Radiation Oncology/Breast/Breast hormonal therapy

Drugs

SERMs (selective estrogen receptor modulators)

• tamoxifen
• Raloxifene

Aromatase inhibitors:

• anastrozole (Arimidex)
• exemestane (Aromasin)
• letrozole (Femara)

Others:

• fulvestrant - unique mechanism of action, binds to ER creating a complex that is destroyed by the cell.

Classification

Tamoxifen

• NSABP B-14, (1982-88) - Tamoxifen for ER-positive tumors
  • 2818 pts. LN negative, ER-positive, any type of surgery, randomized to placebo or tamoxifen 10 mg BID x 5 years. Tamoxifen given concurrently with XRT. Type of surgery: total mastectomy 62%, lumpectomy + RT 38%.
  • Modifications: From 1987-94, a 2nd randomization (643 pts) for those who completed 5 yrs of tamoxifen were randomized to 5 additional years of tamoxifen vs placebo. Also, in 1988, 1211 pts were registered (but not randomized) to tamoxifen x 5 yrs. Those who were event free were randomized (1992-94) to an additional 5 yrs or not.
  • First report, 1989: PMID 2644532, 1989 — "A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors." Fisher B et al. N Engl J Med. 1989 Feb 23;320(8):479-84.
    • 2644 pts. DFS 83% (T) vs 77% (placebo) at 4 yrs. 26% reduction in failures. Reduced both local and distant failure. Decreased ipsilateral breast recurrence. No statistical difference in OS.
  • 1992 - PMID 1627417 — "Systemic therapy in node-negative patients: updated findings from NSABP clinical trials. National Surgical Adjuvant Breast and Bowel Project." J Natl Cancer Inst Monogr. 1992;(11):105-16. (This paper includes B-13 and B-14)
    • 44% reduction in DFS (81% vs 66%) for those 49 or younger and 31% reduction (82% vs 74%) for 50 yrs or older.
  • Endometrial cancer risk; 1994 PMID 8133536 -- "Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14." (Fisher B, J Natl Cancer Inst. 1994 Apr 6;86(7):527-37.)
  • 1996 - PMID 8901851 Full Text — "Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors." Fisher B et al. J Natl Cancer Inst. 1996 Nov 6;88(21):1529-42. 10 yrs f/u.
    • Tamoxifen vs placebo: DFS 69% vs 57% (RR=0.66), DDFS 76% vs 67% (RR=0.70), and OS 80% vs 76% (RR=0.84), all S.S, for both age <49 and >= 50. 37% reduction in contralateral breast cancer.
    • For 5-years vs 10-years: improved DFS and DDFS for 5-years. Thromboembolic events in 1.7%.
      • Conclusion: Benefit persists through 10 years of follow-up. No advantage to continuing tamoxifen beyond 5 yrs.
  • 2001 - PMID 11333290 — "Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial." Fisher B et al. J Natl Cancer Inst. 2001 May 2;93(9):684-90.
    • No additional benefit with more than 5 years of tamoxifen

• Stockholm Breast Cancer Group

• Scottish Cancer Trial
  • Found benefit for TAM regardless of ER status.

• Nolvadex Trial Organization (England)
  • Found benefit for TAM regardless of ER status.

• Early Breast Cancer Trialists' Collaborative Group (a.k.a. Oxford overview)

  See also: Oxford overview of Radiotherapy or Chemotherapy

  • 1998: PMID 9605801 — "Tamoxifen for early breast cancer: an overview of the randomised trials." Lancet. 1998 May 16;351(9114):1451-67.
    • Meta-analysis. 37,000 women in 55 trials of adjuvant tamoxifen. 8,000 had a low or negative ER level and had little benefit. 18K had ER+ and 12K had unknown ER status. With 5 years of tamoxifen, reduction of: 47% in recurrence, 26% in deaths, 47% in contralateral breast cancer. Less of an effect for fewer than 5 years. Quadrupled risk of endometrial cancer (but absolute risk was only 1/2 of the reduction in contralateral breast cancer). For node-positive, absolute survival at 10 years was 61.4% vs 50.5% (10.9% gain) and for node-negative 78.9% vs 73.3% (5.6%).
  • 2005: PMID 15894097 — "Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials." Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet. 2005 May 14-20;365(9472):1687-717.

