectomy Reduces Breast Cancer Penetrance During Prospective, Long-Term Follow-Up of BRCA1 Mutation Carriers) who observed prophylactic oophorectomy (OO) is already established to reduce breast cancer risk by approximately 50% and therefore hypothesized that population differences in oophorectomy prevalence might significantly influence breast cancer penetrance estimates; they found in the affirmative: six of the 33 mutation-positive women who underwent oophorectomy during follow-up developed breast cancer, compared with over four times as many (27 of 65) developed in mutation carriers with intact ovaries, with estimates of absolute breast cancer risk demonstrating that the strong protective effect of oophorectomy was strongest among women who were premenopausal at the time of surgery.

      Finally, the landmark PROSE study (Timothy Rebbeck at the Abramson Cancer Center and colleagues, Effect of Short-Term Hormone Replacement Therapy on Breast Cancer Risk Reduction After Bilateral Prophylactic Oophorectomy in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group; see also the thoughtful commentary of Wendy Rubenstein at the Feinberg School of Medicine, Northwestern University in J Clin Oncol (2005): Surgical Management of BRCA1 and BRCA2 Carriers: Bitter Choices Slightly Sweetened who notes that the bitterness of bilateral prophylactic oophorectomy is somewhat lessened by knowing that the breast cancer risk reduction is not appreciably diminished by hormone replacement therapy (HRT)) has demonstrated that short-term hormone replacement therapy (HRT) use does not negate the protective effect of bilateral prophylactic oophorectomy (OO) on subsequent breast cancer risk in BRCA1/2 mutation carriers, allowing for HRT to combat the symptoms of surgically-induced menopause, and potentially reduce the long-term adverse health effects such as osteoporosis) while at the same time reducing the risk of ovarian and fallopian tube cancers to near negligible levels, along with at least a 37% risk reduction of breast cancer (as demonstrated priorly by Rebbeck et al., N En gl J Med (2002): Prophylactic Oophorectomy in Carriers of BRCA1 or BRCA2 Mutations).

    • Recurrence Risk Reduction for Young (<40) Women
      Of benefit only in premenopausal women, and in this population patients with ER+ tumors who are younger than 40 years of age,       ovarian suppression (OS) significantly decreases the risk of recurrence, although outside of this group OS after adjuvant chemotherapy appears not beneficial (Arriagada et al. Ann Oncol (2005): Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy).

    • Equi-efficacious with CMF, CAF and FEC(50) Chemotherapy
      As effective as CMF and the anthracycline-based CAF and FEC(50) chemotherapy regimens against ER+ tumors      .

    • Post-Chemotherapy Benefit if Menstruation Continues
      May provide further benefit after chemotherapy in
      premenopausal women who continue to menstruate.

    • OS + TAM > OS or TAM Alone
      The benefit of OS + TAM is greater than either modality alone (see our extensive discussion above under LHRH/GnRH + Tamoxifen).

    • Potential Direct Antiproliferative Activity
      May themselves exhibit direct anti-proliferative activity (see for example Guntherdt et al., Eur J Clin Endocrinol (2006): Analogs of GnRH-I and GnRH-II inhibit epidermal growth factor-induced signal transduction and resensitize resistant human breast cancer cells to 4OH-tamoxifen) on the direct anti-proliferative effects of the GnRH analog Triptorelin (Trelstar)).

    • OS + AI (Aromatase Inhibitor)
      Ovarian suppression is known to reduce estrogen production to postmenopausal levels, nonetheless does not inhibit peripheral tissue estrogen, and this provides a rationale for the co-administration of an aromatase inhibitor, as AIs are known to reduce peripheral estrogen production, allowing the combination to optimally reduce estrogen levels: this AI + OS regiment was shown to be of clinical value in the randomized, multicenter ADAGIO Trial (Pollow et al., J Clin Oncol (2004): Safety and tolerability of adjuvant exemestane plus goserelin with or without tibolone in receptor-positive, node-negative primary breast cancer in premenopausal women: The final results of the randomized multicenter ADAGIO pilot study) which added the steroidal aromatase inhibitor exemestane (Aromasin) to ovarian suppression via goserelin (Zoladex), finding the combination regimen of an AI + Z (Zoladex) not more toxic, nor decreased BMD (bone mineral density), than standard treatment with goserelin alone.

      The ADAGIO Trial novelly added tibolone (Livial) to help remedy climacteric (vasomotor menopausal) symptoms, including hot flashes and the pro-osteoporotic activity of AIs, finding that this supplementation (1) induced a trend toward less decrease of BMD in the tibolone arms of the trial, and (2) caused less increase in hot flashes and vaginal dryness in those patients on tibolone; the researchers concluded that the addition of tibolone reduces the severity of some of the climacteric symptoms due to treatment and also may reduce AI-induced bone loss. Breast Cancer Watch notes that tibolone (Livial), although available in over 70 countries including the UK, is not currently available in the US.

      And to this, we add the two studies from the Nottingham team of Cheung and colleagues (AI = anastrozole (Arimidex), the Jannuzzo Trelstar study (AI = exemestane (Aromasin)), the seminal Recchia EBC study, all cited and discussed above, so that we have to date experience of OS + AI in the deployments for premenopausal women of goserelin (Zoladex) combined with either exemestane (Aromasin) or anastrozole (Arimidex), across the spectrum of low-to-intermediate risk and from EBC (early breast cancer) through LABC (locally advanced breast cancer) and MBC (metastatic Breast cancer). In addition, the study of Jong Ro, cited above, in which the combination of AI + LHRH/GnRH agonist was used whenever hormonal levels were not postmenopausal, demonstrated significant clinical benefit (CB) of the AI + LHRH/GnRH combination for all MBC patients with ER+/PR+/HER2- tumors regardless of ages or menopausal status.

    • OS for Fertility Preservation
      Given that goserelin appears to produce comparable, and potentially superior, results in ER+ women relative to chemotherapy, ovarian suppression may be the preferred approach for women with ER+ disease for whom preservation of fertility is a prior ((Prowell & Davidson, Oncologist (2004): What Is the Role of Ovarian Ablation in the Management of Primary and Metastatic Breast Cancer Today?).


  • Guidance of the St Gallen's Consensus

    The guidelines of the St Gallen's Consensus (Goldhirsch et a;, Ann Oncol (2005): Meeting Highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005) with which Breast Cancer Watch is in essential agreement stipulated:

    (1) that tamoxifen plus ovarian suppression is accepted as reasonable for very young patients, especially in intermediate- and high-risk groups, and for premenopausal patients of any age at high risk, especially if chemotherapy did not itself induce ovarian failure;

    (2) that patients with tumors overexpressing HER2/neu may benefit if the entire period of tamoxifen were covered with a GnRH (LHRH) analog for ovarian suppression, in keeping with the conclusions of Love et al. (J Clin Oncol (2003): HER-2/neu Overexpression and Response to Oophorectomy Plus Tamoxifen Adjuvant Therapy in Estrogen Receptor-Positive Premenopausal Women With Operable Breast Cancer) who found that HER-2/neu overexpression does not adversely, and may favorably, influence response to adjuvant oophorectomy and tamoxifen treatment in patients with ER+ tumors;

    (3) that patients who received adjuvant tamoxifen when they were premenopausal for node positive, endocrine responsive disease, might consider later continuation of the adjuvant endocrine treatment with letrozole (Femara) upon the event that they become postmenopausal in the interim.
 

Copyright © 2006. Constantine Kaniklidis