At the same time, guidelines have not recommended this panel for this situation. Mammaprint is a test that purports to determine aggressiveness  of breast cancer. It is widely accepted in Europe and less so in the USA. More recently. TargetPrint is another iteration that purports to provides reliable, quantitative assessment of mRNA expression levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) and BluePrint similarly attempts to provide prognostic information. BluePrint, an 80-gene expression signature for the classification of breast cancer into Basal-type, Luminal-type and ERBB2-type.

Besides that these two latter tests still need to be fully validated, there is no literature support for the three together being more accurate or productive of more benefit than either one. Therefore, it would be important to perform definitive comparison of combinations of these assays.

References:

Nguyen, B., Sinha, R., Kerlin, D., Barone, J., Garcia, A., Yao, K., … & Deck, K. (2011). P3-04-06: Comparison of MammaPrint, BluePrint, and TargetPrint with Clinical Parameters in Patients with Breast Cancer: Findings from a Prospective United States Cohort. Cancer Research, 71(24 Supplement 3).

Nguyen, B., Cusumano, P. G., Deck, K., Kerlin, D., Garcia, A. A., Barone, J. L., … & Generali, D. (2012). Comparison of molecular subtyping with BluePrint, MammaPrint, and TargetPrint to local clinical subtyping in breast cancer patients. Annals of surgical oncology, 19(10), 3257-3263.

Daniel D. Von Hoff et al, Pilot Study Using Molecular Profiling of Patients’ Tumors to Find Potential Targets and Select Treatments for Their Refractory Cancers JCO October 4, 2010

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Companion Diagnostics in Personalized Medicine and Cancer Therapy, Trimark Publications (190 pages), published Apr 2008

Raman G, Avendano EE, Chen M.Update on Emerging Genetic TestsCurrently Available for Clinical Use in Common CancersEvidence Report/TechnologyAssessment.

(Prepared by the Tufts Evidence based Practice Center under Contract No.290-2007-10055-I.)Rockville, MD: Agency for Healthcare Research and Quality.July2013

www.effectivehealthcare.gov/reports/final.cfm

Alice P. Chung, Marissa K. Srour, Farnaz Dadmanesh, Sungjin Kim, Armando E. Giuliano, Jennifer Wei, Yen Huynh, Josien Haan, Shiyu Wang, Andrea Menicucci, Patricia Dauer, and M. William Audeh
Journal of Clinical Oncology 2022 40:16_suppl, 585-585

The study sponsor reported in August 2012 that T-DM1 significantly improved survival.  Median progression-free survival, one of the trial’s primary efficacy end points, was 9.6 months with T-DM1, compared with 6.4 months with capecitabine-lapatinib (hazard ratio, 0.65; P less than .0001). Results were largely the same across patient subgroups, except for an apparent lack of benefit among women aged 65 years or older.

There is also the MARIANNE study, which compares taxane (docetaxel or paclitaxel) plus trastuzumab vs T-DM1 vs T-DM1 plus pertuzumab as first-line treatment for people with HER2 positive unresectable locally advanced or metastatic breast cancer and the TH3RESA stud, which is comparing T-DM1 vs treatment of physician’s choice for people with HER2 positive metastatic breast cancer previously treated with trastuzumab and lapatinib.

 Niculescu-Duvaz I (June 2010). “Trastuzumab emtansine, an antibody-drug conjugate for the treatment of HER2+ metastatic breast cancer”. Curr. Opin. Mol. Ther. 12 (3): 350–60.

Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012 Mar 22;12(4):278-87.

See the Lay version here

One double blind randomized comparatiove study(RCT)  compared tamoxifen 20 mg daily versus placebo. It found that significantly more women experienced pain relief (measured by visual analogue scale over 3 months) with tamoxifen compared with placebo (> 50% reduction in mean pain score: 22/31 [71%] with tamoxifen v 11/29 [38%] with placebo; P < 0.025). The second RCT (93 women) compared tamoxifen, danazol, and placebo. It found that significantly more women taking tamoxifen achieved a good outcome (> 50% reduction in mean pain score) at the end of treatment, 6 months later, and 12 months later, compared with placebo (> 50% reduction in pain score after 6 months of treatment: 23/32 [72%] with tamoxifen v 11/29 [38%] with placebo; P = 0.035). The third RCT (88 women, aged 22–44 years) found that 8 months of tamoxifen increased the proportion of women who achieved complete recovery (outcome not clearly defined) compared with placebo (40/44 [90%] with tamoxifen v 0/44 [0%] with placebo; P value not reported).