Summaries

• Fisher, 2004 - PMID 15351193 — "Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials." Fisher B et al. Lancet. 2004 Sep 4;364(9437):858-68.
  • B-14 + B-20

Radiation with tamoxifen

• NSABP B-21, 2002 (1989-98) - Node negative <1 cm tumors - randomized to tamoxifen alone, RT alone, or tamoxifen + RT
  • 1009 women. Lumpectomy + AND. ER/PR status not required but was available for 70%
  • PMID 12377957 — "Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less." Fisher B et al. J Clin Oncol. 2002 Oct 15;20(20):4141-9.
    • At 8 years, ipsilateral breast recurrence in 16.5% (TAM), 9.3% (XRT), 2.8% (T/RT). (That is, about 0.5% / year for T/RT). No difference in DM. Contralateral breast cancers in 5.4% (XRT without TAM) vs 2.2% (TAM +/- RT). XRT alone group had fewer IBTR than the TAM group for both ER+ and ER-. In ER+ tumors, adding TAM to RT resulted in a N.S. lower rate of IBTR. Adding RT to TAM resulted in a lower IBTR rate for both ER+ and ER-.
    • Risk of IBTR: XRT alone vs TAM alone: 49% reduction with XRT. XRT + TAM vs XRT alone: 63% reduction. XRT + TAM vs TAM alone: 81% reduction.

Sequencing

In vitro studies showed that breast tumor cells are less sensitive to radiation in the presence of tamoxifen. This is believed to be due to the fact that tamoxifen is cytostatic and thus places the cells in a radioresistant part of the cell cycle. Clinical studies showed that chemotherapy + tamoxifen was less effective, and this was extrapolated to radiation.

One randomized study and two retrospective studies.

Retrospective studies:
All 3 studies show no difference in any survival parameters.

• Yale-New Haven, 2005 (1976-99) - PMID 15545666 — "Sequence of radiotherapy with tamoxifen in conservatively managed breast cancer does not affect local relapse rates." Ahn PH et al. J Clin Oncol. 2005 Jan 1;23(1):17-23.
  • Retrospective. Stage I-II invasive breast cancer treated with breast conserving therapy + tamoxifen. 254 pts concurrent RT+TAM, 241 RT followed by TAM. Median f/u 10.4 yrs. No difference in OS, DM, LR. However, pt groups unbalanced--younger pts (58 vs 62 yrs) and more pts given chemo (38% vs 14%) in sequential group.

• Univ. of Pennsylvania, 2005 (1980-95) - PMID 15545665 — "Impact of concurrent versus sequential tamoxifen with radiation therapy in early-stage breast cancer patients undergoing breast conservation treatment." Harris EE et al. J Clin Oncol. 2005 Jan 1;23(1):11-6.
  • 278 pts. Stage I-II, BCT + TAM. 174 concurrent, 104 sequential. Median f/u 8.6 yrs. No difference. However, younger pts (51 vs 59 yrs) and more chemo (63% vs 25%) in sequential group.

Randomised study:

• Pierce, SWOG 8897 / Intergroup 0102, 2005 (1989-93) - PMID 15545669 — "Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer." Pierce LJ et al. J Clin Oncol. 2005 Jan 1;23(1):24-9.
  • Following BCS, patients were randomised to Arm A [107 pts to RT->Chemo->then TAM] and Arm B [202 to chemo then concurrent RT/TAM]. About 50% had hormone receptor negative tumors. Median follow-up of 10.3 years. No difference in OS, DFS, LF, RF, DF.

Chemotherapy with tamoxifen

• NSABP B-09 (1977-80) - Combination chemotherapy PF (L-PAM + 5-FU) +/- tamoxifen
  • 1891 pts. Combination chemotherapy (L-PAM + 5-FU) +/- tamoxifen
  • PMID 2856857, 1986 — "Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial." Fisher B et al. J Clin Oncol. 1986 Apr;4(4):459-71.
    • Mean f/u 72 months. For those 50 or older with 4 or more LN, improved DFS and OS. No benefit in DFS or OS for age < 50.
  • Comment: Was the study that showed that pts who respond to tamoxifen are those who are: 1) age 50-59 with PgR (progesterone receptor) > 10 fmol/mg; 2) age 60 or more with any PgR status.

• NSABP B-16 (1984-89) - Chemo/Tamoxifen vs Tamoxifen alone.
  • 1124 pts. Node-positive, ER+.
  • PMID 2189950, 1990 — "Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16." Fisher B et al. J Clin Oncol. 1990 Jun;8(6):1005-18.
    • 3-years median f/u. Improved DFS for combination therapy vs tamoxifen alone.

• NSABP B-20
  • chemotherapy + tamoxifen vs tamoxifen alone
  • See page at Breast chemotherapy

• NSABP B-23 (1991-98) - Node-negative, ER-negative. Two-by-two randomization: CMF chemo, CMF + tamoxifen, AC chemo, AC + tamoxifen.
  • Purpose: to determine the effect of tamoxifen in ER-negative, node-negative tumors and evaluate the effect of AC vs CMF in this population.
  • PMID 11181655 (2001) — "Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23." Fisher B et al. J Clin Oncol. 2001 Feb 15;19(4):931-42.
  • CMF x 6 cycles monthly. AC x 4 cycles. Tamoxifen 5 years.
  • No differences between AC and CMF nor any between chemotherapy and chemotherapy+tamoxifen.

• International Breast Cancer Study Group IBCSG 13-93 (1993-99)
  • PMID 16505417, 2006 — "Tamoxifen After Adjuvant Chemotherapy for Premenopausal Women With Lymph Node-Positive Breast Cancer: International Breast Cancer Study Group Trial 13-93." Colleoni M et al [International Breast Cancer Study Group]. J Clin Oncol. 2006 Mar 20;24(9):1332-41.
  • Randomized. 1246 pts, premenopausal, node-positive. EC or AC chemo followed by CMF followed by tamoxifen or no hormonal therapy. 59% were ER+.
  • Tam improved DFS for ER+ but not ER-. HR = 0.59 for ER+. In ER-absent (0% staining) pts, Tamoxifen was detrimental with HR=2.10.
  • Conclusion: Tamoxifen improves DFS in ER+ pts after chemotherapy.

Sequencing

• Breast Cancer Intergroup 0100 - Abstract PMID 20004966 Full Text(2009); "Adjuvant chemo-hormonal therapy for primary breast cancer should be sequential instead of concurrent: Initial results from Intergroup trial 0100." Albain K et al. Proc Am Soc Clin Oncol 2002; 21:37a. Abstract #143. &mdash
  • 1477 pts, node-positive, hormone receptor positive. Randomized to 1) TAM alone, 2) CAF followed by TAM, or 3) CAF + TAM concurrently.
  • Median f/u 8.5 yrs. DFS 67% (sequential) vs 62% (concurrent), S.S.
  • Conclusion: antagonism between tamoxifen and chemotherapy. Treatment should be sequential not concurrent.

Aromatase inhibitors

Introduction: Aromatase converts androgens (androstenedione and testosterone) to estrogens--estrone and estradiol. In post-menopausal women, estrogen synthesis takes place in muscle, skin, fat, and breast by aromatase, leading to low levels of estrogen.

Aromatase inhibitors produce a near-total blockade of aromatase activity and lead to an estrogen level of 1-10% of its pretreatment level. Aromatase inhibitors have been ineffective in pre-menopausal women because of higher levels or ovarian aromatase. Commercially available aromatase inhibitors:

• non-steroidals — anastrozole (Arimidex), letrozole (Femara)
• steroidal — exemestane (Aromasin)

Trials:

• ARNO 95 (1996-2002)
  • Randomized. 979 patients, postmenopausal, pT1-3N0-2. Treated with Tamoxifen x2 years, then randomized to Arimidex x3 years vs. Tamoxifen x 3 yrs
  • 3-years, 2007 PMID 17563395 -- "Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study." (Kaufmann M, J Clin Oncol. 2007 Jul 1;25(19):2664-70.) Median F/U 2.5 years after randomization (which was after 2 years of TAM)
    • 3-year outcome: OS benefit (HR 0.53, SS); DFS anastrozole 93% vs. tamoxifen 89% (SS); contralateral incidence 1.4% vs. 1.0%
    • Toxicity: anastrozole 23% vs. tamoxifen 31% (SS), mainly due to fewer endometrial events
    • Conclusion: After 2 years of tamoxifen, switch to Arimidex better
    • JCO Editorial: PMID 17563391