In conclusion, Tamoxifen is not licensed for mastalgia in the UK or USA. There is a consensus to limit its use to no more than 6 months at a time under expert supervision, and with appropriate non-hormonal contraception, because of the high incidence of adverse effects.

Fentiman IS (2004). Management of breast pain. In JR Harris et al., eds., Diseases of the Breast, 3rd ed., pp. 57–62. Philadelphia: Lippincott Williams and Wilkins.

Kontostolis E, Stefanidis K, Navrozoglou I, et al. Comparison of tamoxifen with danazol for treatment of cyclical mastalgia. Gynecol Endocrinol 1997;11:393–397.

Fentiman IS, Caleffi M, Brame K, et al. Double-blind controlled trial of tamoxifen therapy for mastalgia. Lancet 1986;1:287–288.

Grio R, Cellura A, Geranio R, et al. Clinical efficacy of tamoxifen in the treatment of premenstrual mastodynia. Minerva Ginecol 1998;50:101–103.   GEMB Group. Tamoxifen therapy for cyclical mastalgia: dose randomised trial. Breast 1997;5:212–213.

Data from the first-ever randomized, multi-center, open label Phase III trial examining the combination of two targeted therapies, Tykerb™ (lapatinib ditosylate) tablets and Herceptin® (trastuzumab), in women with HER2-positive metastatic breast cancer was presented at the annual American Society of Clinical Oncology (ASCO) meeting in Chicago, in May 2008 and published in 2009. It randomized 296 patients to Tykerb plus Herceptin or Tykerb alone in the treatment of HER2-positive, recurrent breast cancer. Patients had received an average of four or five prior chemotherapy regimens and an average of three prior Herceptin-containing regimens for metastatic disease, with a median time from the last Herceptin regimen being approximately 25 days. Nearly half of all patients were hormone-positive. Patients were randomized to Tykerb (1,500 mg/day) or Tykerb (1,000 mg/day) plus Herceptin (4 mg/kg loading dose followed by 2 mg/kg per week).

•Women treated with a combination of Tykerb and Herceptin remained free of cancer progression for roughly one month longer than women treated with Tykerb alone (12.0 weeks versus 8.1 weeks).
•Overall survival was roughly three months longer among women treated with Tykerb and Herceptin than among women treated with Tykerb alone (51.6 weeks versus 39 weeks). The difference between groups in overall survival was not statistically significant, however, suggesting that it could have occurred by chance alone.
•Women treated with Tykerb and Herceptin were more likely to experience diarrhea than women treated with Tykerb alone.
These results suggest that the combination of Tykerb and Herceptin more effectively delays cancer progression than Tykerb alone.

A recent review from The UK National Techology Assessment concluded that either trastuzumab with an aromatase inhibitor(AI) or lapatinib  with an AI were not superior to AI alone. The same would presumably apply to the combination the two with an AI.

Fleeman N, Bagust A, Boland A, Dickson R, Dundar Y, Moonan M, Oyee J, Blundell M, Davis H, Armstrong A, Thorp N.Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone receptor-positive breast cancer which over-expresses human epidermal growth factor 2 (HER2): a systematic review and economic analysis.
Health Technol Assess. 2011;15(42):1-93,.

UBlackwell KL, Burstein HJ, Storniolo AM et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. Journal of Clinical Oncology. 2010;28:1124-1130.

Gomez HL, Chavez MA, Doval DC et al. A phase II, randomized trial using the small molecule tyrosine kinase inhibitor lapatinib as a first-line treatment in patients with FISH positive advanced or metastatic breast cancer. J Clin Oncol 2005;23(suppl 16):203S.

Trudeau M, Johnston S, Kaufman et al. Lapatinib (Tycerb) monotherapy in patients with recurrent inflammatory breast cancer (IBC): Clinical activity and biologic predictors of response. Ann Oncol 2006;17(suppl 9):ix69

O’Shaughnessy J, Blackwell KL, Burstein H, et al. A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy. Program and abstracts of the 44th American Society of Clinical Oncology Annual Meeting; May 30 – June 3, 2008; Chicago, Illinois. Abstract 1015

José Baselga et al, Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet Volume 379, No. 9816, p633–640, 18 February 2012

NCCN, Breast Cancer 2016

A, Agrawal et al, Overview of tyrosine kinase inhibitors in.clinical breast cancer Endocr Relat Cancer July 1, 2005 12 S135-S144
RJ, Trigo J, Derosa F, Brennscheidt U, Rakhit A, Wright T, Carbonell Castellon X, Twelves C & Baselga J 2003 A Phase 1b study of Tarceva (erlotinib) plus capecitabine and docetaxel in metastatic breast cancer. Proceedings of the American Society of Clinical Oncology 22 45 (abstract 180).