• ATAC Trial (1996-2000) - Arimidex, Tamoxifen Alone or in Combination
  • First results (2002): Abstract Full text — Baum et al. "Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial." Lancet. 2002 Jun 22;359(9324):2131-9.
    • 9366 post-menopausal pts (3125 randomized to anastrozole, 3116 to tamoxifen, 3125 to combination). Treatment for 5 years. Arimidex 1 mg qd; tamoxifen 20 mg qd. Started within 8 weeks after finishing chemotherapy, but could start during XRT. Median F/U 33 months. 84% were hormone receptor positive, 8% negative, 8% unknown. 47% had mastectomy. 60% were N0.
    • At 3-years, DFS 89.4%(A) vs 87.4%(T) vs 87.2%(C). 2% absolute risk reduction. Comparing A vs T: 317 vs 379 events, HR=0.83. Comparing A vs C, HR=0.81. Combination not significantly different than A alone. Time to recurrence hazard ratio = 0.79. DFS improvement seen in hormone receptor positive patients but not receptor negative pts. Decreased rate of contralateral breast cancer 58%. Improved side effect profile (see below). No difference in ischemic heart disease. Further follow-up needed before reporting OS or DM.
    • Initial results showed that a new cancer had developed in 317 women in the Arimidex group (10%), 379 women in the tamoxifen group (12%), and 383 women in the group of women taking both drugs (12%). This means that the relative risk of recurrence for everyone in the study was 17% less for the women taking Arimidex as compared to the women taking tamoxifen. (This analysis included both hormone-receptor-positive and hormone-receptor-negative cancers.) After this publication, stopped randomization to the combination arm.
  • Update (2003): Abstract — Baum et al. "Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses." Cancer. 2003 Nov 1;98(9):1802-10.
  • Update (2004): The Lancet, Dec 2004. Early online publication (requires free registration) — Abstract presented at 27th Annual San Antonio Breast Cancer Symposium, December 2004, Abstract #1
  • 5-years (2005) PMID 15639680 -- "Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer." (Howell A, Lancet. 2005 Jan 1-7;365(9453):60-2.)
    • Median F/U 68 months. Improved DFS (HR=0.87), time to recurrence (HR=0.79), distant mets (HR=0.86), contralateral breast cancers (42% reduction). No difference in overall survival. Improved side effect profile for endometrial cancer (0.2 vs 0.8%), vaginal bleeding (5.4 vs 10.2%) or discharge (3.5 vs 13.23.5%), strokes (2.0 vs 2.8%), thromboembolic events (2.8 vs 4.5%), hot flashes (35.7 vs 40.9%), and need for hysterectomy (1.3 vs 5.1%)—but worse for joint symptoms (35.6 vs 29.4%) and fractures (11 vs 7.7%). Also, the rate of fractures increased approximately two-fold since first publication (for both drugs), showing the long-term effect of antiestrogen therapy or older population.
  • Subset analysis: arimidex more effective for ER+/PR- vs ER+/PR+
  • 9 yrs (2008): PMID 18083636 -- "Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial." (ATAC Trialists' Group, Lancet Oncol. 2008 Jan;9(1):45-53.) -- Median f/u 8.3 yrs
    • Hazard ratios: DFS 0.85, TTR 0.76, TTDR 0.84, CLBC 0.60 -- all S.S. 9-yr TTR 17.0% (A) vs 21.8% (T). No difference in deaths after recurrence or in overall survival.
    • Fractures increased (ratio 1.55; 2.93% vs 1.90%) during active treatment but not after completing treatment. No difference in cardiovascular morbidity or mortality.
    • Conclusion: The efficacy and tolerability of Arimidex persist with long follow-up

• Breast International Group BIG 1-98 (1998-2003) - 5 years of letrozole vs tamoxifen
  • Double-blind. 8010 pts total. Postmenopausal women with ER+ or PR+ tumors. Randomized to: 1) letrozole x 5 yrs, 2) tamoxifen x 5 yrs, 3) L x 2yrs -> T x 3 yrs, 4) T x 2 yrs -> L x 3 yrs. 1835 pts randomized to arms 1 or 2 (1998-2000). Additional 6193 pts randomized to one of the 4 arms (1999-2003).
  • PMID 16382061, 2005 — "A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer." Thurlimann B et al. [The Breast International Group (BIG) 1-98 Collaborative Group] N Engl J Med. 2005 Dec 29;353(26):2747-57.
    • Median f/u 28.5 mo. 5-yr DFS 84% (Letrozole) vs 81.4% (Tamoxifen). HR for DFS 0.81. HR for distant recurrence 0.73.
  • Update (2007): PMID 17200148 — "Five Years of Letrozole Compared With Tamoxifen As Initial Adjuvant Therapy for Postmenopausal Women With Endocrine-Responsive Early Breast Cancer: Update of Study BIG 1-98." Coates AS et al. J Clin Oncol. 2007 Feb 10;25(5):486-92.
    • Analysis limited to 4922 pts randomized to continuous therapy with letrozole or tamoxifen (arms 1 & 2). Median f/u 51 mo. 18% reduction in DFS events for women taking letrozole.
  • Update 2011, PMID 22018631 -- "Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up." (Regan MM, Lancet Oncol. 2011 Oct 20. [Epub ahead of print])
    • Median f/u 8 yrs. No significant differences in DFS,OS,DRFI,or BCFI for any of the sequential treatment arms (L x 2 -> T x 3, or T x 2 -> L x 3) vs Letrozole alone. Letrozole was superior to tamoxifen alone.
    • Conclusion: "For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability."
  • Conclusion: Benefit for letrozole

• Intergroup Exemestane Study IES - switch to exemestane after 2-3 years of tamoxifen.
  • 4724 pts. After 2-3 yrs of tamoxifen, randomized to continuing T or switching to exemestane (total duration 5 yrs).
  • Benefit for switching
  • ASCO 2006 Abstract LBA527 "First mature analysis of the Intergroup Exemestane Study." Coombes RC et al. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: LBA527.
    • Median f/u 58 mo. For ER+, 26% decrease in DFS events, 17% decrease in deaths (both S.S.). For tamoxifen, more thromboembolic events and serious gynecologic events; fewer fractures.

• ABCSG 8 - switch to Arimidex after 2-3 years of tamoxifen vs staying on tamox x 5 yrs

• MA17 - After 5 years of tamoxifen, randomized to 5 additional years of letrozole vs placebo
  • 5187 pts. median f/u 2.4 yrs. 4-year DFS 93% (L) vs 87% (P). Decreased incidence of LF, DM, or new contralateral primary: 2.9% vs 5.1%.
  • PMID 16145047; "Randomized Trial of Letrozole Following Tamoxifen as Extended Adjuvant Therapy in Receptor-Positive Breast Cancer: Updated Findings from NCIC CTG MA.17" Goss PE et al.
    • Median f/u 30 months. HR=0.58 for DFS and HR=0.6 for DDFS, in favor of letrozole. OS was the same in both arms. However, among LN+ pts, HR=0.61 for OS. Incidence of contralateral breast cancer was lower but was not statistically significant.
    • Conclusion: Letrozole after tamoxifen is well-tolerated and improves both disease-free and distant disease-free survival but not overall survival, except in node-positive patients.

• Italian Tamoxifen Anastrozole Trial
  • PMID 16009955 — "Switching to Anastrozole Versus Continued Tamoxifen Treatment of Early Breast Cancer: Preliminary Results of the Italian Tamoxifen Anastrozole Trial." Boccardo F et al. J Clin Oncol. 2005 Jul 11 [Epub ahead of print]
  • 448 pts, N+, ER+. After 2-3 years of Tam, randomize to continued Tam for total of 5 years vs switching to A.
  • Median f/u 36 months. HR=0.35 for DFS and HR=0.15 for local recurrence free survival, in favor of anastrozole. More adverse events in Anastrozole group.

Sequencing RT with Letrozole

• CO-HO-RT, France/Switzerland (2005-2007) -- concurrent vs sequential RT + letrozole
  • Randomized, Phase II. 150 postmenopausal women, early stage BCA, s/p BCT. Arm 1) concurrent RT and letrozole (starting 3 weeks prior to RT) vs Arm 2) sequential RT and letrozole (starting 3 weeks post RT). Whole breast RT 50/25, SCV/IM as necessary. Letrozole 2.5 mg QD x5 years
  • 2010 PMID 20138810 -- "Concurrent or sequential adjuvant letrozole and radiotherapy after conservative surgery for early-stage breast cancer (CO-HO-RT): a phase 2 randomised trial." (Azria D, Lancet Oncol. 2010 Mar;11(3):258-65. Epub 2010 Feb 6.) Median F/U 2.2 years
    • Acute toxicity: Skin Grade 2+ concurrent 41% vs sequential 41% (NS); Dermatitis Grade 3 in 5% vs 8%
    • Late toxicity: Fibrosis Grade 2+ in 3% vs 3% (NS)
    • Conclusion: Letrozole can be safely delivered concurrent with RT