Winer E, Cobleigh M, Dickler M, Miller K, Fehrenbacher L, Jones C & Justice R 2002 Phase II multicenter study to evaluate the efficacy and safety of Tarceva (erlotinib, OSI- 774) in women with previously treated locally advanced or metastatic breast cancer. Breast Cancer Research and Treatment 76 Abstract 445.

Yamasaki F, Zhang D, Bartholomeusz C, Sudo T, Hortobagyi GN, Kurisu K, Ueno NT.
Sensitivity of breast cancer cells to erlotinib depends on cyclin-dependent kinase 2 activity.Mol Cancer Ther. 2007 Aug;6(8):2168-77.

 Please see the Lay version here

This is an exciting development. It must be kept in mind that the study was first line. It is not known how this regimen would work in patients who already failed Herceptin and other agents in the past and it would be premature to view it as a powerful salvage regimen. Baselga et al (2010) did find that the combination of pertuzumab and trastuzumab is active and well tolerated in patients with metastatic HER2-positive breast cancer who had experienced progression during prior trastuzumab therapy. However, how it compares to other available and active therapies is not known.

Intravenous pertuzumab is currently being evaluated in patients with breast cancer in the following trials: MARIANNE (advanced breast cancer), NEOSPHERE (early breast cancer), TRYPHAENA (HER2-positive stage II/III breats cancer) and APHINITY (HER2-positive nonmetastatic breast cancer).

Baselga J, Cortes J, Sung-Bae K, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med.2012; 366:109–119.

José Baselga, Karen A. Gelmon, Shailendra Verma, Andrew Wardley, PierFranco Conte, David Miles, Giulia Bianchi, Javier Cortes, Virginia A. McNally, Graham A. Ross, Pierre Fumoleau and Luca Gianni Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy JCO March 1, 2010 vol. 28 no. 7 1138-1144

Read the Lay version here

Much more research needs to be done and guidelines have not yet incorporated Herceptin and Arimidex as standard recommendation. The accompanying editorial suggested that the such evidence, “should be viewed as pioneering and hypothesis driven; they are likely to become obligatory references in the field of HER2 breast cancer.”

Bella Kaufman, John R. Mackey, Michael R. Clemens, Poonamalle P. Bapsy, Ashok Vaid, Andrew Wardley, Sergei Tjulandin, Michaela Jahn, Michaela Lehle, Andrea Feyereislova, Cédric Révil and Alison JonesTrastuzumab Plus Anastrozole Versus Anastrozole Alone for the Treatment of Postmenopausal Women With Human Epidermal Growth Factor Receptor 2–Positive, Hormone Receptor–Positive Metastatic Breast Cancer: Results From the Randomized Phase III TAnDEM Study JCO November 20, 2009 vol. 27 no. 33 5529-5537

Javier Cortes et al,  How to Treat Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Amplified Breast Cancer
JCO November 20, 2009 vol. 27 no. 33 5492-5494

Howard M. Stern Improving Treatment of HER2-Positive Cancers: Opportunities and Challenges Sci Transl Med Mar 28, 2012:127rv2

Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Read the Layperson version here.

Lapatinib is indicated for the treatment of metastatic HER2-positive breast cancer, both in combination with capecitabine in patients who have received taxane, anthracycline and trastuzumab and in combination with letrozole for postmenopausal patients with hormone receptor- and HER2-overexpressing breast cancer.

Not infrequently one encounters HER+ patients who had not been treated with both anthracycline, such as Adriamycin, and taxanes.  What about Tykerb for them, alone or in combination? As Adriamycin use declines, this situation has become more and more common.

To understand how off label use can still be reasonable and medically appropriate, one must recall that FDA usually, and certainly in the past, based its approval on randomized prospective studies. Because such studies are expensive and time-consuming, once a drug is approved manufacturers do not often attempt to obtain additional indications. Because studies to the FDA were in patients previously exposed  to the anthracyclines and taxanes, the approval was for only such patients; however, Tykerb in other HER+ patients is well supported by a variety of phase II and other studies.

E. Frampton Lapatinib: a review of its use in the treatment of HER2-overexpressing, trastuzumab-refractory, advanced or metastatic breast cancer. Drugs. 2009 Oct 22;69(15):2125-48.

O’Shaughnessy J, Blackwell KL, Burstein H, et al. A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy. Program and abstracts of the 44th American Society of Clinical Oncology Annual Meeting; May 30 – June 3, 2008; Chicago, Illinois. Abstract 1015